ANALOGS OF PRIDOPIDINE. THEIR PREPARATION AND USE
This application claims priority of U.S. Provisional Application No. 62/076,436, filed November 6,
2014, and U.S. Provisional Application No. 62/019,337, filed June 30, 2014, the entire contents of
which are hereby incorporated by reference herein.
Disclosures of the publications cited in this application in their entireties are hereby incorporated by
reference into this application in order to more fully describe the state of the art as of the date of the
invention described herein.
BACKGROUND OF THE INVENTION
Pridopidine (ACR16, TV-7820, Huntexil) is a unique compound developed for the treatment of
patients with motor symptoms associated with Huntington's disease. Its chemical name is 4-(3-
(Methylsulfonyl)phenyl)-l-propylpiperidine, and its Chemical Registry number is 882737-42-0 (U.S.
Publication No. US-2013-0267552-A1). Processes of synthesis of pridopidine and a pharmaceutically
acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459. U.S. Patent No. 6,903,120
disclosed pridopidine for the treatment of Parkinson's disease, dyskinesias, dystonias, Tourette's
disease, iatrogenic and non-iatrogenic psychoses and hallucinoses, mood and anxiety disorders, sleep
disorder, autism spectrum disorder, ADHD, Huntington's disease, age-related cognitive impairment,
and disorders related to alcohol abuse and narcotic substance abuse.
BRIEF SUMMARY OF THE INVENTION
This invention provides an isolated compound having the structure:
or a salt thereof.
This invention also provides a composition comprising pridopidine and a compound which has the
structure:
or a salt thereof, wherein the ratio of the weight of the compound relative to the weight of the
pridopidine in the composition is from 99:1 to 1:99.
This invention also provides a composition comprising a compound having the structure:
SO CH3
or a salt thereof, wherein the composition is free of pridopidine or a salt thereof.
The invention also provides a pharmaceutical composition comprising an amount of pridopidine and
at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,
and Compound 7 wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
g) Compound 7 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method.
This invention also provides a process for preparing Compound 1 comprising the step of oxidizing 4-
hydroxy-4-(3-(methylthio)phenyl)-l-propylpiperidin-l-ium chloride with an oxidizing agent to form
Compound 1.
This invention also provides a process for preparing Compound 2 comprising the steps of:
a) reacting 3-bromothioanisole with ethyl 3-(4-oxopiperidin-l-yl)propanoate to form 1-
(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyl)-4-(3-(methylthio)phenyl)piperidin-
4-ol,
b) dehydrating the l-(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyl)-4-(3-
(methylthio)phenyl)piperidin-4-ol formed in step a) with a dehydrating agent to
obtain l-(3,3-bis(3-(methylthio)phenyl)allyl)-4-(3-(methylthio)phenyl)-l,2,3,6-
tetrahydropyridine,
c) oxidizing the l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)
phenyl)-l,2,3,6-tetrahydropyridine formed in step b) with an oxidizing agent to form
l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)phenyl)-l,2,3,6-
tetrahydropyridine, and
d) hydrogenating the l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)
phenyl)-l,2,3,6-tetrahydropyridine formed in step c) with a hydrogenating agent to
form Compound 2.
This invention also provides a process for preparing Compound 3 comprising the steps of:
a) reacting 3-bromo thiophenol and 1,4-dibromobutane to form l,4-bis((3-
bromophenyl)thio)butane,
b) oxidizing the l,4-bis((3-bromophenyl)thio)butane formed in step a) with an oxidizing agent to
form 1,4-bis((3-bromophenyl)sulfonyl)butane,
c) reacting 4-pyridinylboronic acid with the l,4-bis((3-bromophenyl)sulfonyl)butane formed in
step b) to obtain l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane,
d) reacting 1-iodopropane with l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane formed in step c)
to form 4,4'-((butane-l,4-diyldisulfonyl)bis(3,l-phenylene))bis(l-propyIpyridin-l-ium)iodide,
e) adding a reducing agent to 4,4'-((butane-l,4-diyldisulfonyl)bis(3,l-phenylene))bis(lpropylpyridin-
l-ium)iodide formed in step d) to form l,4-bis((3-(l-propyl-l,2,3,6-
tetrahydropyridin-4-yl)phenyl)sulfonyl) butane, and
f) hydrogenating the l,4-bis((3-(l-propyl-l,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)
butane formed in step e) with a hydrogenating agent to obtain Compound 3.
This invention also provides a process for preparing Compound 4 comprising the steps of:
a) epoxidizing 4-(3-(methylsulfonyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine with an
epoxidizing agent to form (lS,6S)-6-(3-(methylsulfonyl)phenyl)-3-propyl-7-oxa-3-azabicyclo
[4.1.0]heptane, and
b) nucleophilically opening the epoxide of the (lS,6S)-6-(3-(methylsulfonyl)phenyl)-3-propyl-7-
oxa-3-azabicyclo [4.1.0]heptane of step a) with a nucleophile to obtain Compound 4.
This invention also provides a process for preparing Compound 5 comprising the step of reacting
pridopidine with a peroxide to obtain Compound 5.
This invention also provides a process for preparing Compound 6 comprising the step of reacting 4-
(3-(methylsulfonyl)phenyl)piperidine with l-chloro-2-methylpentane to obtain Compound 6.
This invention also provides a process for preparing Compound 7 comprising the steps of.
a) dehydrating 4-hydroxy-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride with
a dehydrating agent to form 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-lium
hydrogen sulfate,
b) oxidizing 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-l-ium hydrogen
sulfate of step b) with an oxidizing agent to form Compound 7. In one embodiment, the
dehydrating agent is a strong acid, preferably sulphuric acid. In another embodiment, the
dehydrating agent is a strong acid. In another embodiment, the dehydrating agent is sulphuric
acid. In another embodiment, the oxidizing agent is a peroxide, preferably hydrogen
peroxide. In another embodiment, the oxidizing agent is a peroxide. In another embodiment,
the oxidizing agent is hydrogen peroxide.
This invention also provides a process for testing whether a sample of a composition comprising
pridopidine contains an undesirable impurity which comprises the step of determining whether the
sample contains a compound having the structure:
This invention also provides a process for producing a pridopidine drug product comprising obtaining
a pridopidine drug substance and mixing the pridopidine drug substance with suitable excipients so as
to produce the pridopidine drug product, wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine.
This invention also provides a process for producing a pridopidine drug product for commercial sale
comprising obtaining a batch of pridopidine drug product that comprises:
i) an amount of Compound 1 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 1, relative to the concentration of
pridopidine, or
ii) an amount of Compound 2 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 2, relative to the concentration of
pridopidine, or
iii) an amount of Compound 3 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 3, relative to the concentration of
pridopidine, or
iv) an amount of Compound 4 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 4, relative to the concentration of
pridopidine, or
v) an amount of Compound 5 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 5, relative to the concentration of
pridopidine, or
vi) an amount of Compound 6 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 6, relative to the concentration of
pridopidine, and
preparing the batch of pridopidine drug product for commercial sale.
This invention also provides a process of distributing a pridopidine drug product comprising a
pridopidine drug substance comprising,
a) obtaining the pridopidine drug product wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not
more than 0.15 area-% Compound 1, relative to the concentration of
pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product comprising the pridopidine drug substance.
This invention also provides a process of distributing a pridopidine drug product comprising,
a) obtaining the pridopidine drug product that comprises:
i) an amount of Compound 1 in the pridopidine drug product that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug product that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug product that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug product that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug product that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug product that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product.
This invention also provides an impurity or a salt thereof for use, as a reference standard to detect
trace amounts of the impurity in a pharmaceutical composition comprising pridopidine or a
pharmaceutically acceptable salt thereof, wherein the impurity is selected from the group consisting of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine, the method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising pridopidine and the diluent solution,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine, the method comprising
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising the impurity,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 n and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the standard solutions,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine and a pharmaceutically acceptable carrier, the
method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising pridopidine and the diluent solution,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine and a pharmaceutically acceptable carrier, the
method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising the impurity,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the standard solutions,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of treating a subject afflicted with a neurodegenerative disease
or a neurodegenerative disorder comprising administering to the subject the pharmaceutical
composition.
This invention also provides a method of treating a subject afflicted with Huntington's disease
comprising administering to the subject the pharmaceutical composition.
This invention also provides a process for validating a batch of a pharmaceutical product containing
pridopidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for
distribution comprising:
a) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
b) validating the batch for distribution only if
i) the batch is determined to have not more than 0.15 area-% Compound 1, relative
to the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15 area-% Compound 2, relative
to the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15 area-% Compound 3, relative
to the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15 area-% Compound 4, relative
to the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15 area-% Compound 5, relative
to the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15 area-% Compound 6, relative
to the concentration of pridopidine.
This invention also provides a process for preparing a validated pharmaceutical composition
comprising pridopidine comprising:
a) obtaining a batch of pridopidine drug substance;
b) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
c) preparing the pharmaceutical composition from the batch only if
i) the batch is determined to have not more than 0.15% Compound 1, relative to
the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15% Compound 2, relative to
the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15% Compound 3, relative to
the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15% Compound 4, relative to
the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15% Compound 5, relative to
the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15% Compound 6, relative to
the concentration of pridopidine.
This invention also provides a process for preparing a pharmaceutical composition comprising
pridopidine, comprising
a) obtaining a batch of pridopidine drug product;
b) performing stability testing with a sample of the batch;
c) determining the total amount of at least one of Compound 1, Compound 2, Compound
3, Compound 4, Compound 5, and Compound 6 in the sample of the batch after
stability testing by an HPLC method; and
d) preparing the pharmaceutical composition from the batch after stability testing if the
sample of the batch after stability testing contains:
i) not more than 0.15% Compound 1, relative to the concentration of
pridopidine, or
ii) not more than 0.15% Compound 2, relative to the concentration of
pridopidine, or
iii) not more than 0.15% Compound 3, relative to the concentration of
pridopidine, or
iv) not more than 0.15% Compound 4, relative to the concentration of
pridopidine, or
v) not more than 0.15% Compound 5, relative to the concentration of
pridopidine, or
vi) not more than 0.15% Compound 6, relative to the concentration of
pridopidine.
This invention also provides an isolated compound having the structure:
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
Figure 1: Typical Chromatogram of the control sample la.
Figure 2 : Typical Chromatogram of the control sample 2b.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides an isolated compound having the structure:
thereof.
In an embodiment of the present invention, the isolated compound has the structure:
, or a salt thereof.
embodiment, the isolated compound has the structure:
o r a s a thereof.
embodiment, the isolated compound has the structure:
, or a salt thereof.
embodiment, the isolated compound has the structure:
, or a salt thereof.
In an embodiment, the isolated compound has the structure:
This invention also provides a composition comprising pridopidine and a compound which has the
structure:
or a salt thereof, wherein the ratio of the weight of the compound relative to the weight of the
pridopidine in the composition is from 99:1 to 1:99.
In an embodiment, the compound has the structure:
or a salt thereof.
In an embodiment, the ratio of the weight of the compound relative to the weight of the pridopidine
the composition is from 90:10 to 10:90 or 85:15 or 15:85.
This invention also provides a composition comprising a compound having the structure:
or a salt thereof, wherein the composition is free of pridopidine or a salt thereof.
In an embodiment, the compound has the structure:
or a salt thereof.
embodiment, the compound has the structure:
o r a s a thereof.
embodiment, the compound has the structure:
or a salt thereof.
embodiment, the compound has the structure:
or a salt thereof.
embodiment, the compound has the structure:
or a salt thereof.
embodiment, the compound has the structure:
or a salt thereof.
embodiment, the compound has the structure:
or a salt thereof.
The invention also provides a pharmaceutical composition comprising an amount of pridopidine and
at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6,
and Compound 7 wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method, or
g) Compound 7 is present in the pharmaceutical composition in an amount not more
than 10 area-% relative to the concentration of pridopidine, based on a determination
by an HPLC method.
In an embodiment,
a) Compound 1 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
f) Compound 6 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method.
In another embodiment,
a) Compound 1 is present in the pharmaceutical composition in an amount greater than
0.01 area-%, and not more than 0.15 area-% relative to the concentration of
pridopidine, based on a determination by an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount greater than
0.01 area-%, and not more than 0.15 area-%, relative to the concentration of
pridopidine, based on a determination by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount greater than
0.03 area-%, and not more than 0.15 area-%, relative to the concentration of
pridopidine, based on a determination by an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount greater than
0.01 area-%, and not more than 0.15 area-%, relative to the concentration of
pridopidine, based on a determination by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount greater than
0.01 area-%, and not more than 0.15 area-%, relative to the concentration of
pridopidine, based on a determination by an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount greater than
0.01 area-% and not more than 0.15 area-%, relative to the concentration of
pridopidine, based on a determination by an HPLC method.
er embodiment,
a) Compound 1 is present in the pharmaceutical composition in an amount less than
0.04 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount less than
0.05 area %, relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount less than
0.05 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount less than
0.04 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount less than
0.04 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
0 Compound 6 is present in the pharmaceutical composition in an amount less than
0.04 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method.
In another embodiment,
a) Compound 1 is present in the pharmaceutical composition in an amount less than
0.01 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount less than
0.01 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount less than
0.03 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount less than
0.01 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount less than
0.0 1 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount less than
0.01 area-% relative to the concentration of pridopidine, based on a determination by
an HPLC method.
In one embodiment, at least two of Compound 1, Compound 2, Compound 3, Compound 4,
Compound 5 and Compound 6 are present. In another embodiment, at least three of Compound 1,
Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6 are present. In another
embodiment, at least four of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
and Compound 6 are present. In another embodiment, least five of Compound 1, Compound 2,
Compound 3, Compound 4, Compound 5 and Compound 6 are present. In another embodiment,
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6 are present.
In another embodiment, at least Compound 1 is present. In another embodiment, at least Compound 3
is present. In another embodiment, at least Compound 4 is present.
In one embodiment, the pharmaceutical composition comprises pridopidine hydrochloride salt.
In an embodiment, the pharmaceutical composition is in the form of a capsule, a tablet, or a liquid
suspension. In another embodiment, the pharmaceutical composition is in an oral dosage unit form.
In an embodiment, the pharmaceutical composition the oral dosage unit form comprises between 22.5
- 315 mg pridopidine. In another embodiment, the oral dosage unit form comprises between 45 - 250
mg pridopidine. In another embodiment, the oral dosage unit form comprises between 45 - 135 mg
pridopidine. In another embodiment, the oral dosage unit form comprises between 90 - 315 mg
pridopidine. In another embodiment, the oral dosage unit form comprises about 22.5 mg pridopidine. In
another embodiment, the oral dosage unit form comprises about 45 mg pridopidine. In another
embodiment, the oral dosage unit form comprises about 67.5 mg pridopidine. In another embodiment
the oral dosage unit form comprises about 90 mg pridopidine. In another embodiment, the oral unit
dosage form comprises about 100 mg pridopidine. In another embodiment, the oral dosage unit form
comprises about 112.5 mg pridopidine. In another embodiment, the oral dosage unit form comprises
about 125 mg pridopidine. In another embodiment, the oral dosage unit form comprises about 135 mg
pridopidine. In another embodiment, the oral dosage unit form comprises about 150 mg pridopidine. In
another embodiment, the oral dosage unit form comprises about 180 mg pridopidine. In another
embodiment, the oral dosage unit form comprises about 200 mg pridopidine. In another embodiment,
the oral dosage unit form comprises about 250 mg pridopidine. In another embodiment, the oral dosage
unit form comprises about 315 mg pridopidine. In another embodiment, the oral dosage unit form is
prepared for once daily administration. In another embodiment, the oral dosage unit form is prepared for
more than once daily administration.
This invention also provides a process for preparing Compound 1 comprising the step of oxidizing 4-
hydroxy-4-(3-(methylthio)phenyl)-l-propylpiperidin-l-ium chloride with an oxidizing agent to form
Compound 1. In one embodiment, the oxidizing agent is a peroxide, preferably hydrogen peroxide. In
another embodiment, the oxidizing agent is a peroxide. In another embodiment, the oxidizing agent is
hydrogen peroxide.
This invention also provides a process for preparing Compound 2 comprising the steps of:
a) reacting 3-bromothioanisole with ethyl 3-(4-oxopiperidin-l-yl)propanoate to form 1-
(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyl)-4-(3-(methylthio)phenyl)piperidin-
4-ol,
b) dehydrating the l-(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyI)-4-(3-
(methylthio)phenyl)piperidin-4-ol formed in step a) with a dehydrating agent to
obtain l-(3,3-bis(3-(methylthio)phenyl)allyl)-4-(3-(methylthio)phenyl)-l,2,3,6-
tetrahydropyridine,
c) oxidizing the l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)
phenyl)- ,2,3,6-tetrahydropyridine formed in step b) with an oxidizing agent to form
l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)phenyl)-l,2,3,6-
tetrahydropyridine, and
d) hydrogenating the l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)
phenyl)- 1,2,3,6-tetrahydropyridine formed in step c) with a hydrogenating agent to
form Compound 2.
In one embodiment, the dehydrating agent is a strong acid, preferably sulfuric acid. In one
embodiment, the dehydrating agent is a strong acid. In another embodiment, the dehydration agent is
sulfuric acid. In another embodiment, the oxidizing agent is a peroxide. In another embodiment, the
oxidizing agent is hydrogen peroxide. In another embodiment, the hydrogenating agent is hydrogen.
This invention also provides a process for preparing Compound 3 comprising the steps of:
a) reacting 3-bromo thiophenol and 1,4-dibromobutane to form l,4-bis((3-
bromophenyl)thio)butane,
b) oxidizing the l,4-bis((3-bromophenyl)thio)butane formed in step a) with an oxidizing agent to
form 1,4-bis((3-bromophenyl)sulfonyl)butane,
c) reacting 4-pyridinylboronic acid with the l,4-bis((3-bromophenyl)sulfonyl)butane formed in
step b) to obtain l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane,
d) reacting 1-iodopropane with l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane formed in step c)
to form 4,4'-((butane-l,4-diyldisulfonyl)bis(3,l-phenylene))bis(l-propylpyridin-l-ium)iodide,
e) adding a reducing agent to 4,4'-((butane-l,4-diyldisulfonyl)bis(3,l-phenylene))bis(lpropylpyridin-
l-ium)iodide formed in step d) to form l,4-bis((3-(l -propyl- 1,2,3,6-
tetrahydropyridin-4-yl)phenyl)sulfonyl) butane, and
f) hydrogenating the l,4-bis((3-(l-propyl-l,2,3,6-tetrahydropyridin-4-yI)phenyl)sulfonyl)
butane formed in step e) with a hydrogenating agent to obtain Compound 3.
In one embodiment, the oxidizing agent is a peroxide, preferably hydrogen peroxide. In another
embodiment, the oxidizing agent is a peroxide. In another embodiment, the oxidizing agent is
hydrogen peroxide. In another embodiment, the reducing agent is sodium borohydride. In another
embodiment, the hydrogenating agent is hydrogen.
This invention also provides a process for preparing Compound 4 comprising the steps of:
a) epoxidizing 4-(3-(methylsulfonyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine with an
epoxidizing agent to form (lS,6S)-6-(3-(methylsulfonyl)phenyl)-3-propyl-7-oxa-3-azabicyclo
[4.1.0]heptane, and
b) nucleophilically opening the epoxide of the (lS,6S)-6-(3-(methylsuIfonyl)phenyl)-3-propyl-7-
oxa-3-azabicyclo [4.1.0]heptane of step a) with a nucleophile to obtain Compound 4.
In one embodiment, the epoxidizing agent is sodium bromate. In another embodiment, the nucleophile
is hydrogen.
This invention also provides a process for preparing Compound 5 comprising the step of reacting
pridopidine with a peroxide to obtain Compound 5. In one embodiment, the peroxide is hydrogen
peroxide.
This invention also provides a process for preparing Compound 6 comprising the step of reacting 4-
(3-(methylsulfonyl)phenyl)piperidine with l-chloro-2-methylpentane to obtain Compound 6.
This invention also provides a process for preparing Compound 7 comprising the steps of:
a) dehydrating 4-hydroxy-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride with
a dehydrating agent to form 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-lium
hydrogen sulfate,
b) oxidizing 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-l-ium hydrogen
sulfate of step b) with an oxidizing agent to form Compound 7.
In one embodiment, the dehydrating agent is a strong acid, preferably sulphuric acid. In another
embodiment, the dehydrating agent is a strong acid. In another embodiment, the dehydrating agent is
sulphuric acid. In another embodiment, the oxidizing agent is a peroxide, preferably hydrogen
peroxide. In another embodiment, the oxidizing agent is a peroxide. In another embodiment, the
oxidizing agent is hydrogen peroxide.
This invention also provides a process for testing whether a sample of a composition comprising
pridopidine contains an undesirable impurity which comprises the step of determining whether the
sample contains a compound having the structure:
This invention also provides a process for producing a pridopidine drug product comprising obtaining
a pridopidine drug substance and mixing the pridopidine drug substance with suitable excipients so as
to produce the pridopidine drug product, wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine.
In one embodiment, the process further comprises determining the amount of the at least one of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6 in the
pridopidine drug substance. In another embodiment, the process further comprises determining the
amount of the at least two of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,
and Compound 6 in the pridopidine drug substance. In another embodiment, the process further
comprises determining the amount of the at least three of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance. In another
embodiment, the process further comprises determining the amount of the at least four of Compound
1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6 in the pridopidine drug
substance. In another embodiment, the process further comprises determining the amount of the at
least five of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6
in the pridopidine drug substance. In another embodiment, the process further comprises determining
the amount of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound
6 in the pridopidine drug substance. In another embodiment, the process further comprises subjecting
a sample of the pridopidine drug substance to stability testing before the step of determining the
amount of the at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,
and Compound 6 in the pridopidine drug substance.
This invention also provides a process for producing a pridopidine drug product for commercial sale
comprising obtaining a batch of pridopidine drug product that comprises:
i) an amount of Compound 1 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 1, relative to the concentration of
pridopidine, or
an amount of Compound 2 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 2, relative to the concentration of
pridopidine, or
iii) an amount of Compound 3 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 3, relative to the concentration of
pridopidine, or
iv) an amount of Compound 4 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 4, relative to the concentration of
pridopidine, or
v) an amount of Compound 5 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 5, relative to the concentration of
pridopidine, or
vi) an amount of Compound 6 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 6, relative to the concentration of
pridopidine, and
preparing the batch of pridopidine drug product for commercial sale.
In an embodiment, the process further comprises determining the amount of the at least one of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6 in the batch
of pridopidine drug product. In another embodiment, the process further comprises determining the
amount of the at least two of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5,
and Compound 6 in the batch of pridopidine drug product. In an embodiment, the process further
comprises determining the amount of the at least three of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product. In an
embodiment, the process further comprises determining the amount of the at least four of Compound
1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6 in the batch of
pridopidine drug product. In an embodiment, the process further comprises determining the amount
of the at least five of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and
Compound 6 in the batch of pridopidine drug product. In an embodiment, the process further
comprises determining the amount of Compound 1, Compound 2, Compound 3, Compound 4,
Compound 5, and Compound 6 in the batch of pridopidine drug product. In another embodiment, the
process further comprises subjecting a sample of the batch of pridopidine drug product to stability
testing before determining the amount of the at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the sample of the batch of pridopidine drug product.
This invention also provides a process of distributing a pridopidine drug product comprising a
pridopidine drug substance comprising,
a) obtaining the pridopidine drug product wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product comprising the pridopidine drug substance.
This invention also provides a process of distributing a pridopidine drug product comprising,
a) obtaining the pridopidine drug product that comprises:
i) an amount of Compound 1 in the pridopidine drug product that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug product that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug product that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug product that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug product that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug product that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product.
This invention also provides an impurity or a salt thereof for use, as a reference standard to detect
trace amounts of the impurity in a pharmaceutical composition comprising pridopidine or a
pharmaceutically acceptable salt thereof, wherein the impurity is selected from the group consisting of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine, the method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising pridopidine and the diluent solution,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine, the method comprising
a) preparing a sample solution from the pharmaceutical composition,
preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising the impurity,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the standard solutions,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
pharmaceutical composition comprising pridopidine and a pharmaceutically acceptable carrier, the
method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising pridopidine and the diluent solution,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of determining the concentration of an impurity in a
phannaceutical composition comprising pridopidine and a pharmaceutically acceptable carrier, the
method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution comprising the impurity,
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the standard solutions,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
This invention also provides a method of treating a subject afflicted with a neurodegenerative disease
or a neurodegenerative disorder comprising administering to the subject the pharmaceutical
composition.
This invention also provides a method of treating a subject afflicted with Huntington's disease
comprising administering to the subject the pharmaceutical composition.
This invention also provides a process for validating a batch of a pharmaceutical product containing
pridopidine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for
distribution comprising:
a) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
b) validating the batch for distribution only if
i) the batch is determined to have not more than 0.15 area-% Compound 1, relative
to the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15 area-% Compound 2, relative
to the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15 area-% Compound 3, relative
to the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15 area-% Compound 4, relative
to the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15 area-% Compound 5, relative
to the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15 area-% Compound 6, relative
to the concentration of pridopidine.
This invention also provides a process for preparing a validated pharmaceutical composition
comprising pridopidine comprising:
a) obtaining a batch of pridopidine drug substance;
b) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
c) preparing the pharmaceutical composition from the batch only if
i) the batch is determined to have not more than 0.15% Compound 1, relative to
the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15% Compound 2, relative to
the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15% Compound 3, relative to
the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15% Compound 4, relative to
the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15% Compound 5, relative to
the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15% Compound 6, relative to
the concentration of pridopidine.
This invention also provides a process for preparing a pharmaceutical composition comprising
pridopidine, comprising
a) obtaining a batch of pridopidine drug product;
b) performing stability testing with a sample of the batch;
c) determining the total amount of at least one of Compound 1, Compound 2, Compound
3, Compound 4, Compound 5, and Compound 6 in the sample of the batch after
stability testing by an HPLC method; and
d) preparing the pharmaceutical composition from the batch after stability testing if the
sample of the batch after stability testing contains:
i) not more than 0.15% Compound 1, relative to the concentration of
pridopidine, or
ii) not more than 0.15% Compound 2, relative to the concentration of
pridopidine, or
iii) not more than 0.15% Compound 3, relative to the concentration of
pridopidine, or
iv) not more than 0.15% Compound 4, relative to the concentration of
pridopidine, or
v) not more than 0.15% Compound 5, relative to the concentration of
pridopidine, or
vi) not more than 0.15% Compound 6, relative to the concentration of
pridopidine.
In an embodiment, the process further comprising step e) distributing the batch if in step d) the batch is
validated for distribution.
This invention also provides an isolated compound having the structure:
Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed
embodiments. Thus, all combinations of the various elements described herein are within the scope of
the invention.
For example, the elements recited in the packaging and pharmaceutical composition embodiments can
be used in the method and use embodiments described herein.
TERMS
As used herein, and unless stated otherwise, each of the following terms shall have the definition set
forth below.
As used herein, "pridiopidine" means pridopidine base or a pharmaceutically acceptable salt thereof,
including pridopidine hydrochloride. Preferably, in any embodiments of the invention as described
herein, the pridopidine is in the form of its hydrochloride salt.
As used herein, "drug substance" refers to the active ingredient in a drug product or to the
composition containing the active ingredient before it is formulated into in a drug product, which
provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of disease, or to affect the structure or any function of the body of man or animals.
As used herein, "drug product" refers to the formulated or finished dosage form containing the drug
substance as well as at least one pharmaceutically acceptable carrier.
As used herein, an "isolated" compound is a compound isolated from the crude reaction mixture
following an affirmative act of isolation. The act of isolation involves separating the compound from
the other known components of the crude reaction mixture, with some impurities, unknown side
products and residual amounts of the other known components of the crude reaction mixture
permitted to remain. Purification is an example of an affirmative act of isolation.
As used herein, "stability testing" refers to tests conducted at specific time intervals and various
environmental conditions (e.g., temperature and humidity) to see if and to what extent a drug product
degrades over its designated shelf life time. The specific conditions and time of the tests are such that
they accelerate the conditions the drug product is expected to encounter over its shelf life. For
example, detailed requirements of stability testing for finished pharmaceuticals are codified in 2 1
C.F.R §21 1.166, the entire content of which is hereby incorporated by reference.
As used herein, "about" in the context of a numerical value or range means ±10% of the numerical
value or range recited.
As used herein, "approximately" in the context of a numerical value or range means ±5% of the
numerical value or range recited or claimed.
As used herein, an "amount" of a compound as measured in milligrams refers to the milligrams of
compound present in a preparation, regardless of the form of the preparation. An "amount of
compound which is 40 mg" means the amount of the compound in a preparation is 40 mg, regardless
of the form of the preparation. Thus, when in the form with a carrier, the weight of the carrier
necessary to provide a dose of 40 mg compound would be greater than 40 mg due to the presence of
the carrier.
As used herein, "treating" and "treatment" encompasses, e.g., inducing inhibition, regression, or stasis
of a disease, disorder or condition, or ameliorating or alleviating a symptom of a disease, disorder or
condition. "Ameliorating" or "alleviating" a condition or state as used herein shall mean to relieve or
lessen the symptoms of that condition or state. "Inhibition" of disease progression or disease
complication in a subject as used herein means preventing or reducing the disease progression and/or
disease complication in the subject.
"Administering to the subject" means the giving of, dispensing of, or application of medicines, drugs,
or remedies to a subject to relieve, cure, or reduce the symptoms associated with a condition, e.g., a
pathological condition.
The drug substance of the present invention, e.g., pridopidine hydrochloride, may be administered in
admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively
referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the
intended form of administration and as consistent with conventional pharmaceutical practices.
Capsules or tablets may contain suitable binders, lubricants, disintegrating agents, diluents, coloring
agents, flow-inducing agents, and melting agents.
A dosage unit of the compounds used in the method of the present invention may comprise a single
compound or mixtures thereof with additional therapeutic agents.
A "dose" or "dosage unit" of pridopidine as measured in milligrams refers to the milligrams of
pridopidine hydrochloride present in a preparation, regardless of the form of the preparation. A
dosage unit may comprise a single compound or mixtures of compounds thereof. A dosage unit can be
prepared for oral dosage forms, such as tablets, capsules, pills, powders, and granules. For example,
the "dose" or "dosage unit" of priopidine may be 22.5, 45, or 67.5 g.
As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans
and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response)
commensurate with a reasonable benefit/risk ratio.
The subject invention is also intended to include all isotopes of atoms occurring on the compounds
disclosed herein, including impurities. Isotopes include those atoms having the same atomic number
but different mass numbers. By way of general example and without limitation, isotopes of hydrogen
include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
As used herein, "detection limit" for an analytical method used in screening or testing for the presence
of a compound in a sample is a threshold under which the compound in a sample cannot be detected
by the analytical method used. The detection limits of a given HPLC method for detecting an impurity
in a sample containing pridopidine may vary based on the method and the impurity or impurities
being detected. For example, the detection limit of the typical HPLC method for detecting
Compounds 1, 2, 4, 5 and 6 is 0.01 area-% and the detecting limit for detecting Compound 3 is 0.03
area-%.
As used herein, "quantitation limit" for an analytical method used in screening or testing for the
presence of a compound in a sample is a threshold under which the compound in a sample cannot be
quantified by the analytical method used. The quantitation limits of a given HPLC method for
detecting an impurity in a sample containing pridopidine may vary based on the impurity or impurities
being detected. For example, the quantitation limit of the typical HPLC method for quantifying
Compounds 1, 4, 5, and 6 is 0.04 area-% and the quantitation limit for Compound 3 is 0.05 area-%.
The quantitation limit for Compound 2 is 0.05 area-%.
A characteristic of a compound refers to any quality that a compound exhibits, e.g., peaks or retention
times, as determined by 1H nuclear magnetic spectroscopy, mass spectroscopy, infrared, ultraviolet or
fluorescence spectrophotometry, gas chromatography, thin layer chromatography, high performance
liquid chromatography, elemental analysis, Ames test, dissolution, stability and any other quality that
can be determined by an analytical method. Once the characteristics of a compound are known, the
information can be used to, for example, screen or test for the presence of the compound in a sample.
As used herein, "NMT" means no more than. As used herein, "LT" means less than.
The amount of impurities are measured by reverse phase HPLC unless otherwise specified.
As used herein, the term "effective amount" refers to the quantity of a component that is sufficient to
yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or
allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this
invention, i.e. a therapeutically effective amount. The specific effective amount will vary with such
factors as the particular condition being treated, the physical condition of the patient, the type of
mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the
specific formulations employed and the structure of the compounds or its derivatives.
As used herein, "preparing drug product for commercial sale" means an activity undertaken i
preparation for commercial sale. Examples include, but are not limited to, coloring, coding, stamping,
packaging the drug product.
It is understood that where a parameter range is provided, all integers within that range, and tenths
thereof, are also provided by the invention. For example, "20-40 mg" includes 20.0 mg, 20.1 mg, 20.2
mg, 20.3 mg, etc. up to 40.0 mg.
Pharmaceutically Acceptable Salts
The active compounds for use according to the invention may be provided in any form suitable for the
intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable
salts, and pre- or prodrug forms of the compound of the invention.
Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic
inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the
perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the
benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate,
the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate,
the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the
succinate, the tartrate, the toluene-p-sulphonate, and the like. Such salts may be formed by procedures
well known and described in the art.
Pharmaceutical Compositions
While the compounds for use according to the invention may be administered in the form of the raw
compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically
acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients,
carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
In an embodiment, the invention provides pharmaceutical compositions comprising the active
compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more
pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic
ingredients know and used in the art. The carrier(s) must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
t
Table 1 shows the structures of Compounds 1-8.
Table 1
This invention will be better understood by reference to the Experimental Details which follow, but
those skilled in the art will readily appreciate that the specific experiments detailed are only
illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Details
Examples
Example 1 - Preparation Of Compound 1 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-4-ol)
4-(3-(methylthio)phenyl)-1 - 4-(3-(methylsulfonyl)phenyl)-
propylpiperidin-4-ol 1-propylpiperidin-4-ol
To a suspension of 4-hydroxy-4-(3-(methylthio)phenyl)-l-propylpiperidin-l-ium chloride (140g,
348mmol) in 710mL water were added 1.5g sodium tungstate dihydrate, and the mixture was heated
to 45°C. 102mL of 33%H 20 2 were added in 20min at 45-55°C. The suspension dissolved after 20mL
addition. The solution was then stirred at 48-5 1°C for 30min after which HPLC showed no more
starting material and two new peaks, one at RT 2.68min (82.3%) and the other at RT 3.66min
(11.8%). After additional stirring for 2hr and 45min HPLC showed that the peak at RT 2.68min
decreases to 7.5% and the peak at RT 3.66min increases to 88.5%. After another 45min the mixture
was cooled to 20°C and into the reaction mixture were added 500mL toluene and 150mL ~5M NaOH.
After stirring for 5min the mixture was poured into separator funnel. The solubility of the product in
toluene is low. Majority of the product settled as very viscous liquid layer in the bottom. The water
phase (and most of the product) was separated, toluene phase was washed successively with 5%
Na2S0 3 solution and with brine and dried on MgSC>4. The water phase was extracted with 500mL
DCM. The organic phase was washed successively with 5% Na2S03 solution and water and was dried
on MgSC>4. Both extracts were concentrated on a rotavapor. 500mL of heptanes were added to both
residues, and the suspensions were stirred at room temperature for 2 hrs. The precipitates were
filtered, washed with heptane and dried. From the DCM extract were obtained 83.8g of white powder,
purity by HPLC 98.8%, IH-NMR assay 97.9%. (From the toluene extract were obtained 13.7g of
white powder, purity by HPLC 98.0%).
NMR Identity Analysis of Compound 1
Compound 1:
The following data in Tables 2 and 3 was determined using a sample of 78.95 mg Compound 1, a
solvent of 0.55 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance IP 400 MHz.
Table 2: Assignment o NMR -
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts.
Weak signal.
Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 3: Assignment of 1 C NMR '
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
b Spectra is calibrated by a solvent peak (39.54 ppm)
Example 2 - Preparation Of Compound 2 (l-(3,3-bis(3-(methylsulfonyI)phenyl)propyl)-4-(3-
(methylsulfonyl) phenyl)piperidine)
Preparation of ethyl 3-(4-oxopiperidin-l-yl)-propanoate (starting material for Compound 2)
3-(4-oxopiperidin-1-yl)-propanoate
Ethanol (1550mL) was poured into a 4 L three-necked round-bottom flask equipped with over-head
stirring followed by the addition of 125g (814mmol, leq) 4-piperidone monohydrate hydrochloride
and 225g (1628mmol, 2eq) potassium carbonate. Ethyl 3-chloropropanoate (lllg, leq) was added
and the reaction mixture was stirred for 3h after which HPLC showed that the product reached only
10% area. Another 0.5eq of K2CO3 was added (56.2g) and stirring continued at 24°C. After total of
45h the product reached 86% area (HPLC). Another 0.2eq of K2CO 3 was added and the reaction
mixture was stirred for additional 4.5h at 35°C after which HPLC showed 96% area of the product.
The mixture was filtered through a sintered glass filter, washed with 200 ml ethanol and concentrated
on vacuum to 156g yellow colored oil that was distilled under vacuum of 2mmHg in 156°C bath. The
main fraction distilled at 120°C to yield 97.8g (60%) of 99.3% area (HPLC).
Preparation of l-('3-hvdroxy-3,3-bis(3-(methylthio)phenyl ')propyl)-4-(3-(methylthio)
phenyl)piperidin-4-ol (Compound 2, 1st intermediate)
- - me y t o pheny p peri n-4-ol
3-Bromothioanisole (170.3g; 0.84mol, 3.2eq) and THF (700mL) were charged to a 2L flask, stirred
under nitrogen and cooled on dry ice/acetone bath to -74°C. A solution of n-hexyllithium in hexane
(2.3M; 237.4g; 0.77mol, 3.0eq) was added and the reaction mixture became slightly yellowish.
Stirring continued for additional 30min at -74°C. A solution of ethyl 3-(4-oxopiperidin-lyl)
propanoate (50.2g; 0.26 mol, leq) in THF (lOOmL) was added during lhl5min to the reaction
mixture and the stirring continued for additional 30min at -74°C to give a yellow clear solution. The
cooling stopped and the reaction warmed to -40°C. A solution of HC1 (33%; 90g, 0.82mol, 3.leq) in
water (lOOmL) was added dropwise for 20min to give a light yellow emulsion in +8°C. The light
yellow organic phase was separated, washed with water (3x200mL) and extracted twice with aqueous
HC1 (33%HC1 40g/300mL water) to give lower yellow phase (234g). The organic upper light yellow
phase was evaporated up to 159g solution and the precipitate formed during concentration was
filtered to give 19. lg yellow sticky precipitate. The precipitate was combined with the lower yellow
phase, methanol (50mL) and THF (200mL) were added and distilled (67°C, 248g distilled). Heptane
(200mL was added, the two liquid phase was stirred for 20min at 40°C and cooled to RT. The upper
heptane phase was discarded and water (200mL) was added to the viscous yellow residue water. After
stirring stopped the colorless water was decanted to leave 182g of very viscous light yellow residue
(HPLC: 82% area).
Preparation of l-(3,3-bis(3-(methylthio)phenyl)allyl)-4-(3-(methylthio)phenyl)-l,2,3.6-
tetrahydropyridine (Compound 2, 2nd intermediate ')
Into the viscous light yellow residue was added 2-propanol (200mL) and the reaction mixture was
distilled at atmospheric pressure to give 200mL of azeotropic distillate, leaving dark yellow oil into
which methanol (50mL), 2-propanol (350mL) and cone, sulfuric acid (36.5g, 0.35mol. 1.35eq) were
added. The reaction mixture was heated for 26 hours (mixture temperature 81-84°C, vapor
temperature 79°C) and about 440mL of distillate were collected. At the end the temperature reached
87°C and the reaction mixture was foaming. After cooling was added toluene (lOOmL) and water
(200mL) and the reaction mixture was heated to reflux (87°C). The heating stopped and after cooling
three phases were formed. The lower oily phase was washed with water (2x200mL) and concentrated
by vacuum distillation to give dark yellow viscous residue. Water (300mL) was added and the
mixture was refluxed then cooled to 40°C and water phase was decanted to leave about 200g orange
turbid liquid (HPLC: 82% area) which was used in the next step.
Preparation of l-(3.3-bis(3-(methylsulfonyl)phenyl ')allyl)-4-(3-(methylsulfonyl) phenyl)- 1,2,3,6-
tetrahydropyridine (Compound 2, 3rd intermediate)
To the 200g orange turbid liquid from the previous stage was added 500mL water, sodium tungstate
dihydrate (2g, 6mmol) and concentrated sulfuric acid (20mL). The mixture was heated to 35°C and
33%¾ q 2 was added drop-wise in l h during which the yellow viscous mass on the bottom of the
flask dissolved slowly and the temperature rose up to 55°C then decreased slowly to 42°C. The
reaction mixture was heated to 50°C for 2hr and additional 32g of 33%¾ q 2 were added. The reaction
continued for another 4h at 50°C and additional 20g of 33%¾ q 2 were added. After 2h the reaction
mixture was cooled down (25°C) and alkalized to pH12 by 50%NaOH solution. Water (300mL) was
added and after 20min of mechanical stirring was discarded. Another 200mL of water were added,
stirred mechanically for 20min and discarded to give 158.2g highly viscous yellow mass (HPLC:
75.4% area). This mass was heated for 30min 4 times with butanol (200mL@95°C, 200mL@100°C,
400mL@100°C and 700mL@114°C) and twice with acetic acid (8mL and 250mL@95°C) to give
light brown oil that was used in the next step ( 114.9g, HPLC: 89% area).
Preparation of l-(3.3-bis(3-(methylsulfonyl)phenyl)propyl)-4-( 3-(methylsulfonyl) phenvDpiperidine
(Compound 2)
The light brown oil from the previous stage ( 114.9g, HPLC: 89% area) was added into a 2L autoclave
with 550mL acetic acid and 10%Pd/C catalyst (25g, 23.5mmol). Hydrogen was introduced (120psi)
and the reaction was heated to 90°C for 16h. After cooling, the catalyst was filtered, washed with
acetic acid (50ml) and the clear yellowish filtrate was concentrated in vacuum to give 134g brown
viscous residue (HPLC: 82% area). Water (300ml) was added, made alkaline (40% NaOH, pH>12)
and extracted with 120mL dichloromethane that after concentration gave 77.2g brown sticky mass
(HPLC: 83% area). The residue was treated with butanol (5xl00mL, 95°C), cooled down and the
butanol phase over an oily phase was filtered. A total of 74.9g solid phase was resulted which was
dissolved in 200mL acetone and the clear yellow solution was evaporated to give 70. l g dark yellow
clear viscous residue. The residue was treated with heptane (2xl00mL, 95°C) which was cooled and
decanted. After evaporation in a rotavapor a pale yellow foamy solid was obtained (65. lg, HPLC:
84% area). The solid was dissolved in 200mL dichloromethane, 85g silica was added and the mixture
was evaporated and loaded on 1.32Kg silica gel column which was eluted by dichloromethane with
0.5-3.0% methanol and 0.5% triethylamine. Compound 2 was isolated to give 25.8g, HPLC: 93.2%
area, lH-NMR assay: 91.2%.
NMR Identity Analysis of Compound 2
Compound 2 :
The following data in Tables 4 and 5 was determined using a sample of 62.03 mg Compound 2, a
solvent of 0.6 ml CDC13, 99.8 atom%D, and the instrument was a Bruker Avance III 400 MHz.
Table 4: Assignment of ¾ NMR -
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts.
b Weak signal.
Spectra is calibrated by the solvent residual peak (7.28 ppm).
Table 5: Assignment of 3C NMR ,b
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
Spectra is calibrated by a solvent peak (77.16 ppm)
Example 3 - Preparation Of Compound 3 (l ,4-bis((3-(l -propylpiperidin-4
yl)phenyI)sulfonyl)butane)
Preparation of 1.4-bis((3-bromophenyl)thio ')butane (Compound 3. 1st int.)
1,4-bis((3-bromophenyl)thio)butane
KOH (56.2g) was added into methanol (1200mL) in 15min. The clear solution was cooled on water
bath to 0°C. A solution of 3-bromo thiophenol (150.2g, 0.79mol) in methanol (200mL) was added in
50min keeping the temperature at 1-3°C. A solution of 1,4-dibromobutane (86.5g; 0.40 mol) in
methanol (150 ml) was added in 40min to give a yellow turbid mixture. After additional 4 hours
stirring the reaction mixture became white turbid and it was stirred for additional 20h at 25°C. The
suspension was filtered and washed with water (3xl00mL) and methanol (2xl00mL) to give 239g
wet white solid that was dried to 163.6g (94.6% yield, HPLC: 97.9%).
Preparation of l,4-bis((3-bromophenyl)sulfonyl)butane ("Compound 3, 2nd intermediate)
1,4-bis((3-bromophenyl)sulfonyl)butane
To a solution of l,4-bis-(3-bromophenylthio)-butane (155.0g, 0.358mol) in acetic acid (1500mL) was
added sodium tungstate dihydrate (2.5 g, 0.0075mol) and the suspension was heated on water-bath to
45°C. 50 ¾ q 2 (300 mL, 5.28 mol) was added drop-wise into the reaction mixture during 3.5h
keeping the temperature at 45-55°C. The reaction mixture was kept under stirring for additional 3h at
45°C and 16h at 23°C. The off white slurry was filtered, washed with water (3x200mL) and dried on
air to give 179.6g (99% crude yield, HPLC: 92.2% product, 7.1% by product). The crude product
(175g) was added to toluene (1400mL) and heated to >85°C for distillation. Distillation stopped when
no more water was distilled (180mL toluene and lOmL water). The clear reaction mixture was
allowed to cool down and was filtered after overnight stirring at ambient temperature. The bright
colorless crystals were washed (150mL toluene) and dried to give 156. l g product (86.7% yield,
HPLC: product 96.0%, main by-product 3.5%).
Preparation of 14-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane (Compound 3 3rd intermediate)
1,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane
To a solution of l,4-Bis-((3-bromophenyl)-sulfonyl)-butane (92.0g, 185mmol) and butanol (1.0L)
was added 4-pyridinylboronic acid (75.0g, 610mmol), potassium carbonate (172g, 1.24mol) and the
catalyst trans-dichlorobis-(triphenylphosphine) palladium (2.0g; 2.8mmol). The violet suspension was
heated at stirring under nitrogen to 90-95°C within lh. The reaction mixture became brown and
heating continued for more 4h. Additional 4-pyridinylboronic acid (3.5g, 28mmol) was added and the
reaction mixture heated up to 100°C for lh. Heating stopped, water (600mL) was added and the
temperature dropped to 60°C. The resulting dark gray suspension was stirred overnight at ambient
temperature and filtered (slowly). The filter cake was washed with water (lOOmL) to give 153g wet
solid which was suspended in hot acetone (2xlL, 50°C). The solid was then suspended with 0.5L
water at 65°C followed by 2xlL acetone suspension. The acetone solution were combined and
concentrated on a rotavapor to give 90.3g pale yellow solid (yield: 91%, HPLC: 91.8% area).
Preparation of 4,4'-((butane- 1,4-diyldisulfony l)bis(3 ,1-phenylene))bis( 1-propylpyridin- 1-iurrOiodide
(Compound 3 4th intermediate)
To a solution of l,4-Bis-((3-(pyridin-4-yl)-phenyl)-sulfonyl)-butane (85. 8g, 160mmol) and butanol
(450mL) was added 1-iodopropane (91.7g, 540mmol). The stirring mixture was heated up to 90-95°C
in nitrogen atmosphere and kept at this temperature for 6 hours. The dark yellow slurry was then
cooled down to room temperature and kept at this temperature for 15h. The yellow clear solution was
then decanted and butanol (300mL) was added. The mixture was heated to 70°C where it dissolved.
Heating continued to 95°C and light brown slurry appeared. The heating was stopped and the mixture
cooled down to 40°C. The yellow cloudy liquid was decanted and a dark yellow solid mass was
filtered to give 173.5g (HPLC: 84% area) which was used as is in the next step.
Preparation of l,4-bis((3-(l -propyl- l,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl) butane
(Compound 3, 5th intermediate)
,4-bis((3-( 1-propy - ,2,3,6-tetrahydropyridin-
4-yl)phenyl)sulfonyl)butane
To the solid crude starting material (173.5g from the previous stage) was added methanol (450mL)
and the mixture was heated to reflux to give dark yellowish red clear solution which after cooling
gave two phases, the lower one weigh 150g (HPLC: 88.4% area, yield corrected to area%: 13 lg,
157mmol). Methanol (400mL) was added and the mixture was cooled (0°C). Sodium borohydride
(23.75g, 624mmol, 4eq) was added and the reaction mixture was allowed to warm to RT and stirred
for additional 9h. The workup includes concentrating filtrates and precipitating from butanol and
methanol, several slurries in butanol, extraction by hot butanol from water and finally active carbon
treatment to the product dissolved in hot butanol to give 63.0g (HPLC: 85% area) which was used as
is in the next step.
Preparation of l,4-bis((3-(l-propylpiperidine-4yl)phenyl)sulfonvnbutane (Compound 3)
1,4-bis((3-(1-propylpiperidin-4-yl)phenyl)sulfonyl)butane
The product from the previous step (60 .Og, 51g as HPLC is 85% area, 87mmol) was added into an
autoclave with 350mL acetic acid. A suspension of 10% Pd C catalyst (lOg, 9.4mmol) in water
(80mL) was added. Air was exchange to nitrogen and then hydrogen was introduced (150psi) and the
reaction was heated to 85°C for 6h. After cooling the catalyst was filtered, washed with acetic acid
(2x30mL) and water (2x30mL) and concentrated under vacuum to give 98g of slightly brownish
viscous residue. The residue was dissolved with water (200mL), filtered (to remove traces of
charcoal) and washed with 50mL water. To the slightly brownish solution was added concentrated
NaOH up to pH 13 and the mixture was stirred for 30m. The massive precipitation was filtered to
give 78. l g slightly beige wet solid. The wet solid was mixed with water (lOOmL) and toluene
(300mL), heated up to 87°C for 30min and the dark yellow water phase was separated. The organic
phase was filtered and cooled down to 30°C. After 4h the slurry was filtered, washed with 20mL
toluene and dried to give 40.8g off-white solid (HPLC: 74.4% area). The solid was then suspended in
toluene (260mL) and water (40mL) and heated up to 85°C. The colorless water phase was separated
and the toluene phase was filtered, cooled down to 5°C for 2hr and filtered to give after drying 38.0g
off-white solid (HPLC: 81.5% area). The solid was then crystallized twice from toluene (300mL,
heating to 90°C, cooled to 3°C, filtered, washed with 30mL toluene, dried) to give 31.2g, HPLC:
96.9% area, 1H-NMR assay: 93.9%.
NMR Identity Analysis of Compound 3
Compound 3:
The following data in Tables 6 and 7 was determined using a sample of 47.82 mg Compound 3, a
solvent of 1.0 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance P 400 MHz.
Table 6 : Assignment of ¾ NMR 'c
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts. Due to the low concentration of dissolved material some expected HMBC signals were masked
by background noise.
b Weak signal.
Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 7: Assignment of C NMR 'b
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
b Spectra is calibrated by a solvent peak (39.54 ppm).
Example 4 - Preparation Of Compound 4 ((3R,4S)-4-(3-(methylsulfonyl)phenyl)-lpropylpiperidin-
3-ol)
Preparation of dS,6S)-6-(3-(methylsulfonvnphenyl)-3-propyl-7-oxa-3-azabicyclo 4 .1.Olheptane
(1S,6S)-6-(3-(methylsulfonyl)phenyl)
-3-propyl-7-oxa-3-azabicyclo
[4.1 .0]heptane
Into a 4L reactor was added at room temperature Compound 8 (229g, 820mmol, leq) and 2N sulfuric
acid (1147mL, 112g sulfuric acid, 1.147mol, 1.4eq). The reaction light yellow mixture was stirred
and sodium bromate (126g, 836mmol, 1.02eq) was added. The mixture became yellow and the
temperature dropped (endothermic dissolution). After 30min the reaction temperature reached 35°C
and heated further to 40°C for 6h to give dark yellow solution with precipitate in the bottom of
reactor. Toluene (2L) and NaOH (24%, 546g, 131g NaOH, 3.28mol, 4.0eq) were added and the
reaction mixture was vigorously stirred for 1 hour at 42°C. The reaction mixture was then poured into
a 4 L separation funnel. The dark water phase was discarded and the dark red organic phase was
washed with 1.1L 5% sodium sulphite solution and 1L 20% brine. The organic phase was then
concentrated on a rotavapor (50°C, 90-65mbar, finally at 45mbar) to give lllg dark red oil with
crystals in the flask. A GC analysis (5mg red oil dissolved in 0.6 ml toluene) showed 53% area
product, 29% and 5.2% area unknown peaks and 0.4% Compound 8. The product goes to the
reduction in the next stage.
Preparation of (3S,4R)-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-3-ol (Compound 4)
(3S,4R)-4-(3-(methylsulfonyl)
phenyl)-1 -propylpiperidin-3-ol
The epoxide from the previous stage ( 1lg of 53% GC purity, 62.0g, 210mmol, leq) was dissolved in
ethanol (1.2L) for lh. The red colored mixture was potired into 2L Parr reactor and a solution of 10%
Pd/C (I4.6g, dry) in ethanol (50mL) was added. The mixture was reacted with hydrogen (4bar) at
30°C for lOhr. Pd/C was filtered through a Celite and the filtrate was concentrated in the rotavapor to
give 108g red oil (65% area product by GC). The product was added to 200g silica gel, 0.5%
triethylamine in dichloromethane were added and the mixture was concentrated and loaded on a
column with 620g silica gel. The purification was done with 0.5% triethylamine in dichloromethane
to give 28g hard residue (97.0% area by GC). The residue was heated to reflux in 34mL
dichloromethane until complete dissolution to give clear red solution which was cooled slowly with
parallel removal of some solvent by nitrogen flow over the solvent. The precipitation was filtered and
washed with dichloromethane (5mL) to give 20g white solid, HPLC: 99.0% area, 1H-NMR assay:
99.4%.
NMR Identity Analysis of Compound 4
Compound 4:
The following data in Tables 8 and 9 was determined using a sample of 54.06 mg Compound 4, a
solvent of 0.55 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance III 400 MHz.
Table 8: Assignment of ¾ NMR
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts.
b Weak signal.
Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 9: Assignment of 1 C NMR 'b
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
Spectra is calibrated by a solvent peak (39.54 ppm)
Example 5 - Preparation Of Compound 5 (4-(3-(methylsulfonyl)phenyl)-l-propylpiperidine 1-
oxide)
Pridopidine (50.0g, 178mmol, leq) was dissolved in methanol (250mL) and 33% hydrogen peroxide
(20mL, 213mmol, 1.2eq). The reaction mixture was heated and kept at 40°C for 20h. The reaction
mixture was then concentrated in a rotavapor to give 71g light-yellow oil. Water (400mL) was added
and the suspension was extracted with isopropyl acetate (150mL) which after separation contains
unreacted pridopidine while water phase contains 91% area of Compound 5 (HPLC). The product
was then washed with dichloromethane (400mL) after adjusting the water phase pH to 9 by sodium
hydroxide. After phase separation the water phase was washed again with dichloromethane (200mL)
to give 100% area of Compound 5 in the water phase (HPLC). The product was then extracted from
the water phase into butanol (lx400mL, 3x200ml) and the butanol phases were combined and
concentrated in a rotavapor to give 80g yellow oil (HPLC: 100% area of Compound 5). The oil was
washed with water (150mL) to remove salts and the water was extracted with butanol. The organic
phases were combined and concentrated in a rotavapor to give 43g of white solid which was
suspended in MTBE for lhr, filtered and dried to give 33g solid that was melted when standing on
air. After high vacuum drying (2mbar, 60°C, 2.5h) 32.23g pure Compound 5 were obtained (HPLC:
99.5% area, 1H-NMR assay: 97.4%).
NMR Identity Analysis of Compound 5
Compound 5:
The following data in Tables 10 and 1 1 was determined using a sample of 63.06 mg Compound 5, a
solvent of 1.2 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance IP 400 MHz.
Table 10: Assignment of ¾ NMR ,
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts.
b Weak signal.
Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 11: Assignment of 13C NMR ,b
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
Spectra is calibrated by a solvent peak (39.54 ppm)
Example 6 - Preparation Of Compound (l-(2-methylpentyl)-4-(3-
(methylsulfonyl)phenyl)piperidine)
1-(2-methylpentyl)-4-(3-
(methylsulfonyl)phenyl)piperidine
Into a 1L autoclave was added KI (28.4g, 171mmol leq) and potassium carbonate (47.4g, 343mmol,
2eq). 4-(3-(methylsulfonyl)phenyl)piperidine (41g, 171mmol, leq) was dissolved in acetonitrile
(420mL) and the mixture was added into the autoclave followed by l-chloro-2-methylpentane
(25.8mL, 188mmol, l.leq). The autoclave was closed and the reaction mixture was heated under
nitrogen atmosphere to 120°C for 30hr. The reaction mixture was cooled down and filtered. The cake
was washed with acetonitrile and the filtrate was concentrated in vacuum to give 70g crude product
with the following HPLC areas: 60% of Compound 6, 1% of 4-(3-(methylsulfonyl)phenyl)piperidine
and 10% of a by-product. The crude product was dissolved in toluene (350ml) and about 20g solid
material was filtered. The toluene phase was washed with water (200mL) and concentrated in a
rotavapor to give 35.5g (73% area of product by HPLC). The residue was then dissolved in ethyl
acetate (180mL) and cooled on ice bath. Into the reaction mixture was then added 33mL of 18% HC1
solution in ethyl acetate in lhr and the mixture was stirred for an additional lh. The precipitate that
was formed was then filtered, washed with ethyl acetate and dried to give 36.3g white solid (HPLC:
94% area. The product was recrystallized by dissolving in methanol (290mL), heating to 70°C, adding
ethyl acetate (400mL) and cooling to room temperature. The precipitate was filtered, washed with
ethyl acetate (60mL) and dried in vacuum at 50°C to give 28.3g Compound 6 (HPLC: 99.5% area,
1H-NMR assay: 99.6%).
NMR Identity Analysis of Compound 6
Compound 6:
The following data in Tables 12 and 13 was determined using a sample of 33.93 mg Compound 6, a
solvent of 8 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance GP 400 MHz.
Two conformers (ca 10:1) at room temperature are observed. Due to the overlap of proton signals of
the major and minor conformers and relatively weak signal of the minor isomer in 2D speactra only
some of the peaks of minor isomer on 1H spectra and corresponding 1 H-l H COSY cross peaks are
given. Due to the low solubility of the material in D6-DMSO some of the expected HMBC signals are
masked by background noise.
Table 12: Assignment of ¾ NMR '
The assignment is based on the coupling pattern of the signals, coupling constants and chemical
shifts.
Weak signal.
Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 13: Assignment of 13C NMR 'b
The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and
HMBC experiments.
Spectra is calibrated by a solvent peak (39.54 ppm)
Example 7 - Preparation Of Compound 7 (4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6-
tetrahydropyridine)
4-(3-(methylsulfinyl)phenyl)-1-propyl-
1,2,3,6-tetrahydropyridin-1-ium chloride
Sulfuric acid (42.23g, 0.43 lmol, leq) was added to a mixture of 4-hydroxy-4-(3-
(methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride (130g, 0.431mo, leq) and toluene (650mL)
at room temperature. The resulting two-phase solution was refluxed for lhour and HPLC showed that
the product reached 95% area. The reaction mixture was cooled down to 20°C and the toluene phase
was decanted to give viscous residue that was diluted with water (600mL) and neutralized with 2N
NaOH to pH~4.2. Hydrogen peroxide (50%, 32.21g, 0.474mol, l.leq) was added dropwise to the
water phase and the mixture was stirred at 60°C for l h after which the product reached 96% area
(HPLC).
Toluene (600mL) was added to the reaction mixture and made basic first with 25% NaOH (60g) and
finally with 10% NaOH up to pH 12. The phases were separated and the water phase was re-extracted
with toluene (2xl00mL). The combined toluene phases were washed with 5% sodium sulfite
(150mL), brine (150mL) and water (150mL). The toluene phase was then concentrated under vacuum
on a rotavapor to give 111 .3g oil (HPLC area: 96.6%). Methanol (50mL) was added to the residue and
it was filtered and cooled down on ice batch. Dry HC1 in ethyl acetate was added up to pH 1-2
(120mL) and lOOmL of ethyl ether were added to give two phases mixture. The mixture was seeded
with the product and precipitation started. The reaction mixture was stirred on ice bath (2-5°C) for
additional lh, filtered and washed with 1/3 ethyl acetate/ether mixture (lOOmL) to give 140g of very
hygroscopic light yellow solid that was dried on a rotavapor for 2h and stored under nitrogen in deep
freeze. The dry 4-(3-(methylsulfinyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine-HCl is slightly
yellowish solid (94.1g, 79% yield, HPLC (254nm): 96.3% area, 1H-NMR assay: 97.5%).
NMR Identity Analysis of Compound 7
Compound 7:
The following data in Tables 14 and 15 was determined using a sample of Compound 7, a solvent of
CDCb, and the instruments were a Bruker AMX500 and Avance III 800 MHz instrument.
Table 14: Assignment of ¾ NMR"
"Spectra is calibrated by the solvent residual peak (2.5 ppm).
bafter addition of small amount of C D
Table 15: Assignment of 1 C NMRa
Spectra is calibrated by a solvent peak (77.0 ppm)
Example 8 - Analysis of the amounts of Compounds 1, 2, 3, 4, 5 and 6 in a sample of
pridopidine drug substance.
Compounds 1-7 are useful to determine the purity of a pridopidine containing composition.
The procedure used for determination of assay and related substances in pridopidine HCl is a reverse
phase HPLC method using X-bridge phenyl column (or equivalent) and gradient elution with UV
detection at 268 nm. The mobile phase consists of a mixture of methanol and ammonium formate
buffer.
Apparatus
HPLC with gradient pump, column thermostat and UV-detector. Column: Waters, X-bridge Phenyl,
75 x 4.6 mm, 2.5 mhi; or an equivalent column.
Analytical instruction
Reagents and solutions
Solvents: Methanol, HPLC grade; Water, MilliQ-water or equivalent
Reagents: Ammonium formate, purum; Ammonium hydroxide, 30 % A.C.S; Formic acid, pa
Ammonium formate buffer, 1.00 mM, pH 8.90 - 9.10: Weigh 6.3 - 6.4 g ammonium formate
accurately into a 1000 mL volumetric flask and add 2.5 m 30% ammonium hydroxide solution.
Dissolve and dilute with milliQ-water to 900 mL. Measure the pH of the solution. The pH should be
between 8.90 and 9.10, otherwise adjust with ammonium hydroxide or formic acid. Dilute to volume
and filter through a 0.45 mh HVLP-filter.
Reference substances: Control Sample la: (pridopidine)(see Figure 1; Control Sample 2b
(Compound 5, Compound 1, Compound 4, pridopidine, Compound 8, Compound 2, Compound 6,
Compound 3)
Table 6
Table 17: Analytical conditions
Flow 0.8 rnL/min
Gradient Time (min) Mobile phase B (%)
0 50
10 100
12 100
Equilibration time 3 min.
Wavelength 268 nm (bandwidth 4nm; reference off)
190-400 nm (for information in stability studies only).
Injected volume 20 L
Needle wash Set wash cycles to two. Use dilution phase in washing vial.
Temperature 40 °C
Table 18: Approximate retention times
Blank preparation: Use dilution phase. Duplicate vials of blank (A and B).
Reference preparation A (only for related substances)
Use Control Sample 2b. Inject as it is.
The Control Sample 2b solution is a pridopidine solution (0.44 mg/ml free base) spiked with
approximately 1% of each of the impurities: Compound 5, Compound 1, Compound 4, Compound 8,
Compound 2, Compound 6 and Compound 3.
Reference preparation B (only for assay)
Duplicate preparation (Bl and B2).
Weigh 43 - 45 mg of pridopidine reference into a 50 mL volumetric flask. Add 25 mL dilution phase
and shake or sonicate at ambient temperature until the reference is dissolved. Make to volume with
dilution phase. Concentration: 0.9 mg/mL pridopidine. The standard solution is stable for 48 hours
when stored in daylight and in room temperature.
Reference preparation C (only for related substances)
Single preparation (C).
Dilute 1mL of reference Bl to 100 mL with dilution phase. Dilute further 1 mL of this solution to 20
mL with dilution phase (sensitivity standard, concentration corresponding to 0.05 % of sample
concentration).
Sample preparation
Duplicate preparation (sample A and B).
Weigh 43 - 45 mg of the sample of pridopidine into a 50 mL volumetric flask. Add 25 mL dilution
phase and shake or sonicate at ambient temperature until the sample is dissolved. Make to volume
with dilution phase. Concentration: 0.9 mg/mL pridopidine. The sample solution should be freshly
prepared before use.
Order of determinations
When the system is equilibrated, inject the solutions in the following order:
Table 19:
Calculation
System suitability
For related substances:
Rl) The Blank B should be free from interfering peaks at the retention times of Compound 5,
Compound 1, Compound 4, pridopidine, Compound 8, Compound 2, Compound 6 and Compound 3.
R2) The retention time of the pridopidine peak should be 4.6 ± 0.5 min.
R3) Compound 5, Compound 1, Compound 4, pridopidine, Compound 8, Compound 2, Compound 6
and Compound 3 in the Control Sample 2b should be possible to identify according to figure 2.
R4) The pridopidine peak in reference C should have a signal-to-noise ratio greater than or equal to 3.
R5) Calculate the number of theoretical plates (N) and the tailing factor (T) for the pridopidine peak
in reference A. Number of theoretical plates 2: 8000 and tailing factor 0.7 - 1.0.
R6) Calculate the resolution between Compound 5 and Compound 1 in the Control Sample 2b, should
be greater than or equal to 1.5.
R7) If the problem with split peaks Compound 1 and Compound 4 shall appear, they should be
calculated as sum of each split peak.
For assay:
Al) The Blank B should be free from interfering peak at the retention time for pridopidine.
A2) The retention time of the pridopidine peak should be 4.6 ± 0.5 min.
A3) Calculate the RSD % of the five areas of reference Bl. The RSD should be ~ 2.0%.
A4) Calculate the assay of each injections of reference B2. The assay should be in the interval 99-101
w/w-% of the assay of the reference B1.
A5) Calculate the number of theoretical plates (N) and the tailing factor (T) for the pridopidine peak
in the first injection of reference Bl. Number of theoretical plates 2: 8000 and tailing factor 0.7 - 1.0.
A6) Calculate the deviation between the two assay determinations (Sample A and B) according to eq.
1. The deviation should be less than or equal to 2%.
Assay & -AssayJ x lOO
- < 2% (cq.l)
Assay A + Assay ) x 0.5
The analytical method description described herein will be updated to include acceptance criteria for
number of theoretical plates (N) and the tailing factor (T) for pridopidine peak.
Result
For related substances:
The content of related substances should be calculated as area-% and corrected with relative response
factors and reported as % according to eq. 2.
% x percent co te n of a impurity x
r e ~ x area-% of an impurity *x calculated from the c ro ato gra
RRFx Relative Response Factor of a Impurity *
Use following response factors:
Table 20
Remaining related substances will be correct for RRF 1.
For assay:
Calculate the assay of pridopidine in w/w-% using the external standard methodology (see below).
Use the mean response factor obtained from the five injections of reference 1 for the calculation.
- ( q.3)
f = pridopidine (w/vv -%) (cq.4)
mean response factor of pridopidine from reference solution B
c concentration of pridopidine n reference solution ( g m
c S concentration of sample solution (mg mL)
AxR area of pridopidine in each injection of reference solution
S re of pridopidine in sample chramatogram
Table 21: Analytical Methods for Determination of Impurities in the Drug Substance
During course of the validation the response factors for Compound 5, Compound 1, Compound 4,
Compound 8, Compound 2, Compound 6 and Compound 3 has been evaluated and compared to the
response factor of pridopidine. The relative response factor of the impurities are presented in Table
5 22:
Table 22: Relative Response Factors
Example 9 - Specification of Pridopidine Hydrochloride Drug Substance
Table 23
Pridopidine HCl is a white to almost white powder. The specifications of pridopidine HCl are as
follows:
Table 24: Specification of Pridopidine Hydrochloride Drug Substance
Test Acceptance Criteria Method
Description White to almost white Visual inspection
powder
Absence of lumps Pass Visual and touching
Identification
IR Conforms to reference IR IR
spectrum
X-ray diffractogram Conforms to reference X- XRPD
ray diffractogram
Chloride Positive Ph. Eur.
Assay, HPLC, %w/w 98.0- 102.0 HPLC
Related substances, HPLC, area%
Compound 5 < 0.15 HPLC
Compound 1 < 0.15 HPLC
Compound 4 < 0.15 HPLC
Compound 8 < 0.15 HPLC
Compound 3 < 0.15 HPLC
Compound 2 < 0.15 HPLC
Compound 6 < 0.15 HPLC
Unknown impurities, each < 0.10 HPLC
Impurities in total < 0.50 HPLC
Example 10 - Accelerated and long term stability in Pridopidine HCl Drug Product.
Batches 1, 2 and 3 were manufactured according to cGMP and in scale as the expected commercial
scale. Batches 4 and 5 were manufactured according to the current route of synthesis.
The stability program for each batch is detailed below in Table 25.
Table 25: Pridopidine HCl Stability Testing Program
Stability data for batches 1, 2, 3, 4 and 5 can be found in Tables 26-37:
Table 26: Stability Data of Pridopidine HCl Batch 1 Stored at 25°C/60%RH
Table 27: Stability Data of Pridopidine HCl Batch 1 Stored at 40°C/75%RH
Table 28: Stability Data of Pridopidine HCl Batch 2 Stored at 25°C/60%RH
Table 29: Stability Data of Pridopidine HCl Batch 2 Stored at 40°C/75%RH
Table 30: Stability Data of Pridopidine HCl Batch 3 Stored at 25°C/60%RH
Table 3 1: Stability Data of Pridopidine HCI Batch 3 Stored at 40°C/75%RH
Table 32: Stability Data of Pridopidine HCl Batch 4 Stored at 25°C/60%RH
Table 33: Stability Data of Pridopidine HCl Batch 4 Stored at 30°C/65%RH
Table 34: Stability Data of Pridopidine HCI Batch 4 Stored at 40°C/75%RH
Table 35: Stability Data of Pridopidine HCI Batch 5 Stored at 25°C/60%RH
Table 36 Stability Data of Pridopidine HCl Batch 5 Stored at 30°C/65%RH
Table 37: Stability Data of Pridopidine HCl Batch 5 Stored at 40°C/75%RH
Summary of the Results in Tables 26-37 and conclusions:
Appearance:
No significant change is observed in color or form when stored at 40°C/ 75% RH for up to 6 months, at
30°C/ 65% RH for up to 12 months or at 25°C/ 60% RH for up to 48 months.
Crystal form:
No change in polymorphic form is observed when pridopidine HCl is stored at 40°C/ 75% RH for up to 6
months and at 30°C/ 65% RH for up to 12 months. X-Ray diffractograms recorded after 18 months at 25°C/
60% RH showed no change. X-Ray analyses will be performed again at the end of the long term stability
program (60 months).
Assay:
When pridopidine HCl is stored at 40°C/ 75% RH for up to 6 months, no significant change in assay is
observed. Similar no significant change is observed when stored at 30°C/ 65% RH for up to 12 months or at
25°C/ 60% RH for up to 48 months.
Impurities:
No degradation of pridopidine HCl is observed when the drug substance is stored at 40°C/ 75% RH for up
to 6 months, at 30°C/ 65% RH for up to 12 months or at 25°C/ 60% RH for up to 48 months.
Water content
No significant change regarding water content is observed when pridopidine HCl is stored at 40°C/75% RH
for up to 6 months, at 30°C/65% RH for up to 12 months or at 25°C/60% RH for up to 48 months.
Conclusion:
No evidence of relevant changes was observed for the parameters tested at any of the storage conditions.
Pridopidine HCl is considered physically and chemically stable when stored at 40°C and 75% RH for up to
6 months, at 30°C/65% RH for up to 12 months or at 25°C and 60% RH for up to 48 months.
Example 11 - Forced degradation study
A forced degradation study has been performed on pridopidine HCl drug product and drug substance. The
studied material was subjected to acid and base hydrolysis, thermal stress both as solid and in solution,
oxidation, humidity induced stress and photolysis.
The study showed that pridopidine HCl is very stable under most of the studied conditions except for when
subjected to oxidative conditions, where considerable degradation was observed. The major degradation
product was Compound 5. There was also some degradation in the basic hydrolysis study but only a minor
total degradation was observed with the largest degradation product being unidentified.
Mass balance was also investigated and found to be good for all studied conditions.
Summary and conclusions of Examples 10-11
The amounts of the organic impurities remained below the accepted criteria in all the conditions tested over
all time periods as shown in Example 10. Compound 5, which is the only known potential degradation
product (Example 11), remained low in all the tested conditions as shown in Example 10.
Example 12 - Specification of Pridopidine HCl Drug Product.
As detailed in example 10, no degradation products have been detected in the pridopidine HCl in any
storage conditions. In addition, no additional impurities are created during the formation of the drug
product. Therefore, the same amounts of the organic impurities Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 which are controlled in the drug substance remain in the drug
product, and the accepted criteria relating to the organic impurities Compound 1, Compound 2, Compound
3, Compound 4, Compound 5, and Compound 6 as detailed in Table 22 are relevant to the drug product.
Example 13 - Batch Analysis Of Pridopidine HCl Drug Substance
A number of batches of Pridopidine HCl drug substance were manufactured at various manufacturing
facilities and subsequently analyzed. All batches contained the known identified impurities Compound 5,
Compound 1, Compound 4, Compound 8 Compound 6 and Compound 3 in levels below the qualification
limit of 0.15%.
Table 38: Analysis of the content of each of the impurities Compound 5, Compound 1, Compound 4,
Compound 8 Compound 6 and Compound 3 available in the API batches used for tox studies
NP - Not perfoi
Example 14 - Batch Analysis of Pridopidme HCl Drug Product
A number of batches of Pridopidme HCl drug product were manufactured at various manufacturing
facilities and subsequently analyzed.
Table 39: Analysis of Pridopidine HCI Batches used for Non-Clinical and Clinical Studies
Compound 9 is 4-hydroxy-4-(3-(methylsulfonyl)phenyl)- l -propylpiperidin-l-ium chloride.

What is claimed is:
1. An isolated compound having the structure:
or a salt thereof.
2. A composition comprising pridopidine and a compound which has the structure:
or a salt thereof, wherein the ratio of the weight of the compound relative to the weight of the
pridopidine in the composition is from 99:1 to 1:99.
3. The composition of claim 2, wherein the compound has the structure:
or a salt thereof.
A composition comprising a compound having the structure:
or a salt thereof, wherein the composition is free of Pridopidine or a salt thereof.
A pharmaceutical composition comprising an amount of pridopidine and at least one of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and
Compound 7 wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
f) Compound 6 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
g) Compound 7 is present in the pharmaceutical composition in an amount not more than 10
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method.
6. The pharmaceutical composition of claim 5, wherein
a) Compound 1 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
b) Compound 2 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
c) Compound 3 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
d) Compound 4 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
e) Compound 5 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, or
f) Compound 6 is present in the pharmaceutical composition in an amount not more than 0.15
area-% relative to the concentration of pridopidine, based on a determination by an HPLC
method, and/or
a) Compound 1 is present in the pharmaceutical composition in an amount greater than 0.01
area-%, and not more than 0.15 area-% relative to the concentration of pridopidine, based on
a determination by an HPLC method, or
b) Compound 2 is present in the pharmaceutical composition in an amount greater than 0.01
area-%, and not more than 0.15 area-%, relative to the concentration of pridopidine, based on
a determination by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount greater than 0.03
area-%, and not more than 0.15 area-%, relative to the concentration of pridopidine, based on
a determination by an HPLC method, or
d) Compound 4 is present in the pharmaceutical composition in an amount greater than 0.01
area-%, and not more than 0.15 area-%, relative to the concentration of pridopidine, based on
a determination by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount greater than 0.01
area-%, and not more than 0.15 area-%, relative to the concentration of pridopidine, based on
a determination by an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount greater than 0.01
area-% and not more than 0.15 area-%, relative to the concentration of pridopidine, based on
a determination by an HPLC method, and/or
a) Compound 1 is present in the pharmaceutical composition in an amount less than 0.04 area-
% relative to the concentration of pridopidine, based on a determination by an HPLC method,
or
b) Compound 2 is present in the pharmaceutical composition in an amount less than 0.05 area %,
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount less than 0.05 area%
relative to the concentration of pridopidine, based on a determination by an HPLC method,
or
d) Compound 4 is present in the pharmaceutical composition in an amount less than 0.04 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount less than 0.04 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
f) Compound 6 is present in the pharmaceutical composition in an amount less than 0.04 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method,
and/or
a) Compound 1 is present in the pharmaceutical composition in an amount less than 0.01 area-
% relative to the concentration of pridopidine, based on a determination by an HPLC method,
or
b) Compound 2 is present in the pharmaceutical composition in an amount less than 0.01 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
c) Compound 3 is present in the pharmaceutical composition in an amount less than 0.03 area-
% relative to the concentration of pridopidine, based on a determination by an HPLC method,
or
d) Compound 4 is present in the pharmaceutical composition in an amount less than 0.01 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
e) Compound 5 is present in the pharmaceutical composition in an amount less than 0.01 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method, or
0 Compound 6 is present in the pharmaceutical composition in an amount less than 0.01 area-%
relative to the concentration of pridopidine, based on a determination by an HPLC method.
7. The pharmaceutical composition of any one of claims 5-6, wherein
a) at least two of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and
Compound 6 are present,
b) at least three of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and
Compound 6 are present,
c) at least four of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and
Compound 6 are present,
d) at least five of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and
Compound 6 are present,
e) Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6
are present,
f) at least Compound 1 is present,
g) at least Compound 3 is present, or
h) at least Compound 4 is present.
8. The pharmaceutical composition of any one of claims 5-7, comprising pridopidine
hydrochloride salt.
9. The pharmaceutical composition of any one of claims 5-8, in the form of a capsule, a tablet,
or a liquid suspension, preferably in an oral dosage unit form.
10. The pharmaceutical composition of claim 9, wherein the oral dosage unit form comprises
between 22.5 - 315 mg pridopidine, between 45 - 250 mg pridopidine, between 45 - 135 mg
pridopidine, or between 90 - 315 mg pridopidine.
11. The pharmaceutical composition of claim 9, wherein the oral dosage unit form comprises
about 22.5 mg, about 45 mg, about 67.5 mg, about 90 mg, about 100 mg, about 112.5 mg, about
125 mg, about 135 mg, about 150 mg, about 180 mg, about 200 mg, about 250 mg, or about
315 mg pridopidine.
12. The pharmaceutical composition of any of claims 9-11, wherein the oral dosage unit form is
prepared for once daily administration.
13. The pharmaceutical composition of any of claims 9-11, wherein the oral dosage unit form is
prepared for more than once daily administration.
14. A process for preparing Compound 1 comprising the step of oxidizing 4-hydroxy-4-(3-
(methylthio )phenyO-l-propylpiperidin-l-ium chloride with an oxidizing agent to form
Compound 1, preferably wherein the oxidizing agent is a peroxide, preferably hydrogen
peroxide.
15. A process for preparing Compound 2 comprising the steps of:
a) reacting 3-bromothioanisole with ethyl 3-(4-oxopiperidin-l-yl)propanoate to form 1-
(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyl)-4-(3-(methylthio)phenyl)piperidin-
4-ol,
b) dehydrating the l-(3-hydroxy-3,3-bis(3-(methylthio)phenyl)propyl)-4-(3-
(methylthio)phenyl)piperidin-4-ol formed in step a) with a dehydrating agent to
obtain l-(3,3-bis(3-(methylthio)phenyl)allyl)-4-(3-(methylthio)phenyl)-l,2,3,6-
tetrahydropyridine,
c) oxidizing the l-(3,3-bis(3-(methylsulfonyl)phenyl)aliyl)-4-(3-(methylsulfonyl)
phenyl)- ,2,3,6-tetrahydropyridine formed in step b) with an oxidizing agent to form
l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)phenyl)-l,2,3,6-
tetrahydropyridine, and
d) hydrogenating the l-(3,3-bis(3-(methylsulfonyl)phenyl)allyl)-4-(3-(methylsulfonyl)
phenyl)- 1,2,3,6-tetrahydropyridine formed in step c) with a hydrogenating agent to
form Compound 2.
16. The process of claim 15, wherein the dehydrating agent is a strong acid, preferably sulfuric
acid and/or
wherein the oxidizing agent is a peroxide, preferably hydrogen peroxide, and/or
wherein the hydrogenating agent is hydrogen.
17. A process for preparing Compound 3 comprising the steps of:
a) reacting 3-bromo thiophenol and 1,4-dibromobutane to form l,4-bis((3-
bromophenyl)thio)butane,
b) oxidizing the l,4-bis((3-bromophenyl)thio)butane formed in step a) with an oxidizing agent to
form 1,4-bis((3-bromophenyl)sulfonyl)butane,
c) reacting 4-pyridinylboronic acid with the l,4-bis((3-bromophenyl)sulfonyl)butane formed in
step b) to obtain l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane,
d) reacting 1-iodopropane with l,4-bis((3-(pyridin-4-yl)phenyl)sulfonyI)butane formed in step c)
to form 4,4'-((butane- 1,4-diyldisulfonyl)bis(3, 1-phenylene))bis( 1-propyIpyridin-1-ium)iodide,
e) adding a reducing agent to 4,4'-((butane-l,4-diyldisulfonyl)bis(3,l-phenylene))bis(lpropylpyridin-
l-ium)iodide formed in step d) to form l,4-bis((3-(l-propyl-l,2,3,6-
tetrahydropyridin-4-yl)phenyl)sulfonyl) butane, and
f) hydrogenating the l,4-bis((3-(l-propyl-l,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyI)
butane formed in step e) with a hydrogenating agent to obtain Compound 3.
18. The process of claim 17, wherein the oxidizing agent is a peroxide, preferably hydrogen
peroxide, and/or
wherein the reducing agent is sodium borohydride, and/or.
wherein the hydrogenating agent is hydrogen.
19. A process for preparing Compound 4 comprising the steps of:
a) epoxidizing 4-(3-(methylsulfonyl)phenyl)-l-propyl-l,2,3,6-tetrahydropyridine with an
epoxidizing agent to form (lS,6S)-6-(3-(methylsulfonyl)phenyl)-3-propyl-7-oxa-3-azabicyclo
[4.1.0]heptane, and
b) nucleophilically opening the epoxide of the (lS,6S)-6-(3-(methylsulfonyl)phenyl)-3-propyl-7-
oxa-3-azabicyclo [4.1.0]heptane of step a) with a nucleophile to obtain Compound 4,
wherein preferably the epoxidizing agent is sodium bromate, and/or
wherein the nucleophile is hydrogen.
20. A process for preparing Compound 5 comprising the step of reacting pridopidine with a
peroxide to obtain Compound 5, wherein preferably the peroxide is hydrogen peroxide.
21. A process for preparing Compound 6 comprising the step of reacting 4-(3-
(methylsulfonyl)phenyOpiperidine with l-chloro-2-methylpentane to obtain Compound 6.
22. A process for preparing Compound 7 comprising the steps of:
a) dehydrating 4-hydroxy-4-(3-(methylsulfonyl)phenyl)-l-propylpiperidin-l-ium chloride with
a dehydrating agent to form 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-lium
hydrogen sulfate,
b) oxidizing 4-(3-(methylthio)phenyl)-l-propyl-l,2,3,6-tetrahydropyridin-l-ium hydrogen
sulfate of step b) with an oxidizing agent to form Compound 7.
23. The process of claim 22, wherein the dehydrating agent is a strong acid, preferably sulphuric
acid and/or
wherein the oxidizing agent is a peroxide, preferably hydrogen peroxide.
24. A process for testing whether a sample of a composition comprising pridopidine contains an
undesirable impurity which comprises the step of determining whether the sample contains a
compound having the structure:
A process for producing a pridopidine drug product comprising obtaining a pridopidine drug
substance and mixing the pridopidine drug substance with suitable excipients so as to produce
the pridopidine drug product, wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine.
26. The process of claim 25, wherein the process further comprises
a) determining the amount of the at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance,
b) determining the amount of the at least two of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance,
c) determining the amount of the at least three of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance,
d) determining the amount of the at least four of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance,
e) determining the amount of the at least five of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the pridopidine drug substance, or
0 determining the amount of Compound 1, Compound 2, Compound 3, Compound 4,
Compound 5, and Compound 6 in the pridopidine drug substance.
27. The process of claim 26, wherein the process further comprises subjecting a sample of the
pridopidine drug substance to stability testing before the step of determining the amount of
the at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and
Compound 6 in the pridopidine drug substance.
28. A process for producing a pridopidine drug product for commercial sale comprising obtaining
a batch of pridopidine drug product that comprises:
i) an amount of Compound 1 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 1, relative to the concentration of
pridopidine, or
ii) an amount of Compound 2 in the batch of pridopidine drug product that is
not more than 0.15 area-% Compound 2, relative to the concentration of
pridopidine, or
iii) an amount of Compound 3 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 3, relative to the concentration of
pridopidine, or
iv) an amount of Compound 4 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 4, relative to the concentration of
pridopidine, or
v an amount of Compound 5 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 5, relative to the concentration of
pridopidine, or
vi) an amount of Compound 6 in the batch of pridopidine drug product that is not
more than 0.15 area-% Compound 6, relative to the concentration of
pridopidine, and
preparing the batch of pridopidine drug product for commercial sale.
29. The process of claim 28, wherein the process further comprises
a) determining the amount of the at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product,
b) determining the amount of the at least two of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product,
c) determining the amount of the at least three of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product,
d) determining the amount of the at least four of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product,
e) determining the amount of the at least five of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6 in the batch of pridopidine drug product,
f) determining the amount of Compound 1, Compound 2, Compound 3, Compound 4,
Compound 5, and Compound 6 in the batch of pridopidine drug product,
30. The process of claim 29, wherein the process further comprises subjecting a sample of the
batch of pridopidine drug product to stability testing before determining the amount of the at
least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and
Compound 6 in the sample of the batch of pridopidine drug product.
31. A process of distributing a pridopidine drug product comprising a pridopidine drug substance
comprising,
a) obtaining the pridopidine drug product wherein the pridopidine drug substance comprises:
i) an amount of Compound 1 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 1; relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug substance that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product comprising the pridopidine drug substance.
32. A process of distributing a pridopidine drug product comprising,
a) obtaining the pridopidine drug product that comprises:
i) an amount of Compound 1 in the pridopidine drag product that is not more
than 0.15 area-% Compound 1, relative to the concentration of pridopidine, or
ii) an amount of Compound 2 in the pridopidine drug product that is not more
than 0.15 area-% Compound 2, relative to the concentration of pridopidine,
or
iii) an amount of Compound 3 in the pridopidine drug product that is not more
than 0.15 area-% Compound 3, relative to the concentration of pridopidine,
or
iv) an amount of Compound 4 in the pridopidine drug product that is not more
than 0.15 area-% Compound 4, relative to the concentration of pridopidine,
or
v) an amount of Compound 5 in the pridopidine drug product that is not more
than 0.15 area-% Compound 5, relative to the concentration of pridopidine,
or
vi) an amount of Compound 6 in the pridopidine drug product that is not more
than 0.15 area-% Compound 6, relative to the concentration of pridopidine;
and
b) distributing the pridopidine drug product.
33. An impurity or a salt thereof for use, as a reference standard to detect trace amounts of the
impurity in a pharmaceutical composition comprising pridopidine or a pharmaceutically
acceptable salt thereof, wherein the impurity is selected from the group consisting of
Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 6.
34. A method of determining the concentration of an impurity in a pharmaceutical composition
comprising pridopidine, the method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution
i) comprising pridopidine and the diluent solution, or
ii) comprising the impurity
) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
f) injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
35. A method of determining the concentration of an impurity in a pharmaceutical composition
comprising pridopidine and a pharmaceutically acceptable carrier, the method comprising,
a) preparing a sample solution from the pharmaceutical composition,
b) preparing a diluent solution comprising methanol and water,
c) preparing a standard solution
i) comprising pridopidine and the diluent solution, or
ii) comprising the impurity
d) preparing a resolution solution comprising pridopidine and the impurity,
e) preparing a buffer solution by dissolving ammonium formate in water and adjusting
to pH of 9.0 ± 0.10 with aqueous ammonia hydroxide or formic acid,
injecting into the HPLC the diluent solution, the resolution solution, the standard
solution, and the sample solution,
g) running the HPLC using ultraviolet absorption at 190-400 nm or 268 nm and a
mixture of the buffer solution, methanol and water as the mobile phase,
h) determining the retention time (RT) and the areas of the peaks of the impurity in the
chromatograms of the sample solution, and
i) performing quantitation of the impurity with respect to the corresponding peaks in the
chromatograms of the sample solution,
wherein the impurity is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5
or Compound 6.
36. A method of treating a subject afflicted with a neurodegenerative disease or a
neurodegenerative disorder comprising administering to the subject the pharmaceutical composition
of any one of claims 5-13.
37. A method of treating a subject afflicted with Huntington's disease comprising administering to
the subject the pharmaceutical composition of any one of claims 5-13.
38. A process for validating a batch of a pharmaceutical product containing pridopidine or a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for distribution
comprising:
a) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
b) validating the batch for distribution only if
i) the batch is determined to have not more than 0.15 area-% Compound 1, relative
to the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15 area-% Compound 2, relative
to the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15 area-% Compound 3, relative
to the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15 area-% Compound 4, relative
to the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15 area-% Compound 5, relative
to the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15 area-% Compound 6, relative
to the concentration of pridopidine.
39. A process for preparing a validated pharmaceutical composition comprising pridopidine
comprising:
a) obtaining a batch of pridopidine drug substance;
b) determining the amount of at least one of Compound 1, Compound 2, Compound 3,
Compound 4, Compound 5, and Compound 6; and
c) preparing the pharmaceutical composition from the batch only if
i) the batch is determined to have not more than 0.15% Compound 1, relative to
the concentration of pridopidine, or
ii) the batch is determined to have not more than 0.15% Compound 2, relative to
the concentration of pridopidine, or
iii) the batch is determined to have not more than 0.15% Compound 3, relative to
the concentration of pridopidine, or
iv) the batch is determined to have not more than 0.15% Compound 4, relative to
the concentration of pridopidine, or
v) the batch is determined to have not more than 0.15% Compound 5, relative to
the concentration of pridopidine, or
vi) the batch is determined to have not more than 0.15% Compound 6, relative to
the concentration of pridopidine.
40. A process for preparing a pharmaceutical composition comprising pridopidine, comprising
a) obtaining a batch of pridopidine drug product;
b) performing stability testing with a sample of the batch;
c) determining the total amount of at least one of Compound 1, Compound 2, Compound
3, Compound 4, Compound 5, and Compound 6 in the sample of the batch after
stability testing by an HPLC method; and
d) preparing the pharmaceutical composition from the batch after stability testing if the
sample of the batch after stability testing contains:
i) not more than 0.15% Compound 1, relative to the concentration of
pridopidine, or
ii) not more than 0.15% Compound relative to the concentration
pridopidine, or
iii) not more than 0.15% Compound 3, relative to the concentration of
pridopidine, or
iv) not more than 0.15% Compound 4, relative to the concentration of
pridopidine, or
v) not more than 0.15% Compound 5, relative to the concentration of
pridopidine, or
vi) not more than 0.15% Compound 6, relative to the concentration of
pridopidine,
preferably further comprising step e) distributing the batch if in step d) the batch is validated for
distribution.
4 1. An isolated compound having the structure: