Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTANTIAL:LY PURE O-DESMETHYLVENLAFAXINE AND
PROCESSES FOR PREPARING IT
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of the following United
States Provisional Patent Application Nos.: 60/792,801, filed April 17, 2006;
60/796,739, filed May 1, 2006; 60/899,166, filed February 1, 2007; 60/902,418,
filed
February 20, 2007; 60/872,95 5, filed December 4, 2006; and 60/903,988, filed
February 27, 2007. The contents of these applications are incorporated herein
by
reference.
FIELD OF THE INVENTION
[0002] The invention encompasses substantially pure
O-desmethylvenlafaxine.
BACKGROUND OF THE ]NVENTION
[0003] Venlafaxine, (t)-1-[2-(Dimethylamino)-1-(4-ethyoxyphenyl) ethyl]
cyclo-hexanol is the first of a class of anti-depressants. Venlafaxine acts by
inhibiting
re-uptake of norepinephrine and serotonin, and is an alternative to the
tricyclic anti-
depressants and selective re-uptake inhibitors. Venlafaxine has the following
chemical formula, Formula I:
iH3
H3C' N
OH
H3C-O
Formula I
[0004] O-desmethylvenlafaxine, 4-[2-(dimethylamino)-1-(1-
hydroxycyclohexyl)ethyl]phenol, is a major metabolite of venlafaxine and has
been
shown to inhibit norepinephrine and serotonin uptake. See Klamerus, K. J. et
al.,
"Introduction of the Composite Parameter to the Pharmacokinetics of
Venlafaxine and
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its Active O-Desmethyl Metabolite," J. Clin. Pharmacol. 32:716-724 (1992). 0-
desmethylvenlafaxine has the following chemical formula, Formula II:
OH
OH
C16H25NOz
Mol. Wt_ 283.38
Formula II
[0005] Processes for the synthesis of 0-desmethylvenlafaxine, comprising a
step of demethylation of the phenol group of venlafaxine, are described in
U.S. patent
No. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392, which
are
incorporated herein by reference.
[0006] The synthesis disclosed in the above references is performed according
to the following scheme:
O UMe unne
OMe I \ I \
HO Reduction HO
CN NH2
CN
MBC CMBC DDMV
OMe OH
~ I \
Methylation Demethylation
HO /CH3 HO NICH3
amine N~CH3 phenol -'CH3
VenlaFe3dne
VNL ODV
"MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl
methylbenzyl
cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV" refers to 0-
desmethylvenlafaxine.
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[0007] Like any synthetic compound, O-desmethylvenlafaxine can contain
extraneous compounds or impurities that can come from many sources. They can
be
unreacted starting materials, by-products of the reaction, products of side
reactions, or
degradation products. Impurities in 0-desmethylvenlafaxine or any active
pharmaceutical ingredient (API) are undesirable and, in extreme cases, might
even be
harmful to a patient being treated with a dosage forrn containing the API.
[0008] It is also known in the.art that impurities in an API may arise from
degradation of the API itself, which is related to the stability of the pure
API during
storage, and the manufacturing process, including the chemical synthesis.
Process
impurities include unreacted starting materials, chemical derivatives of
impurities
contained in starting materials, synthetic by-products, and degradation
products.
[0009] In addition to stability, which is a factor in the shelf life of the
API, the
purity of the API produced in the commercial manufacturing process is clearly
a
necessary condition for commercialization. Impurities introduced during
commercial
manufacturing processes must be limited to very small amounts, and are
preferably
substantially absent. For example, the ICH Q7A guidance for API manufacturers
requires that process impurities be maintained below set limits by specifying
the
quality of raw materials, controlling process parameters, such as temperature,
pressure, time, and stoichiometric ratios, and including purification steps,
such as
crystallization, distillation, and liquid-liquid extraction, in the
manufacturing process.
[0010] The product mixture of a chemical reaction is rarely a single
compound with sufficient purity to comply with pharmaceutical standards. Side
products and by-products of the reaction and adjunct reagents used in the
reaction
will, in most cases, also be present in the product mixture. At certain stages
during
processing of an API, such as 0-desmethylvenlafaxine, it must be analyzed for
purity,
typically, by HPLC, NMR or TLC analysis, to determine if it is suitable for
continued
processing and, ultimately, for use in a pharmaceutical product. The API need
not be
absolutely pure, as absolute purity is a theoretical ideal that is typically
unattainable.
Rather, purity standards are set with the intention of ensuring that an API is
as free of
impurities as possible, and, thus, is as safe as possible for clinical use. As
discussed
above, in the United States, the Food and Drug Administration guidelines
recommend
that the amounts of some impurities be limited to less than 0.1 percent.
[0011] Generally, side products, by-products, and adjunct reagents
(collectively "impurities") are identified spectroscopically and/or with
another
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physical method, and then associated with a peak position, such as that in a
chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H.A.;
Heineman,
W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons:
New York 1989)). Thereafter, the impurity can be identified, e.g., by its
relative
position in the chromatogram, where the position in a chromatogram is
conventionally measured in minutes between injection of the sample on the
column
and elution of the particular component through the detector. The relative
position in
the chromatogram is known as the "retention time."
[0012] Thus, because of its medical uses, it is desirable to obtain
substantially
pure 0-desmethylvenlafaxine.
SUMMARY OF THE INVENTION
[0013] In one embodiment the present invention provides substantially pure
O-desmethylvenlafaxine containing less than about 5% area by HPLC, more
preferably less than about 3% area by HPLC, even more preferably less than
about
1% area by HPLC of total impurities.
[0014] Preferably, the 0-desmethylvenlafaxine contains less than about 0.7%
area by HPLC of total impurities. More preferably, less than about 0.2% area
by
HPLC of total impurities and most preferably, the O-desmethylvenlafaxine
contains
less than about 0.07% area by HPLC of total impurities
[0014] In another embodiment, the present invention provides a process for
preparing substantially pure 0-desmethylvenlafaxine comprising: combining
under
reduced pressure venlafaxine, an organic solvent and a reagent selected from
the
group consisting of: thiophenol, sodium sulfide and C1-Cg alkyl thiolate, to
form a
mixture, heating the mixture to a temperature of about 30 C to about 220 C,
and
recovering 0-desmethylvenlafaxine.
[0015] In another embodiment, the present invention provides a process for
preparing substantially pure O-desmethylvenlafaxine comprising: combining
venlafaxine, an organic solvent and Cl-C$ alkyl thiolate or sodium sulfide to
form a
mixture, heating the mixture to a temperature of about 100 C to about 210 C,
and
recovering O-desmethylvenlafaxine.
[0016] In another embodiment, the present invention provides a process for
preparing substantially pure 0-desmethylvenlafaxine comprising: combining
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venlafaxine and thiophenol to form a mixture, heating the mixture to a
temperature of
about 100 C to about 210 C, and recovering 0-desmethylvenlafaxine.
[0017] In yet another embodiment, the present invention provides the use of
Cj-C8 alkyl thiolate and sodium sulfide for the demethylation of venlafaxine.
[0018] In yet another embodiment, the present invention provides a process
for preparing substantially pure 0-desmethylvenlafaxine comprising: preparing
tridesmethyl venlafaxine as described in the co-pending application 60/849216
(which
is incorporated herein by reference); converting said tridesmethyl venlafaxine
to 0-
desmethylvenlafaxine; and recovering 0-desmethylvenlafaxine.
[0019] In a further embodiment, the invention is directed to an analytical
method for testing the chemical purity of 0-desmethylvenlafaxine.
[0020] In another embodiment, the present invention provides a
pharmaceutical composition comprising substantially pure 0-
desmethylvenlafaxine
and a pharmaceutically acceptable excipient.
[0021] In yet another embodiment, the present invention provides a process
for preparing a pharmaceutical formulation comprising mixing substantially
pure O-
desmethylvenlafaxine and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
[0022] As used herein, the term "substantially pure" refers to 0-
desmethylvenlafaxine having a purity, measured as % area HPLC, of about 95% or
more. Preferably, substantially pure 0-desmethylvenlafaxine has a purity of
about
97% area by HPLC, more preferably of about 99% area by HPLC, even more
preferably of about 99.3% area by HPLC, most preferably of about 99.8% area by
HPLC.
[0023] The present invention provides 0-desmethylvenlafaxine (ODV)
containing less than about 5% area by HPLC, preferably less than about 3% area
by
HPLC, more preferably less than 1% area by HPLC, of total impurities. The tenn
"%
area by HPLC" as used herein refers to the area in an HPLC chromatogram of one
or
more peaks compared to the total area of all peaks in the HPLC chromatogram
expressed in percent of the total area. Further the purity of 0-desmethyl
venlafaxine
may be expressed herein as "HPLC" purity. As such, "HPLC purity", is a
calculation
of the area under the O-desmethyl venlafaxine peak divided by the total area
under the
curve in an HPLC chromatogram.
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[0024] Preferably; the 0-desmethylvenlafaxine contains less than about 0.7%
area by HPLC of total bmpurities. More preferably, less than about 0.2% area
by
HPLC of total impurities and most preferably, the O-desmethylvenlafaxine
contains
less than about 0.07% area by HPLC of total impurities.
[0025] The 0-desmethylvenlafaxine provided by the present invention is
obtained either as a racemate or as optically pure 0-desmethylvenlafaxine.
[0026] It would be apparent to any skilled artisan that further crystallizing
crude 0-desmethylvenlafaxine could afford higher purity.
[0027] In another embodiment, the present invention provides a process for
preparing substantially pure 0-desmethylvenlafaxine comprising: combining,
preferably under reduced pressure, venlafaxine (VNL), an organic solvent and a
reagent selected from the group consisting of: thiophenol, sodium sulfide and
a Cl-C$
alkyl thiolate, to form a mixture, preferably heating the mixture to a
temperature of
from about 30 C to about 220 C, preferably from about 30 C to about 100 C, and
recovering substantially pure 0-desmethylvenlafaxine.
[0028] As used herein, the term "reduced pressure" refers to a pressure below
about 1 atmosphere, preferably to a pressure of less than 0.5 atmosphere, more
preferably to a pressure of less than about 0.1 atmosphere.
[0029] The organic solvent can be selected from the group consisting of: C3-
C7 ketones, C3-C7 esters, C5-C$ aliphatic hydrocarbons or.C6-C12 aromatic
hydrocarbons, high boiling point solvents, C2-Cg ethers, chlorinated
hydrocarbons,
and C2-C8 alcohols. More preferably, the solvent is selected from the group
consisting
of: acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol.
[0030] As used herein, the term "high boiling point solvent" refers to a
solvent
having a boiling point higher than about 100 C. Preferably; the high boiling
point
solvent is selected from the group consisting of toluene, dimethylformamide
(DMF),
dimethylsulfoxide (DMSO), N-methyl-2-pyridone, N-methyl-2-pyrrolidone, 1-
methyl-2-pyrolidinone (NMP) and dimethylacetamide (DMA). More preferably, the
high boiling point solvent is DMA, DMF or NMP.
[0031] Whenever NMP is used, the ratio of NMP to venlafaxine is preferably
I to 20 (by volume), more preferably, 2 to 4 (by volume).
Whenever DMA or DMF are used, the ratio of DMA and DMF to venlafaxine
is preferably at least about 1 volume, more preferably, 1 to 10 (by volume),
most
preferably, about 2.5 volumes.
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[0032] Whenever thiophenol is used in the process, a catalyst is preferably
employed in the reaction mixture. More preferably, the catalyst is a base.
Most
preferably, the catalyst is an alkali metal base, such as potassium carbonate.
[0033] Preferably, the substantially pure 0-desmethylvenlafaxine obtained by
the process above contains less than about 0.7% area by HPLC of total
impurities.
More preferably, less than about 0.2% area by HPLC of total impurities and
most
preferably, the substantially pure 0-desmethylvenlafaxine obtained by the
process
above contains less than about 0.07% area by HPLC of total impurities.
[0034] The 0-desmethylvenlafaxine may be recovered from the mixture by
any method known to the skilled artisan.
[0035] Preferably, the 0-desmethylvenlafaxine thus obtained is in a
crystalline form, characterized by X-ray powder diffraction reflections at
about: 12.1,
13.2, 15.9 and 20.4 degrees two theta f 0.2 degrees two theta.
[0036] In another embodiment, the present invention provides a process for
preparing substantially pure 0-desmethylvenlafaxine comprising: combining
venlafaxine, an organic solvent and a CI-Cg alkyl thiolate or sodium sulfide
to form a
mixture, heating the mixture to a temperature of about 100 C to about 210 C,
preferably of about 100 C to about 190 C, more preferably of about 135 C to
about
190 C, and recovering substantially pure 0-desmethylvenlafaxine.
[0037] The organic solvent used is as described above.
[0038] Whenever NMP is used, the ratio ofNMP to venlafaxine is preferably
I to 20 (by volume), more preferably, 2 to 4 (by volume).
[0039] Whenever DMA or DMF are used, the ratio of DMA and DMF to
venlafaxine is preferably at least about 1 volume, more preferably, I to 10
(by
volume), most preferably, about 2.5 volumes.
[0040] Preferably, the substantially pure 0-desmethylvenlafaxine obtained by
the process above contains less than about 0.7% area by HPLC of total
impurities.
More preferably, less than about 0.2% area by HPLC of total impurities and
most
preferably, the 0-desmethylvenlafaxine obtained by the process above contains
less
than about 0.07% area by HPLC of total impurities.
[0041] The O-desmethylvenlafaxine may be recovered from the mixture by
any method known to the skilled artisan.
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[0042] Preferably, the 0-desmethylvenlafaxine thus obtained is in a
crystalline form, characterized by X-ray powder diffraction reflections at
about: 12.1,
13.2, 15.9 and 20.4 degrees two theta f 0.2 degrees two theta.
[0043] In another embodiment, the present invention provides a process for
preparing substantially pure 0-desmethylvenlafaxine comprising: combining
venlafaxine and thiophenol to form a mixture, heating the mixture to a
temperature of
about 100 C to about 210 C, preferably of about 100 C to about 190 C, more
preferably of about 135 C to about 190 C, and recovering substantially pure 0-
desmethylvenlafaxine.
[0044] Optionally, the process above can be performed in the presence of a
non-hydroxilic or nonethereal solvent. The solvent can be selected from the
group
consisting of: NMP, DMSO, DMF, DMA, carbowax, marlotherm and silicon oil.
Preferably, the solvent is NMP. .
[0045] Whenever NMP is used, the ratio of NMP to venlafaxine is preferably
1 to 20 (by volume), more preferably, 2 to 4 (by volume).
[0046] A catalyst is preferably employed in the reaction mixture of
venlafaxine and thiophenol. More preferably, the catalyst is a base. Most
preferably,
the catalyst is an alkali metal base, such as potassium carbonate.
[0047] Preferably, the substantially pure 0-desmethylvenlafaxine obtained by
the process above, contains less than about 0.7% area by HPLC of total
impurities.
More preferably, less than about 0.2% area by HPLC of total impurities and
most
preferably, the 0-desmethylvenlafaxine obtained by the process above contains
less
than about 0.07% area by HPLC of total impurities.
[0048] The 0-desmethylvenlafaxine may be recovered from the mixture by
any method known to the skilled artisan.
[0049] Preferably, the 0-desmethylvenlafaxine thus obtained is in a
crystalline form, characterized by X-ray powder diffraction reflections at
about: 12.1,
13.2, 15.9 and 20.4 degrees two theta 0.2 degrees two theta.
[0050] All processes for preparing substantially pure 0-desmethylvenlafaxine
described above may be followed by slurrying the obtained 0-
desmethylvenlafaxine
in a mixture of an organic solvent and water, in order to reduce salts
impurities. The
substantially pure 0-desmethylvenlafaxine obtained by slurrying has assay
purity of
at least about 95%, more preferably, an assay purity of 99%. Preferably, the
organic
solvent/water mixture can be an alcohol/water mixture or water/acetonitrile
mixture,
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more preferably the alcohol/water mixture is a CI-C4 alcohol/water mixture,
most
preferably the alcohol/water mixture is an isopropanol/water mixture.
[0051] As used herein the term "assay purity" refers to a purity determined by
a well known method which calculates the mass of 0-desmethyl venlafaxine by
comparing the area percent of the sample to the area percent of a standard.
[0052] Optionally, 0-desmethylvenlafaxine is slurried in a water/IPA mixture.
Preferably, the water/IPA mixture is in a ratio of 15:25 to 80:20 (by volume),
more
preferably the ratio is 80:20 (by volume).
[0053] The slun-y-is may be maintained for about 5 minutes to about 5 hours,
preferably for about 30 minutes to about 4 hours, more preferably for about 1
hour to
about 3 hours, most preferably for about 2 hours, at a temperature of about 20
C to
about 70 C, preferably at about 20 C to about 40 C, more preferably at about
room
temperature, to obtain substantially pure 0-desmethylvenlafaxine having an
assay
purity of about 95%, preferably of about 99%. The substantially pure 0-
desmethylvenlafaxine may be recovered from the slurry by any, method known to
the
skilled artisan. Preferably, recovery comprises precipitation of 0-desmethyl
venlafaxine from an aqueous solution or suspension in water/IPA wherein the pH
is
adjusted to 7.5 -13.5, preferably to 7.5 to 10, more preferably to a pH of
about 8.
Adjusting the pH comprises adding an acid, preferably, the acid is selected
from HCI
and an or.ganic acid, more preferably the acid is citric acid or succinic
acid, most
preferably the acid is succinic acid.
[0054] In yet another embodiment, the present invention provides the use of
Cl-C8 alkyl thiolate and sodium sulfide for the demethylation of venlafaxine.
[0054] In yet another embodiment, the present invention provides a process
for preparing substantially pure 0-desmethylvenlafaxine comprising: preparing
tridesmethyl venlafaxine (TDMV) as described in the co-pending application
60/849216, which is incorporated herein by reference; converting said
tridesmethyl
venlafaxine to 0-desmethylvenlafaxine; and recovering substantially pure 0-
desmethylvenlafaxine from the reaction mixture.
[0055] A process for preparing tridesmethyl venlafaxine comprises:
combining didesmethylvenlafaxine, a high boiling point solvent, and a thiolate
to
form a mixture, heating the mixture to a temperature of about 100 C to about
220 C,
preferably of about 140 C to about 210 C, more preferably to a temperature of
about
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155 C to about 210 C, and optionally recovering tridesmethyl venlafaxine from
the
mixture.
[0056] The tridesmethyl venlafaxine obtained by the process above preferably
contains less than 5% area by HPLC of total impurities.
[0057] Preferably, the high boiling point solvent is as described above.
[0058] Preferably, the thiolate is a high molecular weight thiolate or arene
thiolate. More preferably, the thiolate is sodium dodecanethiolate or
thiophenol. The
sodium dodecanethiolate can be obtained by any method known to the skilled
artisan,
such as combining sodium methoxide, methanol and dodecanethiol.
[0059] Whenever thiophenol is used, a catalyst is preferably employed in the
reaction mixture. More preferably, the catalyst is a base. Most preferably,
the catalyst
is an alkali metal base, such as potassium carbonate is the catalyst.
[0060] Preferably, the mixture is heated to a temperature of about 155 C to
about 210 C.
[0061] The tridesmethyl venlafaxine may be recovered from the mixture by
any method known to the skilled artisan. ,
[0062] The conversion of tridesmethyl venlafaxine to 0-desmethylvenlafaxine
can also be performed as described in the co-pending application 60/849216,
which is
incorporated herein by reference. This process comprises: combining a solution
of
tridesmethyl venlafaxine and a formaldehyde source with sodium borohydride or
sodium triacetoxy borohydride to obtain a slurry and optionally recovering the
0-
desmethylvenlafaxine from the slurry.
[0063] Optionally, the tridesmethyl venlafaxine starting material is in a
solution with an organic solvent such as a C1.4 alcohol.
[0064] . Optionally, the process is performed under acidic conditions.
Preferably, the acidic source is an organic acid, such as formic acid or an
acetic acid.
[0065] Preferably, prior to combining the sodium borohydride or sodium
triacetoxy borohydride, the solution is cooled to a temperature of less than
about
C, more preferably less than about 5 C.
[0066] Substantially pure 0-desmethylvenlafaxine may be further recovered
from the reaction mixture by any method known to the skilled artisan.
Preferably,
recovering substantially pure O-desmethylvenlafaxine comprises adjusting the
pH of
a suspension containing crude 0-desmethylvenlafaxine, for example the reaction
mixture from the conversion step, to a pH of about 7.5 -13.5, obtaining
substantially
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pure 0-desmethylvenlafaxine. Adjusting the pH of the suspension containing
crude
O-desmethylvenlafazine may result or enable precipitation of substantially
pure 0-
desmethylvenlafaxine from the suspension. The suspension containing crude 0-
demethylvenlafaxine may be the suspension from the reaction mixture of the
conversion of tridesmethylvenlafaxine to 0-desmethylvenlafaxine or a
suspension in
a water/Cl-C4 alcohol mixture. The pH may be adjusted with any suitable
organic or
inorganic acid, preferably the pH is adjusted with citric acid or succinic
acid. In
recovering substantially pure 0-desmethylvenlafaxine the pH is preferably
adjusted to
pH of about 7.5-10, more preferably to pH of about 8. Recovering the
substantially
pure 0-desmethylvenlafaxine may further comprise filtering the obtained
substantially pure 0-desmethylvenlafaxine. Optionally, an anti-solvent is
added to
the pH adjusted suspension, wherein the anti-solvent is a water miscible
solvent.
Preferably, the anti-solvent is a C1-C4 alcohol, more preferably isopropanol
(IPA).
[0067] Preferably, the substantially pure 0-desmethylvenlafaxine obtained by
the process above, contains less than about 0.7% area by HPLC of total
impurities.
More preferably, less than about 0.2% area by HPLC of total impurities and
most
preferably, the 0-desmethylvenlafaxine obtained by the process above contains
less
than about 0.07% area by HPLC of total impurities.
[0068] The O-desmethy.lvenlafaxine may be recovered from the slurry by any
method known to the skilled artisan.
[0069] In a further embodiment, the invention is directed to an analytical
method for testing the chemical purity of 0-desmethylvenlafaxine comprising
combining an 0-desmethylvenlafaxine sample with a mixture of
acetonitrile:buffer in
a ratio of about 3:7, to obtain a solution; injecting the solution onto a C-18
column,
for example a Zorbax SB C-18 4.6*250mm Part No.28105-020 or similar column,
followed by eluting the sample from the column at about 55 min using a mixture
of
acetonitrile: buffer (about 3:7) (referred to as eluent A) and a mixture of
acetonitrile:
buffer: trifluoroacetic acid: triethylamine (referred to as eluent B) as an
eluent, and
measuring the chemical purity of the relevant sample with a UV detector.
Eluent B is
preferably prepared by adding to a mixtuie of about 700 parts acetonitrile and
about
300 parts buffer, about 1.6 parts trifluoroacetic acid and about 2.9 parts
triethylamine
and adjusting the resulting mixture to about pH 3.0, more preferably eluent B
is
prepared by combining about 700 ml acetonitrile, about 300 ml Buffer, about
1.6 ml
trifluoroacetic acid, and 2.9 ml triethylamine and adjusting to a pH of about
3Ø
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[0070] Preferably, the buffer contains about 0.4% trifluoroacetic acid, about
0.7% triethylamine arid about 98.9% water having a pH of about 3Ø
[0071] Preferably, the eluent used may be a mixture of eluent A and eluent B,
wherein the ratio of them varies over the time, i.e. a gradient eluent. At the
time 0
minutes, the eluent contains 100% of eluent A and 0% of eluent B. At about 21
minutes, the eluent preferably contains about 100% of eluent A and about 0% of
eluent B. At about 55 minutes, the eluent preferably contains about 45% of
eluent A
and about 55% of eluent B.
[0072] In another embodiment, the present invention provides a
pharmaceutical composition comprising substantially pure 0-
desmethylvenlafaxine
and a pharmaceutically acceptable excipient.
[0073] In yet another embodiment, the present invention provides a process
for preparing a pharmaceutical formulation comprising mixing substantially
pure O-
desmethylvenlafaxine and a pharmaceutically acceptable carrier.
[0074] Pharmaceutical compositions may be prepared as medicaments to be
administered orally, parenterally, rectally, transdermally; bucally., or
nasally. Suitable
forms for oral administration include tablets, compressed or coated pills,
dragees,
sachets, hard or gelatin capsules, sub-lingual tablets, syrups, and
suspensions.
Suitable forms of parenteral administration include an aqueous or non-aqueous
solution or emulsion, while for rectal administration, suitable forms for
administration
include suppositories with hydrophilic or hydrophobic vehicle. For topical
administration, the invention provides suitable transdermal delivery systems
known in
the art, and for nasal delivery, there are provided suitable aerosol delivery
systems
known in the art.
[0075] In addition to the active ingredient(s), the pharmaceutical
compositions
of the present invention may contain one or more excipients or adjuvants.
Selection
of excipients and the amounts to use may be readily determined by the
formulation
scientist based upon experience and consideration of standard procedures and
reference works in the field.
[0076] Diluents increase the bulk of a solid phanmaceutical composition and
may make a pharmaceutical dosage form containing the composition easier for
the
patient and care giver to handle. Diluents for solid compositions include, for
example, microcrystalline cellulose (e.g. Avicel'8'), microfine cellulose,
lactose, starch,
pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates,
dextrin,
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dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate,
kaolin,
magnesium carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates
(e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride,
sorbitol,
and talc.
[0077] Solid pharmaceutical compositions that are compacted into a dosage
form, such as a tablet, may include excipients whose funct'ions include
helping to bind
the active ingredient and other excipients together after compression. Binders
for
solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin,
guar gum,
hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose
(e.g.
Klucele), hydroxypropyl methyl cellulose (e.g. Methoce?'), liquid glucose,
magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates,
povidone (e.g. Kollidon , Plasdone), pregelatinized starch, sodium alginate,
and
starch.
[0078] The dissolution rate of a compacted solid pharmaceutical composition
in the patient's stomach may be increased by the addition of a disintegrant to
the
composition. Disintegrants include alginic acid, carboxymethylcellulose
calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol , Primellose ), colloidal
silicon
dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon , Polyplasdone),
guar
gum, magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose,
polacrilin potassium, powdered cellulose, pregelatinized starch, sodium
alginate,
sodium starch glycolate (e.g. Explotabs'), and starch.
[0079] Glidants can be added to improve the flowability of a non-compacted
solid composition and to improve the accuracy of dosing. Excipients that may
function as glidants include colloidal silicon dioxide, magnesium trisilicate,
powdered
cellulose, starch, talc, and tribasic calcium phosphate.
[0080] When a dosage form such as a tablet is made by the compaction of a
powdered composition, the composition is subjected to pressure from a punch
and die.
Some excipients and active ingredients have a tendency to adhere to the
surfaces of
the punch and die, which can cause the product to have pitting and other
surface
irregularities. A lubricant can be added to the composition to reduce adhesion
and
ease the release of the product from the die. Lubricants include magnesium
stearate,
calcium stearate, glyceryl monostearate, glyceryl palmitostearate,
hydrogenated castor
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oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium
benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc
stearate.
0081] Flavoring agents and flavor enhancers make the dosage form more
palatable to the patient. Common flavoring agents and flavor enhancers for
pharmaceutical products that may be included in the composition of the present
invention include maltol, vanillin, ethyl vanillin, menthol, citric acid,
fumaric acid,
ethyl maltol, and tartaric acid.
[0082] Solid and liquid compositions may also be died using any
pharmaceutically acceptable colorant to improve their appearance and/or
facilitate
patient identification of the product and unit dosage level.
[0083] In liquid pharmaceutical compositions of the present invention, the
active ingredient and any other solid excipients are suspended in a liquid
carrier such
as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or
glycerin.
[0084] Liquid pharmaceutical compositions may contain emulsifying agents
to disperse uniformly throughout the composition an active ingredient or other
excipient that is not soluble in the liquid carrier. Emulsifying agents that
may be
useful in liquid compositions of the present invention include,. for example,
gelatin,
egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl
cellulose,
carbomer, cetostearyl alcohol, and cetyl alcohol.
[0085] Liquid pharmaceutical compositions of the present invention may also
contain a viscosity enhancing agent to improve the mouth-feel of the product
and/or
coat the lining of the gastrointestinal tract. Such agents include acacia,
alginic acid
bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl
alcohol,
methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,
polyvinyl
alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium
alginate,
sodium starch glycolate, starch tragacanth, and xanthan gum.
[0086] Sweetening agents such as sorbitol, saccharin, sodium saccharin,
sucrose, aspartame, fructose, mannitol, and invert sugar may be added to
improve the
taste.
[0087] Preservatives and chelating agents such as alcohol, sodium benzoate,
butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine
tetraacetic
acid may be added at levels safe for ingestion to improve storage stability.
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[0088] According to the present invention, a liquid composition may also
contain a buffer such as gluconic acid, lactic acid, citric acid or acetic
acid, sodium
gluconate, sodium lactate, sodium citrate, or sodium acetate.
[0089] Selection of excipients and the amounts used may be readily
detennined by the formulation scientist based upon experience and
consideration of
standard procedures and reference works in the field.
[0090] The solid compositions of the present invention include powders,
granulates, aggregates, and compacted compositions. The dosages include
dosages
suitable for oral, buccal, rectal, parenteral (including subcutaneous,
intramuscular, and
intravenous), inhalant, and ophthalmic administration. Although the most
suitable
administration in any given case will depend on the nature and severity of the
condition being treated, the most preferred route of the present invention is
oral. The
dosages may, be conveniently presented in unit dosage form and prepared by any
of
the methods well known in the pharmaceutical arts.
[0091] Dosage forms include solid dosage fonms like tablets, powders,
capsules, suppositories, sachets, troches, and lozenges, as well as liquid
syrups,
suspensions, and elixirs.
[0092] The dosage form of the present invention may be a capsule containing
the composition, preferably a powdered or granulated solid composition of the
invention, within either a hard or soft shell. The shell may be made from
gelatin, and,
optionally, contain a plasticizer such as glycerin and sorbitol, and an
opacifying agent
or colorant.
[0093] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet
granulation. In wet granulation, some or all of the active ingredients and
excipients in
powder form are blended, and then further mixed in the presence of a liquid,
typically
water, that causes the powders to clump into granules. The granulate is
screened
and/or milled, dried, and then screened and/or milled to the desired particle
size. The
granulate may then be tableted or other excipients may be added prior to
tableting,
such as a glidant and/or a lubricant.
[0094] A tableting composition may be prepared conventionally by dry
blending. For example, the blended composition of the actives and excipients
may be
CA 02646368 2008-08-25
WO 2007/120923 PCT/US2007/009558
compacted into a slug or a sheet, and then comminuted into compacted granules.
The
compacted granules may subsequently be compressed into a tablet.
[0095] As an alternative to dry granulation, a blended composition may be
compressed directly into a compacted dosage form using direct compression
techniques. Direct compression produces a more uniform tablet without
granules.
Excipients that are particularly well suited for direct compression tableting
include
microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate
and
colloidal silica. The proper use of these and other excipients in direct
compression
tableting is known to those in the art with experience and skill in particular
formulation challenges of direct compression tableting.
[0096] A capsule filling of the present invention may comprise any of the
aforementioned blends and granulates that were described with reference to
tableting,
however, they are not subjected to a final tableting step.
[0097] In another embodiment, the present invention provides a method of
treating a patient comprising administering to a patient in need thereof a
therapeutically effective amount of the above substantially pure 0-
desmethylvenlafaxine. Preferably, the method is treating a patient suffering
from a
condition which may be treated with a norepinephrine or a serotonin re-uptake
inhibitor. Such patient may be suffering from depression.
[0097] . Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art
from
consideration of the specification. The invention is further defined by
reference to the
following examples describing in detail the synthesis of the novel compound
tridesmethyl venlafaxine and further its conversion to 0-desmethylvenlafaxine.
It
will be apparent to those skilled in the art that many modifications, both to
materials
and methods, may be practiced without departing from the scope of the
invention.
EXAMPLES
[0098] The XRD diffraction was performed on Scintag X-ray powder
diffractometer
model X'TR.A with a solid state detector. Copper radiation of 1.5418 A was
used.
The sample holder was a round standard aluminum sample holder with rough zero
16
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background. The scanning parameters were range: 2-40 degrees two-theta; scan
mode: continuous scan;,step size: 0.05 deg.; and at a rate of 5 deg/min.
HPLC method for measuring the chemical purity:
Column Zorbax SB C-18 4.6*250mm Part No.28105-020 or equivalent
column
Buffer 0.4% trifluoroacetic acid, 0.7% triethylamine 98.9% of water
(adjusted to pH=3.0).
Eluent A: 30% Acetonitrile 70% Buffer
Eluent B: Prepared by adding to a mixture of 700m1 Acetonitrile and
300m1 buffer, 1.6m1 of trifluoroacetic acid and 2.9m1 of
triethylamine (adjusted to pH=3.0)
Stop time: 55 min
Gradient of Eluent: Time (min) Eluent A (%) Eluent B (%)
0 100 0
21 100 0
55 45 55
Equilibration time: 10 min
Flow: 1.0 mLJmin
Detector: 230 nm
Injection volume: 10 L
Diluent: Eluent A
Column temperature: 25 C
Example 1: Preparation of 0-desmethylvenlafaxine in NMP
[0099] Venlafaxine (50g, 180 mmol), thiophenol (20 ml, 195 mmol), K2C03
(1 g, 6 mmol), and NMP (90 ml) were charged in a 500 ml 3 necks flask equipped
with stirrer, condenser and thermometer. The mixture was heated to 190 C.
After 5
hours at 190 C the heating bath was removed. (less than 1.5% VNL). At 80 C IPA
(300m1) was added. The solution was cooled to 0-5 C overnight. The solid was
filtered under reduced pressure and washed with IPA and water. The solid was
then
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dried-overnight at 50 C under vacuum to get pure ODV base. ODV was obtained
with
a purity of 97% and aran Assay of 93.5%.
,
Example 2: Preparation of 0-desmethylvenlafaxine in NMP
[0100] To one neck flask equipped with magnetic stirrer, dean stark,
condenser and thenmometer were added at room temperature under flow of
nitrogen
VNL (5g, 18.2 mmol), Na2S Hydrate (1.58g, 12 mmol, assay >60%) and NMP (12
ml). The reaction mixture was heated to 150 C in 1 hour and kept at this
temperature
for 7.5 hours. Then the reaction mixture was cooled to room temperature and
stirred
overnight at this temperature. Afterwards Na2S hydrate (0.71 g, 5.4 mmol,
assay
>60%) was added. The mixture was heated to 165 C in 1 hour and kept at this
temperature for 5 hours. After this time the reaction was cooled to 40 C, IPA
(30m1)
and a 10% aqueous solution of citric acid (20 ml) were added slowly through a
dropping funnel until light precipitation was observed (pH 10). The suspension
was
stirred over weekend at room temperature and the solid was filtered under
reduced
pressure and washed with 1PA (20 ml): The solid was dried overnight in a
vacuum
oven at 50 C to obtain dry ODV (assay 55.2%, HPLC purity 99.11%)
Example 3: Preparation of 0-desmethylvenlafaxine under pressure
[0101] A 250 ml autoclave is charged with 5g VNL (0.0182mo1), 3.81 g
Sodium Ethanethiolate (0.0458mo1, 2.5eq) and NMP (10 ml). The reaction mixture
is
stirred from 30 C to 220 C and 1-20 bar pressure for 4h. The mixture is then
cooled
to room temperature. At ambient temperature IPA (10 ml) and water (10 ml) are
added. To this mixture a 10% aqueous solution of citric acid is added in order
to reach
pH about 12. A solid begins to precipitate and is stirred at RT for 2.5 h. The
solid is
then filtered under reduced pressure and washed with solvent. The wet cake is
dried in
a vacuum oven at 50 C to obtain pure ODV.
Example 4: PLeparation of 0-desmethylvenlafaxine in DMA
[0102] To a 100 ml three necks flask equipped with mechanical stirrer,
thermometer and condenser were added 5g VNL (0.0182mo1), 3.81g Sodium
Ethanethiolate (0.0458mol, 2.5eq) and Dimethylacetamide (10 ml). The mixture
was
heated to 135 C for 4h, and then it was cooled to room temperature. At ambient
temperature IPA (10 ml) and water (10 ml) were added. The reaction mixture was
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WO 2007/120923 PCT/US2007/009558
clear. To this mixture (pH 13) a 10% aqueous solution of citric acid was added
in
order to reach pH 12.4:. A solid began to precipitate and was stirred at RT
for 2.5 h.
The solid was then filtered under reduced pressure and washed with IPA. The
wet
cake was dried in a vacuum oven at 50 C to obtain crude ODV (assay of 78%,
HPLC
99.84%).
Example 5: Preparation of 0-desmethylvenlafaxine in DMA
[0103] To a 100m1 three necks flask equipped with mechanical stirrer,
thermometer and condenser were added 10g VNL (0.0364mo1), 7.62g Sodium
ethanethiolate (0.091mo1, 2.5eq) and dimethylacetamide (20 ml). The mixture
was
heated at 110 C for 9 hours and then was cooled to room temperature. At this
temperature IPA (25 ml) and water (15 ml) were added. The reaction mixture was
clear. To this mixture (pH 12.43) HC132% was added to reach pH 10. A solid
began
to precipitate and was stirred at ambient temperature for 2.5 hours. The solid
was then
filtered and washed with IPA. The wet cake was dried in a vacuum oven at 50 C
to
obtain ODV crude (assay of 77.9%, HPLC 94.98%).
Example 6: Preparation of 0-desmethylvenlafaxine in DMF
[0104] To a 100m1 three necks flask equipped with mechanical stirrer,
thermometer and condenser were added 5g VNL (0.0364mo1), 3.81g Sodium
ethanethiolate (0.0454mo1, 2.5eq) and Dimethylformamide (10 ml). The mixture
was
heated to 135 C for 3 hours and 20 minutes. The solution was then cooled to
room
temperature.
At this temperature ethylacetate (10 ml) was added and some material
precipitated.
The mixture was heated back to 70 C and then cooled slowly to ambient
temperature.
The mixture was stirred overnight at this temperature. Then to the mixture
were added
IPA, brine and citric acid 10% to pH 9-10. The suspension was stirred at RT
for five
minutes and filtered under reduced pressure. The wet cake was washed with IPA
and
dried in a vacuum oven overnight at 50 C to obtain crude ODV (assay of 76.3%,
HPLC 99.29%).
Example 7: Preparation of O-desmethyIvenlafaxine by slurry in water/IPA
[0105] lg of ODV (GS 1652) was stirred for 2h at ambient temperature in 5
ml of a mixture water: IPA (80:20). The slurry was stirred for 2 hours at
ambient
temperature and the solid was filtered under reduced pressure and washed with
2 ml
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WO 2007/120923 PCT/US2007/009558
of water:IPA (80:20). The solid was dried in a vacuum oven overnight at 50 C
to
obtain dry pure ODV (assay of 98.7%, HPLC 99.93%)
Example 8: Preparation of 0-desmethylvenlafaxine by slurry in water
[0106] To a 100 ml flask equipped with magnetic stirrer were added at room
temperature wet ODV (5.65 g) previously produced and water (40 ml). The
suspension was stirred at ambient temperature for 2.5 hours. The suspension
was then
filtered under reduced pressure and washed with water (lOml). The solid was
dried in
a vacuum oven overnight at 50 C to get a white pure solid ODV (assay 95%, HPLC
purity 99%).
Example 9: Preparation of 0-desmethylvenlafaxine in NMP
[0107] To a three necks flask equipped with mechanical stirrer, condenser and
thermometer were added at room temperature under flow of nitrogen VNL (12g,
43.26 mmol), Na2S Hydrate (6.2g, 47.69 mmol, assay >60%) and NMP (24 ml). The
reaction mixture was heated to 175 C in 1 hour and kept at this temperature
for 3
hours. Then the reaction mixture was cooled to 90 C. Water (36ml) and succinic
acid
(5g, 42.34 mmol) were added and a light precipitation was observed (pH 8.0).
Diethylcarbonate (24m1) was added to the solution and the suspension was
stirred at
60 C 0.5 hours. The reaction mixture was then cooled to room temperature and
the
solid was filtered under reduced pressure and washed with H20 (2X20 ml). The
solid
was dried overnight in a vacuum oven at 50 C to obtain 9.26g (yield=79.43%) of
dry
pure ODV base (assay 97.7%, HPLC purity 99.34%)
Example 10: Preparation of 0-desmethylvenlafaxine in NMP
[0108] To a three necks flask equipped with mechanical stirrer, condenser and
thermometer were added at room temperature under flow of nitrogen VNL (12g,
43.26 minol), Na2S Hydrate (6.2g, 47.69 mmol, assay >60%) and NMP (24 ml). The
reaction mixture was heated to 175 C in 1 hour and kept at this temperature
for 3
hours. Then the reaction mixture was cooled to 90 C. Water (36m1) and succinic
acid
(6g 50.8 mmol) were added and a light precipitation was observed (pH 8.0).
Acetonitrile (24ml) was added and the suspension was stirred at 60 C for 0.5
hour.
Then the reaction mixture was cooled to room temperature, the solid was
filtered
under reduced pressure and washed with H20 (2X20 ml). The solid was dried
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overnight in a vacuum oven at 50 C to obtain pure dry ODV base (assay 95.8%,
HPLC purity 99.47%)
Example 11: Preparation of O-desmethylvenlafaxine in NMP
[0109] To a three necks flask equipped with mechanical stirrer, condenser and
thermometer were added at room temperature under flow of nitrogen VNL (12g,
43.26 mmol), Na2S Hydrate (6.2g, 47.69 mmol, assay >60%) and NMP (24 ml). The
reaction mixture was heated to 175 C in 1.5 hour and kept at this temperature
for 4
hours. Then the reaction mixture was cooled to room temperature. Water (60m1)
and
succinic acid (5g 42.34 mmol) were added and precipitation was observed (pH
8.0).The suspension was heated to 95 C and stirred at 95 C 1 hour. Then the
reaction
mixture was cooled to room temperature, the solid was filtered under reduced
pressure and washed with H20 (2X20 ml). The solid was dried overnight in a
vacuum
oven at 50 C to obtain 11.34g of ODV base (yield=95.38%, assay 95.8%, HPLC
purity 98.07%).
Example 12: Preparation of tridesmethyl venlafaxine
.[0110] DDMVxHCI (10 g, 40 mmol), KZCO3 (6g, 44 nunol), Thiophenol
(8m1, 60 mmol) and NMP (40 ml) were charged in a 250 ml flask equipped with
magnetic stirrer, condenser and nitrogen inlet, and heated in a sand bath. The
temperature of the bath was kept at 210 C for 5.5 hours. HPLC analysis
confirmed
full consumption of DDMV. TDMV was obtained with a purity of 95%.
Example 13: Preparation of substantiallYpure 0-desmethylvenlafaxine
[0111] TDMV (0.2 g, 0.85 mmol) was dissolved in methanol. Formalin
solution (0.4 ml, 5 mmol) was added and the resulting solution was cooled in
an ice
bath. To the cold solution, NaBH4 (65 mg, 1.7 mmol) was added. After 15 min a
sample was analyzed by HPLC, and determined to contain 85 % ODV in the
reaction
mixture.
Then to the mixture is added IPA, and citric acid 10% to pH 9-10. The
suspension is
stirred at RT for five minutes and filtered under reduced pressure. The wet
cake is
washed with IPA and dried in a vacuum oven overnight at 50 C to obtain pure
ODV.
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Comparative Example with WO 03/048104 example 4
[0112] NaOMe Q.3 g, 24mmol) dissolved in Methanol (3 ml) and
dodecanethiol (5.83 ml=4.92 g, 24 mmol) were mixed together and placed in
rotovapor under reduced pressure at 90 C. To this residue Venlafaxine (5.12 g,
18
mmol) and PEG 400 (3.7g, 0.75vo1) were added. The mixture was then heated at
200 C. (TiõtmaI=190 C). After 3 hours IPA (18m1) was added and the pH adjusted
to
9.5 with aqueous HCI. The solid was filtered under reduced pressure and washed
with
IPA and water. The wet ODV was dried under reduced pressure to get ODV. ODV
was obtained with a purity of 73.5% and an Assay of 74.2%
Comparative Example with WO 03/048104 example 2
[0113] Venlafaxine (2.8g, 10.1mmo1), Benzenethiolate sodium salt (3.45g,
26mrnol), and PEG 400 (12.5g, 4.5vol) were charged in a 100 ml flask with
magnetic
stirrer. The mixture was heated in a sand bath to 160 C. At 90 C we observed a
complete dissolution. After 5 hours at 160 C the bath was removed and water
(30 ml)
was added. The pH was adjusted with H3PO4 85% to pH=3.5. The mixture was
extracted with 25ml Hexane to remove organic by-products, and the aqueous
phase
pH was readjusted to pH 9.5 with aqueous ammonia. A solid precipitated from
the
reaction mixture. The solid was filtered, reslurried in water (40 ml) and
filtered under
reduced pressure. The solid so-obtained was dried under reduced pressure to
get
ODV. ODV was obtained with a purity of 95.6% and an Assay of 78.5%.
22
