U.S. patent application number 09/312617 was filed with the patent office on 2001-08-16 for compressed tablet formulation.
Invention is credited to BATRA, UDIT, HIGGINS, RAYMOND J., KATDARE, ASHOK V..
Application Number | 20010014352 09/312617 |
Document ID | / |
Family ID | 26775309 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014352 |
Kind Code |
A1 |
BATRA, UDIT ; et
al. |
August 16, 2001 |
COMPRESSED TABLET FORMULATION
Abstract
This invention relates to a 50% drug loaded compressed tablet
formulation for efavirenz. Efavirenz is a non-nucleoside reverse
trancriptase inhibitor being studied clinically for use in the
treatment of HIV infections and AIDS.
Inventors: |
BATRA, UDIT; (LANSDALE,
PA) ; HIGGINS, RAYMOND J.; (LANSDALE, PA) ;
KATDARE, ASHOK V.; (NORRISTOWN, PA) |
Correspondence
Address: |
KENNETH R. WALTON
C/O MERCK & CO., INC., PATENT DEPT.
RY60-30
P. O. BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
26775309 |
Appl. No.: |
09/312617 |
Filed: |
May 17, 1999 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60086921 |
May 27, 1998 |
|
|
|
Current U.S.
Class: |
424/464 ;
424/465; 514/229.8; 514/230.5 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61K 9/2866 20130101; A61K 9/2095 20130101; A61K 9/2054 20130101;
A61K 31/535 20130101; A61K 9/2893 20130101 |
Class at
Publication: |
424/464 ;
424/465; 514/229.8; 514/230.5 |
International
Class: |
A61K 031/535; A61K
009/20 |
Claims
What is claimed is:
1. A compressed tablet comprising: efavirenz, filler/disintegrant,
superdisintegrant, binder, surfactant, diluent/compression aid,
lubricant, and solvent, wherein efavirenz is about 50% by weight of
the total composition of the compressed tablet.
2. The compressed tablet, as recited in claim 1, wherein the filler
comprises: lactose, calcium carbonate, calcium sulfate,
compressible sugars, dextrates, dextrin, dextrose, calcium
phosphate, kaolin, magnesium carbonate, magnesium oxide,
maltodextrin mannitol, powdered cellulose, pregelatinized starch,
and sucrose.
3. The compressed tablet, as recited in claim 2, wherein the
disintegrant and superdisintegrant comprise: alginic acid,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, croscarmellose sodium, crospovidone,
guar gum, magnesium aluminum silicate, methylcellulose,
microcrystalline cellulose, polyacrilin potassium, powdered
cellulose, pregelatinized starch, sodium alginate and starch.
4. The compressed tablet, as recited in claim 3, wherein the binder
comprises: acacia, alginic acid, carbomer, dextrin, ethylcellulose,
gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum
silicate, maltodextrin, methylcellulose, polymethacrylates,
povidone, pregelatinized starch, sodium alginate, starch, and
zein.
5. The compressed tablet, as recited in claim 4, wherein the
surfactant comprises: sodium lauryl sulfate, docusate sodium,
benzalkonium chloride, benzethonium chloride, and cetrimide.
6. The compressed tablet, as recited in claim 5, wherein the
filler/compression aid comprises: calcium carbonate, calcium
sulfate, compressible sugars, confectioner's sugar, dextrates,
dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl
palmitostearate, hydrogenated vegetable oil (type I), kaolin,
lactose, such as lactose hydrous spray dried, magnesium carbonate,
magnesium oxide, maltodextrin, mannitol, polymethacrylates,
potassium chloride, powdered cellulose, pregelatinized starch,
sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and
tribasic calcium phosphate.
7. The compressed tablet, as recited in claim 6, wherein the
lubricant comprises: calcium stearate, glyceryl monostearate,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable oil, light mineral oil, magnesium stearate, mineral oil,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium
stearyl fumarate, stearic acid, talc and zinc stearate.
8. The compressed tablet, as recited in claim 7, wherein the
solvent comprises: water, ethanol or mixtures thereof.
9. The compressed tablet, as recited in claim 8, wherein the
filler/disintegrant is a microcrystalline cellulose.
10. The compressed tablet, as recited in claim 9, wherein the
superdisintegrant is a croscarmellose sodium.
11. The compressed tablet, as recited in claim 10, wherein the
binder is a hydroxypropyl cellulose.
12. The compressed tablet, as recited in claim 11, wherein the
surfactant is a sodium lauryl sulfate.
13. The compressed tablet, as recited in claim 12, wherein the
filler/compression aid is a lactose hydrous spray dried.
14. The compressed tablet, as recited in claim 13, wherein the
lubricant is a magnesium stearate.
15. The compressed tablet, as recited in claim 14, comprising
efavirenz, microcrystalline cellulose NF, hydroxypropyl cellulose
LF NF, croscarmellose sodium, sodium lauryl sulfate, lactose
hydrous spray dried (EG), and magnesium stearate (EG).
16. The compressed tablet, as recited in claim 15, containing about
300 mg of efavirenz, about 120 mg microcrystalline cellulose NF,
about 19.2 mg hydroxypropyl cellulose LF NF, about 30 mg
croscarmellose sodium, about 6 mg sodium lauryl sulfate, about
118.8 mg lactose hydrous spray dried (EG), and about 6 mg magnesium
stearate (EG).
17. A process for the preparation of a 50% drug loaded compressed
tablet comprising the following steps: (a) blending efavirenz with
a filler/disintegrant, super-disintegrant, binder and surfactant;
(b) adding at least 1.1% by weight of water per weight of efavirenz
to wet granulate the blended mixture to agglomerate the mixture;
(c) drying the granulated mixture to a moisture content of about 0%
to about 10%; (d) milling the dried mixture to granulate to a
uniform size; (e) blending the milled mixture with a
filler/compression aid; (f) lubricating the blended mixture with a
lubricant; and (g) compressing the lubricated mixture to a
compressed tablet of the desired shape.
18. The process as recited in claim 19 which comprises the
additional step of film coating the compressed tablet with a film
coating suspension to produce the desired film coated compressed
tablet.
19. The process as recited in claim 18 wherein the granulated
mixture is dried to a moisture content of about 2% to about 5%.
20. A process for the preparation of a 50% drug loaded film coated
compressed tablet comprising the following steps: (a) blending
efavirenz with microcrystalline cellulose, sodium lauryl sulfate,
hydroxypropyl cellulose and croscarmellose sodium; (b) adding at
least 1.1 weight % water per weight of efavirenz to wet granulate
the blended mixture for about 3 minutes to about 8 minutes to
agglomerate the mixture; (c) drying the granulated mixture to a
moisture content of about 2% to about 5%; (d) milling the dried
mixture to a granulate of about 250.mu. to about 75.mu.; (e)
blending the milled mixture with lactose; (f) lubricating the
blended mixture with magnesium stearate; (g) compressing the
lubricated mixture to a compressed tablet of the desired shape; and
(h) film coating the compressed tablet with a film coating
suspension to about 1% to about 10% by weight of the weight of
compressed tablet.
21. The process as recited claim 20, wherein the blended mixture is
wet granulated for about 6 minutes.
22. The process as recited claim 21, wherein the film coating
suspension comprising hydroxypropylcellulose, hydroxypropyl
methylcellulose, and titanium dioxide.
23. The process as recited claim 22, wherein the compressed tablet
is film coated with the film coating suspension to about 3.1% to
about 3.3% by weight of the weight of compressed tablet.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to a compressed tablet formulation
for efavirenz, which is 50 percent by weight drug loaded and can
optionally be film coated. Efavirenz is a non-nucleoside reverse
trancriptase inhibitor being studied clinically for use in the
treatment of HIV infections and AIDS. A process for the manufacture
of the compressed tablet is also disclosed.
[0002] The synthesis of efavirenz and structurally similar reverse
transcriptase inhibitors are disclosed in U.S. Pat. Nos. 5,519,021,
5,663,169, 5,665,720 and the corresponding PCT International Patent
Application WO 95/20389, which published on Aug. 3, 1995.
Additionally, the asymmetric synthesis of an enantiomeric
benzoxazinone by a highly enantioselective acetylide addition and
cyclization sequence has been described by Thompson, et al.,
Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT
publication, WO 96/37457, which published on Nov. 28, 1996.
[0003] Additionally, several applications have been filed which
disclose various aspects of the synthesis
of(-)-6-chloro-4-cyclopropyl-ethynyl-4-t-
rifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one including: 1) a
process for making the chiral alcohol, U.S. Ser. No. 60/035,462,
filed Jan. 14, 1997; 2) the chiral additive, U.S. Ser. No.
60/034,926, filed Jan. 10, 1997; 3) the cyclization reaction, U.S.
Ser. No. 60/037,059, filed Feb. 12, 1997; and the anti-solvent
crystallization procedure, U.S. Ser. No. 60/037,385 filed Feb. 5,
1997 and U.S. Ser. No. 60/042,807 filed Apr. 8, 1997.
[0004] The compressed tablet is an improved formulation which
allows one to utilize a tablet over a capsule. The compressed
tablet has been demonstrated to have comparable bioavailability
data to that seen with the capsule. The key feature of the
formulation is the use of a superdisintegrant and disintegrant
intragranularly to achieved a bioequivalent formulation. The
compressed tablet form was difficult to manage as efavirenz is
fragile and the drug loses crystallinity upon compression. This was
overcome by adding lactose extragranularly.
SUMMARY OF THE INVENTION
[0005] The instant invention relates to a compressed tablet of
efavirenz which is a 50 percent drug loaded formulation.
[0006] The instant invention also relates to the process for
manufacture of the compressed tablet using a wet granulation
method.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The instant invention relates to a compressed tablet of
efavirenz formulation which is 50 percent by weight drug loaded and
can optionally be film coated.
[0008] The compressed tablet comprises: efavirenz,
filler/disintegrant, superdisintegrant, binder, surfactant,
filler/compression aid, lubricant, and solvent, wherein of
efavirenz is about 50% by weight of the total composition of the
compressed tablet.
[0009] The efavirenz concentration can be varied from about 1 to
about 75 % by changing the concentration of remaining excipients.
Furthermore, changing the tooling can give a wide ranges of doses,
e.g. a 20 mg dose in a 40 mg tablet, a 300 mg dose in a 600 mg
tablet, or a 600 mg dose in a 1200 mg compressed tablet, with the
same composition. Removing the lactose from the formulation gives
about 70% drug in the formulation giving a 600 mg dose in a 860 mg
compressed tablet. These variations are very straightforward to
effect. This formulation will allow one to formulate efavirenz as a
single 600 mg dose as an 860 mg compressed tablet, where as a
capsule formulation requires the administration of at least two
capsules to dose with 600 mg of efavirenz.
[0010] The invention contemplates the use of any pharmaceutically
acceptable fillers/compression aids, disintegrants,
super-disintegrants, lubricants, binders, surfactants, film
coatings, and solvents. Examples of these components are set forth
below and are described in more detail in the Handbook of
Pharmaceutical Excipients, Second Edition, Ed. A. Wade and P. J.
Weller, 1994, The Pharmaceutical Press, London, England.
[0011] Fillers and compression aid concentrations can be varied
between about 5% to about 80% to complement the drug amount.
Examples of fillers/compression aids include: lactose, calcium
carbonate, calcium sulfate, compressible sugars, dextrates,
dextrin, dextrose, calcium phosphate, kaolin, magnesium carbonate,
magnesium oxide, maltodextrin mannitol, powdered cellulose,
pregelatinized starch, and sucrose.
[0012] Examples of disintegrants include: alginic acid,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, croscarmellose sodium, crospovidone,
guar gum, magnesium aluminum silicate, methylcellulose,
microcrystalline cellulose, polyacrilin potassium, powdered
cellulose, pregelatinized starch, sodium alginate and starch.
[0013] Examples of fillers (also referred to as a diluent) include:
calcium carbonate, calcium sulfate, compressible sugars,
confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, glyceryl palmitostearate, hydrogenated
vegetable oil (type I), kaolin, lactose, magnesium carbonate,
magnesium oxide, maltodextrin, mannitol, polymethacrylates,
potassium chloride, powdered cellulose, pregelatinized starch,
sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and
tribasic calcium phosphate.
[0014] Superdisintegrant concentration can be varied between about
1% to about 20% to complement the drug amount and obtain reasonable
dissolution. Examples of super-disintegrants include the
disintegrants listed above, carboxymethylcellulose sodium,
croscarmellose sodium, povidone, guar gum, polacrilin potassium,
and pregelatinized starch.
[0015] Binder concentration can be varied between 1 and 10% to
complement the drug amount. Examples of binders include: acacia,
alginic acid, carbomer, carboxymethylcellulose sodium, dextrin,
ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type
I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, liquid glucose, magnesium aluminaum silicate,
maltodextrin, methylcellulose, polymethacrylates, povidone,
pregelatinized starch, sodium alginate, starch, and zein.
[0016] Examples of surfactants comprises anionic and cationic
surfactants, such as sodium lauryl sulfate, docusate sodium
(dioctyl sulfosuccinate sodium salt), benzalkonium chloride,
benzethonium chloride, and cetrimide (alkyltrimethylammonium
bromide, predominantly C.sub.14 alkyl).
[0017] Examples of lubricants include: calcium stearate, glyceryl
monostearate, glyceryl palmitostearate, hydrogenated castor oil,
hydrogenated vegetable oil, light mineral oil, magnesium stearate,
mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl
sulfate, sodium stearyl fumarate, stearic acid, talc and zinc
stearate.
[0018] Examples of solvent comprises: water, ethanol or mixtures
thereof.
[0019] The compressed tablet can also be film coated. Film coat
concentration can be varied up to about 10% to complement the drug
amount, and preferably about 3.1% to about 3.3%. Film coating
suspensions include combinations of one, two or three of the
following components: carboxymethylcellulose sodium, carnauba wax,
cellulose acetate phthalate, cetyl alcohol, confectioner's sugar,
ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, liquid glucose,
maltodextrin, methyl cellulose, microcrystalline wax, Opadry and
Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose,
talc, titanium dioxide, and zein.
[0020] The preferred filler/disintegrant is microcrystalline
cellulose. The preferred superdisintegrant is croscarmellose
sodium. The preferred binder is hydroxypropyl cellulose. A
preferred surfactant is sodium lauryl sulfate. The preferred
diluent/compression aid is lactose hydrous spray dried. The
preferred lubricant is magnesium stearate. The preferred solvent
for formulating this compressed tablet is water. The preferred film
coating comprises: hydroxypropylcellulose, hydroxypropyl
methylcellulose, and titanium dioxide.
[0021] The 300 mg film coated efavirenz tablet contains:
1 Ingredient Amt per tablet Percent w/w Core Tablet: efavirenz 300
mg 50 microcrystalline cellulose NF 120 mg 20 hydroxypropyl
cellulose LF NF 19.2 mg 3.2 croscarmellose sodium 30 mg 5 sodium
lauryl sulfate 6 mg 1 lactose hydrous spray dried (EG) 118.8 mg
19.8 magnesium stearate (EG) 6 mg 1 Film Coating Material per
Tablet: 3.1% by wt hydroxypropyl cellulose LF NF 8.05 mg 1.4
hydroxypropyl methylcellulose USP 6CPS 8.05 mg 1.4 titanium dioxide
USP 3.1 mg 0.3 Tablet Weight: 619.2 mg
[0022] A process for the preparation of a 50% drug loaded
compressed tablet comprising the following steps:
[0023] (a) blending efavirenz with a filler/disintegrant,
super-disintegrant, binder and surfactant;
[0024] (b) adding at least 1.1% by weight of water per weight of
efavirenz to wet granulate the blended mixture to agglomerate the
mixture;
[0025] (c) drying the granulated mixture to a moisture content of
about 0% to about 10%;
[0026] (d) milling the dried mixture to granulate to a uniform
size;
[0027] (e) blending the milled mixture with a filler/compression
aid;
[0028] (f) lubricating the blended mixture with a lubricant;
and
[0029] (g) compressing the lubricated mixture to a compressed
tablet of the desired shape.
[0030] The process as recited above which comprises the additional
step of film coating the compressed tablet with a film coating
suspension to produce the desired film coated compressed
tablet.
[0031] The process as recited above wherein the granulated mixture
is dried to a moisture contant of about 2% to about 5%.
[0032] A process for the preparation of a 50% drug loaded
compressed tablet comprising the following steps:
[0033] (a) blending efavirenz with microcrystalline cellulose,
sodium lauryl sulfate, hydroxypropyl cellulose and croscarmellose
sodium;
[0034] (b) adding at least 1.1 weight % water per weight of
efavirenz to wet granulate the blended mixture for about 3 minutes
to about 8 minutes to agglomerate the mixture;
[0035] (c) drying the granulated mixture to a moisture content of
about 2% to about 5%;
[0036] (d) milling the dried mixture to a granulate of about
250.mu. to about 75.mu.;
[0037] (e) blending the milled mixture with lactose;
[0038] (f) lubricating the blended mixture with magnesium
stearate;
[0039] (g) compressing the lubricated mixture to a compressed
tablet of the desired shape; and
[0040] (h) film coating the compressed tablet with a film coating
suspension to about 3.1% to about 3.3% of weight of compressed
tablet.
[0041] The process as recited above wherein the blended mixture is
wet granulated for about 6 minutes.
[0042] The process as recited above wherein the film coating
suspension comprising hydroxypropylcellulose, hydroxypropyl
methylcellulose, and titanium dioxide.
[0043] Wet granulation can be conducted using granulator mixers,
such as a Fielder 10 L high shear granulator mixer, a drum or pan
granulator, and a fluid bed granulator. Granulation can also be
achieved by conducting dry granulation (without water) using a
roller compaction process.
[0044] The drying step can be conducted using a Glatt WST-15 fluid
bed drier or a tray drier.
[0045] The milling step can be conducted using mills such as a
Comil or a Fitz mill.
[0046] The lubricating and blending steps can be conducted in a
V-blender or a ribbon blender.
[0047] The compression step to form the tablet can be done a
variety of presses including a beta press, single station F-press,
the 6-station Korsh, etc.
[0048] Film coating can be performed in a Glatt Column coater, a
smaller Hi-coater (9"-12" pan), etc.
[0049] The formulation also is bioequivalent to a capsule with a
smaller dose (200 mg), and more bioavailable than other tablet
compositions. The advantages over the capsule include robust
processing and sorting steps, smaller size with a larger dose, and
market preference. The tablet composition also overcomes the expect
loss of crystallinity of efavirenz by adding the lactose
extra-granularly while maintaining the dissolution profile.
[0050] The increased drug loading often compromises the dissolution
profile of the drug. This hurdle was overcome by including the
super-disintegrant intragranularly, as well as the disintegrant
intragranularly. The lactose was added extra-ganularly to maintain
the crystallinity of efavirenz.
[0051] This formulation was determined to be bioequivalent to the
capsule formulation being used in clinical trials. The wet
granulation process has been used to optimize the formulation such
that about 80% dissolution of the drug occurs within 10 minutes in
a 1% Sodium Dodecyl sulfate (SDS) solution, while stirring at a 50
rpm paddle speed.
[0052] Preparation of
(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl--
1,4-dihydro-2H-3,1-benzoxazin-2-one (currently referred to by its
generic name efavirenz or code name DMP-266).
[0053] Scheme 1 outlines the key steps in the synthesis of
(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-be-
nzoxazin-2-one (efavirenz). The chiral addition step allows for the
enantioselective addition of the cyclopropylacetylide across the
trifluoromethylketone of 1. The p-methoxybenzyl (PMB)-protected
amino alcohol, 2, produced is then deprotected to give the amino
alcohol, 3. The amino alcohol is then cyclized using a
chloroformate and base to give efavirenz. 1
[0054] Scheme 2 outlines the preparation of efavirenz using an
alternative process which is a chiral addition reaction. The new
chiral addition reaction allows for the elimination of the
protection-deprotection sequence as outlined in Scheme 1. 2
[0055] Scheme 3 describes the process for the synthesis of the
chiral intermediate used in the preparation of efavirenz. This
reaction has been demonstrated to work using about 1.2 equivalents
of cyclopropylacetylene and chiral additive, much lesss than the
prior methods. The numerous chiral additives have been run and give
high yields with a commerically available chiral ligand, such as
N-methyl ephedrine and N-pyrrolidinyl norephedrine. 3
[0056] The cyclization of the amino alcohol, 3 to produce the
1,4-dihydro-2H-3,1-benzoxazin-2-one, 4 is outlined in Scheme 4
below. The reaction can be carried out as a one-step process, or
alternatively a two step process with the potential isolation of
the intermediate carbamate, 5 depending upon the chloroformate
utilized. It has been demonstrated that the aryl chloroformates
form less stable carbamates such that when they are treated with
aqueous base they cyclize to the product, in a one-step process.
The alkyl chloroformate, alternatively, provides an alkyl
carbamate, a key intermediate capable of being isolated and
purified prior to carrying out the cyclization step. Based upon the
stability of the alkyl carbamates, a viable two step process for
the preparation of efavirenz has been developed which comprises the
formation of the alkyl carbamate intermediate, 5 followed by the
cyclization of the carbamate to give the desired product, 4.
Additionally, it has been demonstrate that phosgene can also be
used. 4
[0057] The compressed tablet is formulated following the sequence
of steps outlined in Scheme 5. 5
[0058] The following examples are meant to be illustrative of the
present invention. These examples are presented to exemplify the
invention and are not to be construed as limiting the scope of the
invention.
EXAMPLE 1
[0059]
2 6 Materials Amount Mol MW Ketone 1a 1.00 kg g 4.47 223.58 (1R,
2S)-N-pyrrolidinyl norephedrine 1.35 kg 6.58 205.30 cyclopropyl
acetylene 361.9 g 5.47 66.10 n-BuMgCl (2.0 M in THF) 2.68 L 5.37
2,2,2-trifluoroethanol (99%) 429.5 g 4.29 100.04 ZnEt.sub.2 (0.892
M in hexane) 6.02 L 5.37 THF 9.36 L 30% K.sub.2CO.sub.3 550 mL 30%
citric acid 2.0 L Toluene (for crystallization, 2 mL/g of 4) 2.6 L
Heptane (for crystallization, 4 mL/g of 4) 5.2 L
[0060] To a solution of trifluoroethanol and (1R,
2S)-N-pyrrolidinyl norephedrine in THF (9 L) under nitrogen is
added a solution of diethylzinc in hexane at 0.degree. C. slowly
enough to keep the temperature below 30.degree. C. The mixture is
stirred at room temperature for 0.5.about.1 h. In another dry flask
a solution of chloromagnesium cyclopropyl acetylide is prepared as
follows: To neat cyclopropyl acetylene at 0.degree. C. is added a
solution of n-butylmagnesium chloride slowly enough to keep the
internal temperature .ltoreq.30.degree. C. The solution is stirred
at 0.degree. C. for .about.40 min and transfered to the zinc
reagent via cannula with 0.36 L of THF as a wash. The mixture is
cooled to -10.degree. C. and ketoaniline 1a is added. The mixture
is stirred at -2 to -8.degree. C. for 35 h, warmed to room
temperature, stirred for 3 h, and quenched with 30% potassium
carbonate over 1.5 h. The mixture is stirred for 4 h and the solid
is removed by filtration and washed with THF (2 cake volume). The
wet solid still contains .about.18 wt % of pyrrolidinyl
norephedrine and is saved for further study. The filtrate and wash
are combined and treated with 30% citric acid. The two layers are
separated. The organic layer is washed with water (1.5 L). The
combined aqueous layers are extracted with 2.5 L of toluene and
saved for norephedrine recovery. The toluene extract is combined
with the organic solution and is concentrated to .about.2.5 L.
Toluene is continuously feeded and distilled till THF is not
detectable by GC. The final volume is controlled at 3.9 L. Heptane
(5.2 L) is added over 1 h. The slurry is cooled to 0.degree. C.,
aged for 1 h, and filtered. The solid is washed with heptane (2
cake volume) and dried to give 1.234 Kg (95.2% yield) of amino
alcohol 3 as a white crystalline. The material is 99.8 A % pure and
99.3% ee.
EXAMPLE 2
[0061]
3 7 FW g mL mmol equiv amino alcohol 3 289 100 346 1
4-nitrophenylchloroformate 201.6 73.2 363 1.05 KHCO.sub.3 100 45
450 1.3 2N KOH 56 346 692 2.0 H.sub.2O 654 MTBE 500
[0062] To a three necked round bottom flask, equipped with a
mechanical stirrer, nitrogen line, and thermocouple, was charged
the solid amino alcohol 3, MTBE (500 mL), and aqueous KHCO.sub.3
(45 g in 654 mL H.sub.2O). Solid 4-nitrophenyl chloroformate was
added, in 4 batches, at 25.degree. C. During the addition the
solution pH was monitored. The pH was maintained between 8.5 and 4
during the reaction and ended up at 8.0. The mixture was stirred at
20-25.degree. C. for two hours. Aqueous KOH (2N) was added over 20
minutes, until the pH of the aqueous layer reached 11.0.
[0063] The layers were separated and 500 mL brine was added to the
MTBE layer. 0.1 N Acetic acid was added until the pH was 6-7. The
layers were separated and the organic phase was washed with brine
(500 mL). At this point the mixture was solvent switched to
EtOH/IPA and crystallized as recited in Examples 5 and 6.
EXAMPLE 3
[0064]
4 8 FW g mL mmol equiv amino alcohol 3a 289 100 346 1 phosgene (20
wt % in toluene) 99 41 216 415 1.2 KHCO.sub.3 100 86.5 865 2.5
H.sub.2O 500 Toluene 500
[0065] To a three necked round bottom flask, equipped with a
mechanical stirrer, nitrogen line, and thermocouple, was charged
the solid amino alcohol 3a, toulene (500 mL), and aqueous
KHCO.sub.3 (86.5 g in 500 mL H.sub.2O). Phosgene solution in
toulene was added at 25.degree. C., and the mixture was stirred at
20-25.degree. C. for two hours.
[0066] The layers were separated and the organic phase was washed
with brine (500 mL). At this point the mixture was solvent switched
to EtOH/IPA and crystallized as recited in Examples 5 and 6.
EXAMPLE 4
[0067]
5 9 FW g mL mmol equiv amino alcohol 3a 289 100 346 1 phosgene
(gas) 99 KHCO.sub.3 100 86.5 865 2.5 H.sub.2O 500 MTBE 500
[0068] To a three necked round bottom flask, equipped with a
mechanical stirrer, nitrogen line, and thermocouple, was charged
the solid amino alcohol 3a, MTBE (500 mL), and aqueous KHCO.sub.3
(86.5 g in 500 mL H.sub.2O). Phosgene gas was slowly passed into
the solution at 25.degree. C., until the reaction was complete.
[0069] The layers were separated and the organic phase was washed
with brine (500 mL). At this point the mixture was solvent switched
to EtOH/IPA and crystallized as recited in Examples 5 and 6.
EXAMPLE 5
[0070] Crystallization of efavirenz from 30% 2-Propanol in Water
using a ratio of 15 ml solvent per gram efavirenz Using Controlled
Anti-Solvent Addition on a 400 g Scale.
[0071] 400 g. of efavirenz starting material is dissolved in 1.8 L
of 2-propanol. The solution is filtered to remove extraneous
matter. 1.95 L of deionized (DI) water is added to the solution
over 30 to 60 minutes. 10 g. to 20 g. of efavirenz seed (Form II
wetcake) is added to the solution. The seed bed is aged for 1 hour.
The use of Intermig agitators is preferred to mix the slurry. If
required (by the presence of extremely long crystals or a thick
slurry), the slurry is wet-milled for 15-60 seconds. 2.25 L of DI
water is added to the slurry over 4 to 6 hours. If required (by the
presence of extremely long crystals or a thick slurry), the slurry
is wet-milled for 15-60 seconds during the addition. The slurry is
aged for 2 to 16 hours until the product concentration in the
supernatant remains constant. The slurry is filtered to isolate a
crystalline wet cake. The wet cake is washed with 1 to 2 bed
volumes of 30% 2-propanol in water and then twice with 1 bed volume
of DI water each. The washed wet cake is dried under vacuum at
50.degree. C.
EXAMPLE 6
[0072] Crystallization of efavirenz from 30% 2-Propanol in Water
using a ratio of 15 ml solvent per gram efavirenz Using a
Semi-Continuous Process on a 400 g Scale.
[0073] 400 g. of efavirenz starting material is dissolved in 1.8 L
of 2-propanol. A heel slurry is produced by mixing 20 g. of Form II
efavirenz in 0.3 L of 30% (v/v) 2-propanol in water or retaining
part of a slurry from a previous crystallization in the
crystallizer. The dissolved batch and 4.2 L of DI water are
simultaneously charged to the heel slurry at constant rates over 6
hours to maintain a constant solvent composition in the
crystallizer. Use of Intermig agitators during the crystallization
is preferred. During this addition the slurry is wet-milled when
the crystal lengths become excessively long or the slurry becomes
too thick. The slurry is aged for 2 to 16 hours until the product
concentration in the supernatant remains constant. The slurry is
filtered to isolate a crystalline wet cake. The wet cake is washed
with 1 to 2 bed volumes of 30% 2-propanol in water and then twice
with 1 bed volume of DI water each. The washed wet cake is dried
under vacuum at 50.degree. C.
EXAMPLE 7
[0074] Preparation of Amino Alcohol 3 and ee Upgrading--Through
Process
6 10 Materials Amount Mol MW Ketone 1 1.00 kg 4.47 223.58 (1R,
2S)-N-Pyrrolidinyl norephedrine 1.35 kg 6.58 205.30 Cyclopropyl
acetylene 361.9 g 5.47 66.10 n-BuMgCl (2.0 M in THF) 2.68 L 5.37
Trifluoroethanol (99%) 429.5 g 4.29 100.04 ZnEt.sub.2 (0.892 M in
hexane) 6.02 L 5.37 THF 9.36 L 30% K.sub.2CO.sub.3 1.2 L 1 M Citric
acid 3.5 L Heptane 12 L Isopropyl acetate (IPAc) 40 L 12N HCl 405
mL 4.88 tert-Butyl methyl ether (MTBE) 6 L Toluene 6.25 L
Na.sub.2CO.sub.3 1.2 kg 11.25
[0075] A solution of diethyl zinc in hexane was added to a solution
of trifluoroethanol (429.5 g, 4.29 mol) and (1R, 2S)-N-pyrrolidinyl
norephedrine (1.35 kg, 6.58 mol) in THF (9 L), under nitrogen, at
0.degree. C. The resulting mixture was stirred at room temperature
for approx. 30 min. In another dry flask a solution of
chloromagnesiumcyclopropylacetylide was prepared as follows. To a
solution of n-butylmagnesium chloride in THF (2 M, 2.68 L, 5.37
mol) was added neat cyclopropylacetylene at 0.degree. C. keeping
the temperature .ltoreq.25.degree. C. The solution was stirred at
0.degree. C. for 1-2 h. The solution of
chloromagnesiumcyclopropylacetylide was then warmed to room
temperature and was transferred into the zinc reagent via cannula
over 5 min followed by vessel rinse with 0.36 L of THF. The
resulting mixture was aged at .about.30.degree. C. for 0.5 h and
was then cooled to 20.degree. C. The ketoaniline 1 (1.00 kg, 4.47
mol) was added in one portion as a solid, and the resulting mixture
was stirred at 20-28.degree. C. for 3 h.
[0076] The reaction was quenched with 30% aq. potassium carbonate
(1.2 L) and aged for 1 h. The solid waste was filtered and the cake
was washed with THF (3 cake volumes). The filtrate and wash were
combined and solvent switched to IPAc.
[0077] The IPAc solution of product 3 and pyrrolidinyl norephedrine
was washed with citric acid (3.5 L) and with water (1.5 L). The
combined aqueous layers were extracted with IPAc (2 L) and saved
for norephedrine recovery. To the combined organic layers was added
12N HCl (405 mL, 4.88 mol), to form a thin slurry of the amino
alcohol-HCl salt. The mixture was aged for 30 min at 25.degree. C.
and was then dried azeotropically.
[0078] The slurry was aged at 25.degree. C. for 30 min and
filtered. The cake was washed with 2.5 L of IPAc and dried at
25.degree. C. under vacuum/nitrogen for 24 h to give 1.76 kg of the
wet HCl salt.
[0079] The salt was dissolved in a mixture of MTBE (6 L) and aq
Na.sub.2CO.sub.3 (1.18 kg in 6.25 L water). The layers were
separated and the organic layer was washed with 1.25 L of water.
The organic layer was then solvent switched into toluene.
[0080] Heptane (5 L) was added over 1 h at 25.degree. C. The slurry
was cooled to 0.degree. C., aged for 1 h, and filtered. The solid
was washed with heptane (2 cake volumes) and was dried to give
1.166 kg (90% overall yield) of amino alcohol 3 as a white
crystalline solid. Norephedrine recovery
[0081] The aqueous solution was basified to pH13 using 50% aq NaOH,
and extracted with heptane (2 L). The heptane solution was washed
with water (1 L) and concentrated to remove residual IPAc and
water. The final volume was adjusted to about 3 L. The heptane
solution was cooled to -20.degree. C., aged for 2 h, and filtered.
The solid was washed with cold heptane (1 cake volume) and dried to
give 1.269 kg solid (94% recovery).
EXAMPLE 8
[0082]
7 50% Drug-Loaded Compressed tablet Of Efavirenz Ingredient Amt per
batch Core Tablet: efavirenz 950 g microcrystalline cellulose NF
380 g hydroxypropyl cellulose LF NF 60.8 g croscarmellose sodium 95
g sodium lauryl sulfate 19 g lactose hydrous spray dried (EG)*
19.8% w/w magnesium stearate (EG)* 1% w/w water 1.045 L Film
Coating Material per Tablet: 3.3% by wt of tablet hydroxypropyl
cellulose LF NF 8.54 mg (2.5%) hydroxypropyl methylcellulose USP
6CPS 8.54 mg (2.5%) titanium dioxide USP 3.42 mg (1%) water (94 %)
*EG = extragranular
[0083] Efavirenz (950 g) was blended with microcrystalline
cellulose (380 g) , sodium lauryl sulfate (19 g) , hydroxypropyl
cellulose (60.8 g) and croscarmellose sodium (95 g) in a Fielder 10
L high shear granulator mixer for four minutes. At least about 1.1
weight % water per weight of efavirenz (1.045 L) was added to wet
granulate the blended mixture over about 6 minutes to about 8
minutes to agglomerate the mixture using an appropriate spray
nozzle. The granulated mixture is dried to a moisture content of
about 2% to about 5% in a Glatt WST-15 fluid bed drier. The dried
mixture was milled using a 40 G round screen in a Comil. The milled
mixture was blended in a V-Blender with lactose for 4 minutes
(calculated amount is the amount needed to make the final
composition contain 19.8% lactose by weight). The blended mixture
was lubricated with magnesium stearate (calculated amount is the
amount needed to make the final composition contain 1% magnesium
stearate by weight) in the V-Blender for 3 minutes. The lubricated
mixture was compressed using a beta press to give a compressed
tablet of the desired shape. The compressed tablets were film
coated with an aqueous coating suspension that contains 2.5%
hydroxypropyl cellulose (HPC); 2.5% hydroxymethylcellulose (HPMC);
and 1% titanium dioxide (TiO.sub.2) and 94% water by weight percent
in a 19" O'Hara pan coater to a coat weight of about 3.3% per
tablet. Note that the coat is the dried form of the suspension.
* * * * *