METHODS FOR PREPARING NEVIRAPINE HEMIHYDRATE AND AN AQUEOUS SUSPENSION THEREOF

METHODES POUR LA PREPARATION D'HEMIHYDRATE DE NEVIRAPINE ET UNE SUSPENSION AQUEUSE CONNEXE

English Abstract

The invention relates to a method for preparing nevirapine hemihydrate and a method for preparing an aqueous suspension of nevirapine hemihydrate. The method for preparing nevirapine hemihydrate which method comprises the steps of: (a) treating an aqueous suspension of anhydrous nevirapine with a strong acid, to yield a solution of the acid addition salt; (b) treating the solution of the acid addition salt produced in the previous step with a strong base, to yield the free base of nevirapine as a precipitate, in the hemihydrate form; and, (c) separating the precipitated nevirapine hemihydrate from the aqueous medium by filtration; and, (d) washing the precipitated nevirapine hemihydrate produced in the previous step with water.

French Abstract

L'invention concerne une méthode permettant de préparer de l'hémihydrate de névirapine et une méthode permettant de préparer une suspension aqueuse d'hémihydrate de névirapine. La méthode permettant de préparer de l'hémihydrate de névirapine comporte les étapes suivantes : a) traitement d'une suspension aqueuse de névirapine anhydre au moyen d'un acide fort pour produire une solution contenant le sel d'addition acide; b) traitement de ladite solution contenant le sel d'addition acide au moyen d'une base forte pour produire la base libre de la névirapine sous forme de précipité hémihydraté; c) séparation de l'hémihydrate de névirapine précipité du milieu aqueux par filtration; et d) rinçage à l'eau de l'hémihydrate de névirapine précipité obtenu à l'étape précédente.

Claims

CLAIMS:
1. A method for preparing nevirapine hemihydrate
which method comprises the steps of:
(a) treating an aqueous suspension of anhydrous
nevirapine with a strong acid, to yield a solution of the
acid addition salt;
(b) treating the solution of the acid addition
salt produced in the previous step with a strong base, to
yield the free base of nevirapine as a precipitate, in the
hemihydrate form; and,
(c) separating the precipitated nevirapine
hemihydrate from the aqueous medium by filtration; and,
(d) washing the precipitated nevirapine
hemihydrate produced in the previous step with water.
2. The method for preparing nevirapine hemihydrate in
accordance with claim 1, wherein the separated nevirapine
hemihydrate produced in step (d) is dried until the water
content is between about 3.1 and 3.9% by weight.
3. A method for preparing an aqueous suspension of
nevirapine hemihydrate wherein the crystal size of the
nevirapine hemihydrate is pharmaceutically acceptable and
remains stable over time, which method comprises the steps
of:
(a) treating an aqueous suspension of anhydrous
nevirapine with a strong acid, to yield an acid addition
salt;
(b) treating the acid addition salt produced in
the previous step with a strong base, to yield the free base
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of nevirapine as a precipitate, in the hemihydrate form;
and,
(c) separating the precipitated nevirapine
hemihydrate from the aqueous medium by filtration;
(d) washing the separated nevirapine hemihydrate
with water;
(e) optionally milling the dried nevirapine
hemihydrate to obtain a particle size that is suitable for
producing a pharmaceutically acceptable suspension, if the
particles are not already of such size; and,
(f) mixing the dried and optionally milled
nevirapine hemihydrate with water, to obtain the aqueous
suspension.
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Description

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METHODS FOR PREPARING NEVIRAPINE HEMIHYDRATE AND AN AQUEOUS
SUSPENSION THEREOF
This is a divisional application of Canadian
Patent Application No. 2,301,646 filed August 11, 1998.
Background of the Invention
(1) Field of the Invention
The invention relates to a novel composition of
matter which is a pharmaceutical suspension comprising
nevirapine hemihydrate.
The subject matter of this divisional application
is directed to a method of preparing nevirapine hemihydrate
and a method of preparing an aqueous suspension of
nevirapine hemihydrate.
The subject matter of the parent application has
been restricted to pharmaceutical compositions comprising
nevirapine hemihydrate. However, it should be understood
that the expression "the invention" and the like, as used
herein, encompasses the subject matter of both the parent
application and this divisional application.
(2) Description of the Related Arts
Nevirapine, or 11-cyclopropyl-5,11-dihydro-4-
methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, is a
known agent for the treatment of infection by HIV-1 (human
immunodeficiency virus, type 1), which acts through specific
inhibition of HIV-1 reverse transcriptase. Its synthesis
and use are described in various publications including,
inter alia, U.S. Patent Nos. 5,366,972; 5,571,912; and
5,569,760 and Published European Patent Application
No. 0 429 987. Viramune tablets, a pharmaceutical
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comprising nevirapine in tablet form, has recently been
approved by the U.S. Food and Drug Administration for use in
the treatment of HIV-1 infection.
Angel et al. [Proc. 50th Annual Meeting of the
Electron Microscopy Society of America, pp. 1326-1327
(1992)] have disclosed that nevirapine exists as the
hemihydrate stable form and as the anhydrous metastable
form. This same reference describes an attempt to make an
aqueous suspension of nevirapine, suitable for pediatric
use, from the anhydrous form of the compound. The attempt
was unsuccessful because, when formulated in aqueous
suspension, the anhydrous nevirapine slowly converted to the
hemihydrate form, yielding crystals of the hemihydrate
which, over time, grew so large as to adversely affect drug
dissolution and pharmaceutical performance.
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Summary of the Invention
The invention is an aqueous suspension of the
hemihydrate form of nevirapine. It has been found,
unexpectedly, that, when placed in aqueous suspension, the
crystal size of the hemihydrate remains stable over time.
For this reason, aqueous suspensions of nevirapine
hemihydrate are pharmaceutically acceptable. Nevirapine
hemihydrate may be used to treat HIV-1 infection or to
prepare a medicament for treating HIV-1 infection.
According to one aspect of the present invention,
there is provided a method for preparing an aqueous
suspension of nevirapine which method comprises admixing
nevirapine hemihydrate, having a particle size between about
1 and 150 microns, with water.
According to another aspect of the present
invention, there is provided a pharmaceutical composition
consisting essentially of nevirapine hemihydrate, having a
particle size between about 1 and 150 microns, and water.
According to one aspect of the invention of the
present divisional invention, there is provided a method for
preparing nevirapine hemihydrate which method comprises the
steps of: (a) treating an aqueous suspension of anhydrous
nevirapine with a strong acid, to yield a solution of the
acid addition salt; (b) treating the solution of the acid
addition salt produced in the previous step with a strong
base, to yield the free base of nevirapine as a precipitate,
in the hemihydrate form; and, (c) separating the
precipitated nevirapine hemihydrate from the aqueous medium
by filtration; and, (d) washing the precipitated nevirapine
hemihydrate produced in the previous step with water.
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According to another aspect of the invention of
the present divisional invention, there is provided a method
for preparing an aqueous suspension of nevirapine
hemihydrate wherein the crystal size of the nevirapine
hemihydrate is pharmaceutically acceptable and remains
stable over time, which method comprises the steps of: (a)
treating an aqueous suspension of anhydrous nevirapine with
a strong acid, to yield an acid addition salt; (b) treating
the acid addition salt produced in the previous step with a
strong base, to yield the free base of nevirapine as a
precipitate, in the hemihydrate form; and, (c) separating
the precipitated nevirapine hemihydrate from the aqueous
medium by filtration; (d) washing the separated nevirapine
hemihydrate with water; (e) optionally milling the dried
nevirapine hemihydrate to obtain a particle size that is
suitable for producing a pharmaceutically acceptable
suspension, if the particles are not already of such size;
and, (f) mixing the dried and optionally milled nevirapine
hemihydrate with water, to obtain the aqueous suspension.
Detailed Description of the Invention
Anhydrous nevirapine can be made by any of several
known methods, including those described in the references
mentioned above.
The hemihydrate is conveniently produced by
recrystallization of the anhydrous material from an aqueous
medium. This can be accomplished by treating an aqueous
suspension of the anhydrous material, which is a free base,
with a strong acid, such as HC1, to yield the acid addition
salt. The salt is, in turn, treated with a strong base,
such as NaOH, to yield the free base as a precipitate, in
the hemihydrate form. The precipitate is removed from the
aqueous medium by filtration, washed with water and dried
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until the water content is between about 3.1 and 3.9% by
weight. Further drying, which would convert the hemihydrate
to the anhydrous form is to be avoided. The term
hemihydrate is intended to refer to nevirapine which
contains about 0.5 mole of water.
For use in a pharmaceutically acceptable aqueous
suspension, the particle size of the hemihydrate should be
between about 1 and 150 microns in diameter. The
hemihydrate produced as described above can be milled, if
necessary, so that particle size will fall within this
range.
A pharmaceutically acceptable aqueous suspension
of nevirapine hemihydrate can be made by adding the
hemihydrate to purified water, in ratios from 1 to 50 mg
nevirapine hemihydrate to 1 mL of water, followed by
agitation. The formulation can additionally comprise
conventional pharmaceutical additives, such as, but not
limited to, suspending
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agents and/or viscosity thickening agents such as, for example cellulose-basea
poiymers
or synthetic polymers, preferably cross-linked polymers such as the carbomers;
wetting
agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan
fatty acid
esters (polysorbates); sweetening or flavoring agents, such as sucrose; and
preservatives,
such as, for example, the parabens.
By way of non-limiting description, a typical formulation in accordance with
the
invention would be one as described in the following table.
Constituent Range of Amount
(g/l00 mL)
Nevirapine Hemihydrate 0.1 - 50
Carbomer 934P, NF 0.17 - 0.22
Polysorbate 80, NF 0.01 - 0.2
Sorbitol Solution, USP 5- 30
Sucrose, NF 5 - 30
Methylparaben, NF 0.15 - 0.2
Propylparaben, NF 0.02 - 0.24
Sodium Hydroxide, N.F.* q.s. to pH 5.5 - 6.0
Purified Water, USP q.s. ad 100.0 mL
*20% solution prepared
The invention is furthei illustrated by the following non-limiting examples.
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Example I.
Prenaration of nevirapine hemihvdrate
A glass lined reactor containing 318 Kg of nevirapine (anhydrous) is charged
with 319
Kg of 37% HCl at a flow rate to maintain the internal temperature below 35 C.
The
mixture is agitated at 25-35 C until all_material is dissolved. The solution
is filtered and
diluted with 1601iters of purified water. The solution is neutralized with a
25% sodium
hydroxide solution, while maintaining the temperature below 40 C. The
resulting
crystalline suspension is cooled to 15-20 C for 30 minutes. The crystals are
centrifuged
io and washed with purified water and dried at 30-40 C. The crystals are then
dried under
vacuum using a conventional vacuum tumble dryer for 8-24 hours, an air
circulation
tray dryer for 24-72 hours, or a Titus centrifuge dryer (TZD) for 1 to 8
hours. The'
drug substance, which is the hemihydrate, is dried until the water content is
between 3.1
- 3.9% as determined by a moisture balance on 100 C for 30 min.
Example 2
Prenaration of neviranine hemihvdrate
26 g of nevirapine (anhydrous) are suspended in 100 mL of water. To the
stirred
mixture is added 30 mL of concentrated hydrochloric acid with cooling to
maintain the
temperature below 30 C. After 10-to 20 minutes, the colored solution is
filtered and
neutralized by the addition of 14.4 g sodium hydroxide in 50 mL of water. The
resulting precipitate is filtered and washed with water. The wet crystalline
material is
transferred to trays and dried at 35-45 C until a water content of 3.1 to 3.9%
is obtained.
The melting point of the resulting hemihydrate is 242-245 C and analyzes for
3.1 to
3.6% of water, or about 0.5 mole of water.
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Examtfle 3
Preparation of aaueous 50 me/5 ml Dharmaceutical suspension of neviranine
hemihvdrate
Comnosition
Constituent Amount
(g/100 mL)
Nevirapine Hemihydrate 1.035
Carbomer 934P, NF 0.2100
Polysorbate 80, NF 0.05000
Sorbitol Solution, USP 23.13
Sucrose, NF 15.00
Methylparaben, NF 0.1800
Propylparaben, NF 0.02400
Sodium Hydroxide, N.F.* li q.s. to pH 5.5 - 6.0
Purified Water, USP q.s. ad 100.0 mL
*20% solution prepared
Processing Method
A portion of purified water is heated to approximately 70 C and the
methylparaben and propylparaben are added while continuously mixing. Once the
parabens have completely dissolved, the solution is allowed to cool to less
than
35 C, and then the carbomer 934P is dispersed in the preservative solution
while
mixing. The pH is adjusted to pH 5.5 - 5.8 with 20% sodium hydroxide Solution.
The gel is continually stirred for approximately 20 minutes and the pH
remeasured. The sorbitol solution is added while mixing. Then the sucrose is
added and mixing continued for 30 minutes. The polysorbate 80 is dissolved in
a
portion of purified water, the nevirapine is then added to the polysorbate 80
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solution, and the mixture is homogenized for at least 40 minutes. The
nevirapine/polysorbate 80 drug concentrate is thoroughly blended into the
carbomer gel. The suspension is adjusted to volume or weight with purified
water
and blended for 30 minutes.
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