U.S. patent application number 11/521594 was filed with the patent office on 2007-08-30 for methods of stabilizing azithromycin.
Invention is credited to Edit Berger, Julia Hrakovsky, Sarah Isaacs, Lev Khondo, Tania Lessen, Mathi Mathivanan, Michael Pesachovich, Eduard Schwartz, Joseph Schwarz, Claude Singer, Ruth Tenengauzer.
Application Number | 20070199856 11/521594 |
Document ID | / |
Family ID | 38442979 |
Filed Date | 2007-08-30 |
United States Patent
Application |
20070199856 |
Kind Code |
A1 |
Pesachovich; Michael ; et
al. |
August 30, 2007 |
Methods of stabilizing azithromycin
Abstract
A method of packaging of azithromycin which provides improved
stability of azithromycin upon storage. Additionally, compositions
and methods of stabilizing azithromycin compositions are described.
Stabilized azithromycin compositions comprise an intimate admixture
of azithromycin and a stabilizing-effective amount of an
antioxidant to improve the resistance of the azithromycin to
degradation. Coprecipitation or co-milling of azithromycin and an
antioxidant are particularly preferred means of achieving an
intimate admixture. Pharmaceutical formulations comprising a
stabilized azithromycin composition and methods of making such
formulations are also described.
Inventors: |
Pesachovich; Michael;
(Givat-Shmuel, IL) ; Isaacs; Sarah; (Hertzelia,
IL) ; Singer; Claude; (Kfar Saba, IL) ;
Schwartz; Eduard; (Rehovot, IL) ; Berger; Edit;
(Tel-Aviv, IL) ; Tenengauzer; Ruth; (Raanana,
IL) ; Schwarz; Joseph; (Richmond Hill, CA) ;
Hrakovsky; Julia; (Rosh Ha-Ayin, IL) ; Lessen;
Tania; (Toronto, CA) ; Khondo; Lev; (Toronto,
CA) ; Mathivanan; Mathi; (Markham, CA) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
38442979 |
Appl. No.: |
11/521594 |
Filed: |
September 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10782047 |
Feb 19, 2004 |
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11521594 |
Sep 14, 2006 |
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10936075 |
Sep 7, 2004 |
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11521594 |
Sep 14, 2006 |
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10822773 |
Apr 13, 2004 |
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10936075 |
Sep 7, 2004 |
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10247097 |
Sep 19, 2002 |
6669502 |
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10822773 |
Apr 13, 2004 |
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60448946 |
Feb 19, 2003 |
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60336346 |
Oct 18, 2001 |
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60331931 |
Nov 21, 2001 |
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60341295 |
Dec 17, 2001 |
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Current U.S.
Class: |
206/524.4 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 9/2027 20130101; A61K 9/2054 20130101; A61K 9/2013
20130101 |
Class at
Publication: |
206/524.4 |
International
Class: |
B65D 85/84 20060101
B65D085/84 |
Claims
1. A container for packaging azithromycin made of gas impermeable
material wherein after storage azithromycin degradation products do
not exceed 5% by weight of the azithromycin.
2. The container according to claim 1, wherein after storage
azithromycin degradation products do not exceed 3% by weight of
azithromycin.
3. The container according to claim 1, wherein the gas impermeable
material is laminated aluminum.
4. The container according to claim 1, wherein the container
comprises at least two layers of gas impermeable material, wherein
at least one of those layers is aluminum.
5. The container according to claim 1, wherein the azithromycin is
azithromycin solvate.
6. The container according to claim 5, wherein the azithromycin is
selected from the group consisting of ethanol solvate, propanol
solvate, and a hydrate.
7. The container according to claim 6, wherein the azithromycin is
monohydrate azithromycin.
8. A container for packaging azithromycin monohydrate made of gas
impermeable material wherein after storage less than about 5% of
azithromycin monohydrate is transformed to azithromycin dihydrate
upon storage of one year.
9. The container according to claim 8, wherein the gas impermeable
material is laminated aluminum.
10. The container according to claim 1, wherein the container is in
the form of a bag or pouch.
11. The container according to claim 1, wherein the gas impermeable
material is impermeable to oxygen.
12. The container according claim 1, wherein the gas impermeable is
on the interior of the container.
13. The container according to claim 1, wherein the azithromycin is
stored at a temperature of about 25.degree. C. to about 55.degree.
C.
14. The container according to claim 1, wherein the azithromycin is
stored at 60% relative humidity.
15. The container according to claim 1, wherein the azithromycin is
stored for at least one month.
16. The container according to claim 1, wherein the degradation
products are identified by HPLC relative to retention times of
about 0.26, 0.34, 0.37, or 0.80 as compared to azithromycin.
17. A method for storing azithromycin comprising packaging
azithromycin in a container comprising a gas impermeable material
wherein after storage azithromycin degradation products do not
exceed 5% by weight of the azithromycin.
18. The method according to claim 17, wherein the gas impermeable
material is laminated aluminum.
19. The method according to claim 18, wherein the container
comprises at least two layers of gas impermeable material, wherein
at least one of those layers is laminated aluminum.
20. A dry blend, used for forming azithromycin tablets by direct
compression, comprising: (a) azithromycin obtained from the
packaging of claim 1; and (b) at least one pharmaceutically
acceptable excipient, wherein said azithromycin is not azithromycin
dihydrate.
21-102. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation in part of U.S.
application Ser. No. 10/782,047, filed Feb. 19, 2004, which claims
the benefit of priority to U.S. provisional application Ser. No.
60/448,946, filed Feb. 19, 2003, herein incorporated by reference.
This application is also a continuation in part of U.S. application
Ser. No. 10/936,075, filed Sep. 7, 2004, which is a continuation of
U.S. application Ser. No. 10/822,773, filed Apr. 13, 2004, which is
a continuation of U.S. application Ser. No. 10/247,097, filed Oct.
18, 2002, which claims the benefit of priority to U.S. provisional
application Ser. Nos. 60/336,346, filed Oct. 18, 2001; 60/331,931,
filed Nov. 21, 2001; and 60/341,295, filed Dec. 17, 2001, herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses methods of packaging azithromycin
to prevent the degradation of azithromycin upon storage. The
invention also relates to stabilized azithromycin compositions,
methods of preparing stabilized azithromycin compositions,
pharmaceutical formulations containing the stabilized azithromycin
compositions and methods of making such formulations.
BACKGROUND OF THE INVENTION
[0003] Azithromycin has the chemical name
[2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-13-[(2,6-dideoxy-3-C--
methyl-3-O-methyl-.alpha.-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydr-
oxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-.be-
ta.-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one and
the following chemical structure: ##STR1##
[0004] Azithromycin is one of the macrolide antibiotics, so named
because they contain a many-membered lactone ring to which are
attached one or more deoxy sugars. Other macrolide antibiotics
include erythromycin and clarithromycin. Azithromycin and the other
macrolide antibiotics are bacteriostatic agents which act by
binding to the 50S ribosomal subunit of susceptible microorganisms,
and thus interfering with microbial protein synthesis.
[0005] Macrolide antibiotics of the erythromycin class, such as
erythromycin A, are known to be unstable in an acidic environment
and are inactivated by gastric acids. See, Goodman and Gilman's,
The Pharmacological Basis of Therapeutics 1137 (Joel G. Hardman et
al., eds.) 9th ed. 1996; C. Vinckier et al., Int. J. Pharmaceutics,
55, 67-76 (1989); T. Cachet et al., Int. J. Pharmaceutics, 55,
59-65 (1989); E. F. Fiese and S. H. Steffen, J. Antimicrobial
Chemother., 25 (suppl.A) 39-47 (1990).
[0006] Azithromycin is a semi-synthetic antibiotic which differs
chemically from erythromycin in that a methyl-substituted nitrogen
atom is incorporated into the lactone ring. The replacement of the
keto group in the lactone ring with the N-methyl group in the
lactone ring improves the stability of azithromycin over
erythromycin in an acidic environment.
[0007] U.S. Pat. Nos. 4,517,359 and 4,474,768 disclose processes
for the preparation of azithromycin and the use of azithromycin as
an antibiotic. These patents are incorporated herein by
reference.
[0008] Azithromycin is subject to degradation that may occur during
manufacture and/or storage. For example, azithromycin is
susceptible to degradation if exposed to elevated temperatures
and/or air during manufacturing processes, processes that include
formulation of the pharmaceutical dosage form. One particular
example of oxidative degradation is the oxidation of the exocyclic
amine group of azithromycin. The susceptibility of azithromycin to
degradation may lead to deviation of the drug product from
regulatory purity requirements even prior to the product reaching
the patient. In addition, once formulated, azithromycin tends to
degrade under normal storage conditions, which may result in the
presence of unacceptable levels of impurities at the time of
administration.
[0009] Therefore, a continuing need exists to provide consistent
dosages of azithromycin by providing methods that delay or prevent
the production of degradation products by improving storage methods
for azithromycin. Likewise, a continuing need exists to provide
azithromycin compositions having a reduced tendency to degrade.
SUMMARY OF THE INVENTION
[0010] In some embodiments, the invention encompasses methods for
packaging azithromycin which show improved stability of
azithromycin upon storage.
[0011] For example, one embodiment encompasses methods for
packaging azithromycin comprising storing azithromycin in a gas
impermeable package made of at least one sheet of gas impermeable
material, wherein after storage azithromycin degradation products
do not exceed 5%, preferably less than about 3% by weight of
azithromycin. The gas impermeable material is impermeable to
oxidizing agents, preferably to oxygen. The gas impermeable package
may be selected from any material known in the art. The sheet may
be a laminated sheet preferably an aluminum laminate package. The
package may be comprised of a bag or a pouch.
[0012] Another embodiment of the invention encompasses methods for
storing azithromycin comprising storing azithromycin in a gas
impermeable package comprising at least one layer, wherein the
intimate layer is prepared from a gas impermeable material and is
capable of being sealed. The gas impermeable material may be
selected from any material known in the art. The gas impermeable
material is preferably an aluminum laminate. After the storage
azithromycin degradation products do not exceed 5%, preferably less
than about 3% by weight of the azithromycin. In another embodiment,
the azithromycin storage conditions include at least one of a
temperature of about 25.degree. C. to about 55.degree. C.; 60%
relative humidity; or a time of at least one month.
[0013] Another embodiment of the invention encompasses methods for
packaging azithromycin comprising storing a unit dosage of
azithromycin in a gas impermeable package. The gas impermeable
package may be selected from any material known in the art. The gas
impermeable package is preferably an aluminum laminate package.
[0014] Another embodiment of the invention encompasses methods for
packaging azithromycin wherein less than about 5% of azithromycin
monohydrate is transformed to the dihydrate form on storage for one
year.
[0015] The degradation products may be identified by HPLC relative
retention times of about 0.26, 0.34, 0.37, and 0.80.
[0016] In another embodiment, the invention is directed to
stabilized azithromycin compositions. A stabilized azithromycin
composition preferably includes an intimate admixture of
azithromycin and a stabilizing-effective amount of an antioxidant.
Coprecipitation and co-milling of azithromycin and an antioxidant
are particularly preferred methods of achieving an intimate
admixture.
[0017] Another embodiment of the invention is directed to, a method
for preparing a stabilized azithromycin composition. The method
comprises dissolving azithromycin and a stabilizing-effective
amount of an antioxidant in a solvent and co-precipitating the
azithromycin and antioxidant, and, recovering a stabilized
azithromycin composition.
[0018] Stabilized azithromycin compositions can also be prepared by
dissolving azithromycin and a stabilizing-effective amount of an
antioxidant in a first solvent to form a mixture; drying the
mixture; redissolving the mixture in a second solvent;
co-precipitating azithromycin and the antioxidant and recovering a
stabilized azithromycin composition.
[0019] Yet another method for making a stabilized azithromycin
composition in accordance with the present invention includes
co-milling azithromycin and a stabilizing-effective amount of an
antioxidant. In this embodiment, co-milling may be achieved by, for
example, grinding the azithromycin and antioxidant together by
conventional means such as using a mortar and pestle or
co-micronization processes as are generally known in the art.
[0020] Once a stabilized azithromycin composition is prepared in
accordance with the present invention, it is preferably formulated
into pharmaceutical formulations such as conventional dosage forms,
including tablets, capsules (e.g., hard and soft gelatin capsules),
suspensions, sachets, dragees, suppositories, etc. Tablets are
preferred dosage forms. Tablets may be made with the stabilized
azithromycin compositions and optional excipients by processes
including, e.g., wet granulation, dry granulation such as slugging
or compaction, or direct compression, followed by shaping into
tablets.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 illustrates the X-ray powder diffraction pattern for
azithromycin Form A.
[0022] FIG. 2 illustrates the X-ray powder diffraction pattern for
the dihydrate.
[0023] FIG. 3 is an HPLC chromatogram depicting elution profiles of
azithromycin standards.
[0024] FIG. 4 is an HPLC chormoatogram depicting typical elution
profiles of azithromycin impurities.
[0025] FIG. 5.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0026] Unless otherwise indicated, the term "azithromycin" includes
salts, solvates, hydrates thereof, and physiologically functional
derivatives thereof, e.g. propanol solvate, ethanol solvate,
monohydrate and other crystalline and polymorph forms.
[0027] The term "Form A" refers to a crystalline form of
azithromycin having an X-ray powder diffraction with peaks at 6.3,
8.0, 10.0, 11.4, 11.6, 12.0, 12.6, 14.0, 14.5, 14.7, 15.0, 15.4,
15.9, 17.3, 18.7, 19.1, 20.0, 20.3, and 21.2 degrees two-theta. The
peaks of Form A are listed in FIG. 1.
[0028] The term "dihydrate azithromycin" refers to a crystalline
form of azithromycin having an X-ray powder diffraction with peaks
at 9.3, 12.1, 13.0, 16.4, and 18.7 degrees two-theta. The peaks of
the dihydrate are listed in FIG. 2.
[0029] As used herein, the term "AZT" refers to azithromycin. As
used herein, the term "DMAZT" refers to azithromycin A (USP),
desmethyl azithromycin. DMZAT is an intermediate used in the
synthesis of azithromycin. The term "TAZT" refers to tosyl
azithromycin. The term "BH" refers to butylated hydroxyanisole. The
term "BHT" refers to butylated hydroxytoluene. The term "PG" refers
to propyl gallate. The term "PVP" refers to polyvinylpyrrolidone.
The term "SLS" refers to sodium lauryl sulfate. The term "LOD"
refers to loss on dry. The terms "API" and "Apr" refers to active
pharmaceutical ingredient. The term "intimate layer" refers to the
layer of gas impermeable packaging which contacts the stored
material.
[0030] As used herein, the term "gas impermeable" refers to a
property of a material wherein the passage of gases through the
material is delayed or prohibited. As used with packaging, "gas
impermeable" refers to the packaging of products having improved
barrier characteristics better than those of low density
polyethylene (LDPE) having been manufactured by coextrusion,
lamination, metallization, or coating.
[0031] As used herein, the term "unit dosage form" refers to the
amount of azithromycin, or a derivative thereof, which is effective
to produce a therapeutic effect in a subject.
[0032] As used herein, the term "lamination" refers to a situation
when two or more individuals films are bonded together with special
adhesives and run through rolling, heated cylinders to produce a
composite film structure.
[0033] The term "stabilizing-effective amount," used in reference
to the amount of antioxidant in the stabilized azithromycin
composition, means (1) an amount such that no more than about 3.8%,
preferably no more than about 1.2%, and, most preferably, no more
than about 0.86% by weight of azithromycin in the stabilized
azithromycin composition is degraded upon exposure to 55.degree. C.
for seven days or, (2) an amount such that no more than about
1.25%, preferably no more than about 0.8%, and, most preferably, no
more than about 0.35% by weight of azithromycin in the stabilized
azithromycin composition is degraded upon exposure to 50.degree. C.
for 20 hours.
DESCRIPTION OF THE INVENTION
[0034] Azithromycin is unstable and prone to produce degradation
products upon manufacture and/or storage and/or when exposed to
temperatures above about 25.degree. C. Not to be bound by theory,
it is believed that one degradation pathway is the oxidation of
azithromycin in the presence of oxidizing agents, such as oxygen.
The degradation products may be identified by HPLC relative
retention times of about 0.26, 0.34, 0.37, and 0.80.
[0035] Thus, in one aspect, the invention encompasses methods of
storing azithromycin and containers for storing azithromycin
comprising at least one gas impermeable material wherein the
containers diminish or protect azithromycin from either: a)
degradation, in particular degradation by oxidation, or b) changing
of azithromycin solvate composition (water or solvent or a
combination thereof as compared to the composition before AZT is
packaged).
[0036] The advantage of using at least one gas impermeable
container to protect azithromycin from oxidation is the increase in
azithromycin shelf life.
[0037] Also, the invention encompasses containers for storing
azithromycin comprising at least one gas impermeable material
effective to protect azithromycin from degradation, especially at
elevated temperatures.
[0038] One embodiment of the invention encompasses containers for
storing azithromycin comprising a container having at least one gas
impermeable material and capable of being sealed. Generally, the
container may include bottles, jar, pouches, envelopes, bags, and
the like. Preferably, the container is in the form of a pouch or
bag and comprises at least one gas impermeable material in the form
of a sheet. The gas impermeable package may be selected from any
material known in the art to be gas impermeable. Preferably, the
material is oxygen and/or air impermeable. Preferably, the material
is in the form of at least one laminate aluminum containing
polymer. More preferably, the material is in the form of laminate
aluminum containing polymer. An example of the polymer is
polyethylene. The sheet may contact itself to form an envelope or a
bag or may contact a second sheet of gas impermeable material to
form a cavity wherein the azithromycin is placed.
[0039] There may be a better stabilizing effect of proposed double
aluminum laminate instead of polyethylene in aluminum laminate.
[0040] Another embodiment of the invention encompasses methods for
storing azithromycin comprising placing azithromycin in a container
comprising at least one gas impermeable layer having an exterior
and an intimate layer, wherein the intimate layer is prepared from
a gas impermeable material and is capable of being sealed. The
azithromycin may be in the form of a unit dosage of azithromycin.
The unit dosage form may be a 250 mg, 500 mg, or 600 mg unit.
[0041] Another embodiment of the invention encompasses methods for
packaging azithromycin, wherein the packaging delays or prevents
azithromycin from degradation caused by water, oxygen, or both. As
used herein, the term "delay or prevents degradation" as applied to
azithromycin refers to the formation of no more than 5% by weight
of azithromycin degradation products, preferably, no more than 3%
by weight of degradation products. In another embodiment, the
azithromycin storage conditions include at least one of a
temperature of about 25.degree. C. to about 55.degree. C.; 60%
relative humidity; or a time of at least one month. Alternatively,
the packaging allows for less than about 5% of azithromycin
monohydrate to transform to azithromycin dihydrate upon storage for
one year. In another embodiment, the azithromycin storage
conditions include at least one of a temperature of about
25.degree. C. to about 55.degree. C.; wherein at 55.degree. C. with
uncontrolled humidity the azithromycin monohydrate is stable for at
least one month, preferable for at least 3 months, and wherein at
25.degree. C. with 60% relative humidity, the azithromycin
monohydrate is stable for at least one month, preferable at least 3
months and more preferably for at least one year.
[0042] The regular packaging material, which is used for stability
studies, is polyethylene of low density wrapped into aluminum
laminate. The polyethylene of low density is penetrable for
gases.
[0043] The stability of azithromycin is substantially increased
when the material is packed directly in aluminum laminate bags. Use
of this packaging material enables one to store safely the
azithromycin at normal temperatures.
[0044] It has also been found that the addition of antioxidants to
azithromycin protects azithromycin from degradation at elevated
temperatures, which may be due to oxidation and/or other means.
[0045] Thus, some of embodiments of the present invention are
directed to a stabilized azithromycin composition. In several
embodiments, the azithromycin used is azithromycin ethanolate
monohydrate. Azithromycin ethanolate monohydrate is a stable
azithromycin compound disclosed in U.S. Pat. No. 6,365,574, which
is incorporated herein by reference.
[0046] In one embodiment, the stabilized azithromycin composition
comprises azithromycin and an stabilizing-effective amount of an
antioxidant. As used herein, "antioxidant" refers to a substance
known to inhibit oxidation. Among preferred antioxidants suitable
for use in accordance with the present invention are included
ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbic
palmitate, butylated hydroxyanisole, butylated hydroxytoluene,
2,4,5-trihydroxybutyrophenone,
4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum
guaiac, propyl gallate, thiodipropionic acid, dilauryl
thiodipropionate, tert-butylhydroquinone and tocopherols such as
vitamin E, and the like, including pharmaceutically acceptable
salts and esters of these compounds. Preferably, the antioxidant is
a food grade antioxidant, however any antioxidant which is
generally recognized as pharmaceutically acceptable may be
used.
[0047] More preferably, the antioxidant is butylated
hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic
acid, pharmaceutically acceptable salts or esters thereof, or
mixtures thereof. Most preferably, the antioxidant is butylated
hydroxytoluene or sodium ascorbate.
[0048] Preferably, the antioxidant is present in the stabilized
azithromycin compositions in an effective amount to retard or
prevent degradation of azithromycin, thereby stabilizing the
azithromycin. Preferably, the amount of antioxidant is in the range
of about 0.01-10% by weight azithromycin. More preferably, the
amount of antioxidant is in the range of about 0.1-5% by weight
azithromycin. In preferred embodiments, (1) the amount of
antioxidant used is such that no more than about 3.8%, preferably
no more than about 1.2%, and, most preferably, no more than about
0.86% by weight of azithromycin in the stabilized azithromycin
composition is degraded upon exposure to 55.degree. C. for seven
days, or (2) the amount of antioxidant used is such that no more
than about 1.25%, preferably no more than about 0.8%, and, most
preferably, no more than about 0.35% by weight of azithromycin in
the stabilized azithromycin composition is degraded upon exposure
to 50.degree. C. for 20 hours.
[0049] In another aspect, the present invention is directed to a
method for manufacturing a stabilized azithromycin composition.
[0050] In one embodiment, the stabilized azithromycin composition
is made by the addition of an antioxidant to a solution of
azithromycin before crystallizing the azithromycin from the
solution. Upon crystallization, a co-precipitate of azithromycin
and antioxidant is formed and recovered from the solution. The
co-precipitate comprises azithromycin and antioxidant in intimate
admixture. The stabilized composition of azithromycin may then be
formulated into suitable dosage forms with conventional
excipients.
[0051] In another embodiment, the stabilized azithromycin
composition is made by the addition of an antioxidant to an
azithromycin solution at the onset of crystallization of
azithromycin from the solution. A co-precipitate of azithromycin
and antioxidant is formed and recovered from the solution. The
co-precipitate comprises azithromycin and antioxidant in intimate
admixture. The stabilized composition of azithromycin may then be
formulated into suitable dosage forms with conventional
excipients.
[0052] In yet another embodiment, a stabilized azithromycin
composition is made by addition of an antioxidant to an
azithromycin solution and the partial or total evaporation of the
solvent. Preferably, this embodiment comprises the steps of: 1)
dissolving azithromycin and an antioxidant in a first solvent; 2)
evaporating the first solvent to form a dry residue; 3)
redissolving the dry residue in a second (not necessarily
different) solvent; 4) crystallizing azithromycin and 5) adding
additional antioxidant at the onset of crystallization. A
co-precipitate of azithromycin and antioxidant is formed and
recovered from the solution. The co-precipitate comprise
azithromycin and antioxidant in intimate admixture. The stabilized
composition of azithromycin may then be formulated into suitable
dosage forms with conventional excipients.
[0053] The preferred solvent in the disclosed methods is an
alcohol. More preferably, the solvent is a lower straight or
branched-chain alkanol such as ethanol, propanol, isopropanol,
etc.
[0054] In still another embodiment, a stabilized azithromcyin
composition is made by co-milling azithromycin and antioxidant to
form an intimate admixture. Co-milling may be done by grinding the
azithromycin and antioxidant using conventional methods such as
with a mortar and pestle or by co-micronizing the azithromycin and
antioxidant.
[0055] In another aspect, the present invention is directed to
pharmaceutical formulations comprising a stabilized azithromycin
composition as described herein and methods for making such
pharmaceutical formulations. The pharmaceutical formulations
typically contain, in addition to the stabilized azithromycin
composition, one or more pharmaceutically acceptable excipients,
such as binders, fillers, disintegrants, carriers, lubricants,
glidants, flavorants, colorants, buffers, thickening agents, etc.
Some excipients can serve multiple functions, for example as both
binder and disintegrant.
[0056] The pharmaceutical formulations comprising a stabilized
azithromycin composition include dosage forms such as tablets,
granulates, dragees, hard or soft capsules, powders, solutions,
emulsions, suspensions, or the like. Tablets are particularly
preferred dosage forms of the pharmaceutical formulations in
accordance with the present invention. Among the methods for
forming preferred tablet dosage forms are included, e.g., wet
granulation, dry granulation, e.g., compaction and slugging, and
direct compression.
[0057] Examples of tablet disintegrants useful in accordance with
the present invention are starch, pregelatinized starch, sodium
starch glycolate, sodium carboxymethylcellulose, cross inked sodium
carboxymethylcellulose (sodium croscarmellose; crosslinked starch
available under the registered trademark Ac-Di-Sol from FMC Corp.,
Philadelphia, Pa.), clays (e.g. magnesium aluminum silicate),
microcrystalline cellulose (of the type available under the
registered trademark Avicel from FMC Corp. or the registered
trademark Emcocel from Mendell Corp., Carmel, N.Y.), alginates,
gums, surfactants, effervescent mixtures, hydrous aluminum
silicate, cross-linked polyvinylpyrrolidone (available commercially
under the registered trademark PVP-XL from International Specialty
Products, Inc.), and others as known in the art.
[0058] Among preferred disintegrants are sodium croscarmellose
(Ac-Di-Sol), sodium starch glycolate (available commercially under
the registered trademarks Primojel from Avebe (Union, N.J.) or
Generichem, (Little Falls, N.J.), pregelatinized starch and
Explotab from Mendell Corp.), microcrystalline cellulose (Avicel),
and cross-linked polyvinylpyrrolidone (PVP-XL).
[0059] Examples of binders include, e.g., acacia, cellulose
derivatives (such as methylcellulose and carboxymethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose), gelatin, glucose, dextrose, xylitol,
polymethacrylates, polyvinylpyrrolidone, starch paste, sucrose,
sorbitol, pregelatinized starch, gum tragacanth, alginic acids and
salts thereof such as sodium alginate, magnesium aluminum silicate,
polyethylene glycol, guar gum, bentonites, and the like.
[0060] Flavors incorporated in the composition may be chosen from
synthetic flavor oils and flavoring aromatics and/or natural oils,
extracts from plants leaves, flowers, fruits, and so forth and
combinations thereof. These may include cinnamon oil, oil of
wintergreen, peppermint oils, clove oil, bay oil, anise oil,
eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage,
oil of bitter almonds, and cassia oil. Also useful as flavors are
vanilla, citrus oil, including lemon, orange, grape, lime and
grapefruit, and fruit essences, including apple, banana, pear,
peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and
so forth. The amount of flavoring may depend on a number of factors
including the organoleptic effect desired. Generally the flavoring
will be present in an amount of from 0.5 to about 3.0 percent by
weight based on the total tablet weight, when a flavor is used.
[0061] A variety of materials may be used as fillers or diluents.
Examples are spray-dried or anhydrous lactose, sucrose, dextrose,
mannitol, sorbitol, starch (e.g. starch 1500), cellulose (e.g.
microcrystalline cellulose; Avicel), dihydrated or anhydrous
dibasic calcium phosphate (available commercially under the
registered trademark Emcompress from Mendell or A-Tab and Di-Tab
from Rhone-Poulenc, Inc., Monmouth Junction, N.J.), calcium
carbonate, calcium sulfate, and others as known in the art. A
preferred filler in accordance with the present invention is
dibasic calcium phosphate dihydrate or anhydrous.
[0062] Lubricants can also be employed herein in the manufacture of
certain dosage forms, and will usually be employed when producing
tablets. Examples of lubricants are magnesium stearate, talc,
stearic acid, glycerylbehenate, polyethylene glycol, ethylene oxide
polymers (for example, available under the registered trademark
Carbowax from Union Carbide, Inc., Danbury, Conn.), sodium lauryl
sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl
fumarate, DL-leucine, colloidal silica, and others as known in the
art. Preferred lubricants are magnesium stearate, and mixtures of
magnesium stearate with sodium lauryl sulfate. Lubricants generally
comprise 0.5 to 7.0% of the total tablet weight.
[0063] Other excipients such as glidants and coloring agents may
also be added to azithromycin tablets. Coloring agents may include
titanium dioxide and/or dyes suitable for food such as those known
as F. D. & C, dyes and natural coloring agents such as grape
skin extract, beet red powder, beta carotene, annato, carmine,
turmeric, paprika, and so forth. A coloring agent is an optional
ingredient in the compositions of this invention, but when used
will generally be present in an amount up to about 3.5 percent
based on the total tablet weight.
[0064] As known in the art, tablet blends may be dry-granulated or
wet granulated before tableting. Alternatively, tablet blends may
be directly compressed. The choice of processing approach depends
upon the properties of the drug and chosen excipients, for example
particle size, blending compatibility, density and flowability. For
azithromycin tablets, granulation is preferred, with wet
granulation being most preferred. The stabilized azithromycin
composition may be wet-granulated, and then other excipients may be
added extragranularly. Alternatively, the stabilized azithromycin
composition and one or more excipients may be wet-granulated. Dry
granulation, such as compaction and/or slugging with or without an
intragranular excipient may also be used to make the tablets,
followed by tabletting with or without extragranular excipients. In
addition, tablets may also be coated, with a coating that exhibits
little or no effect on or interference with tablet dissolution, to
assure ease of swallowing or to provide an elegant appearance.
[0065] Tablets may be film-coated to provide ease of swallowing and
an elegant appearance. Many polymeric film-coating materials are
known in the art, including, e.g., hydroxypropylmethylcellulose
(HPMC). HPMC may be obtained commercially, for example from
Colorcon Corp., in coating formulations containing excipients which
serve as coating aids, under the registered trademark Opadry.
Opadry formulations may contain lactose, polydextrose, triacetin,
polyethyleneglycol, polysorbate 80, titanium dioxide, and one or
more dyes or lakes. Other suitable film-forming polymers also may
be used herein, including, hydroxypropylcellulose, and
acrylate-methacrylate copolymers.
[0066] Conventional tableting processes are employed, e.g., by
forming a tablet from a desired blend or mixture of ingredients
into the appropriate shape using a conventional tablet press.
Tablet formulation and conventional processing techniques have been
widely described, for Example in Pharmaceutical Dosage Forms:
Tablets; Edited By Lieberman, Lachman, and Schwartz; Published by
Marcel Dekker, Inc., 2d Edition, Copyright 1989, the text of which
is herein incorporated by reference.
[0067] The azithromycin dosage forms of this invention also include
powders to make oral suspensions, and also the oral suspensions
themselves. Generally the powder is a non-caking, free flowing
powder which is sold direct to pharmacies or other retail outlets
and then made up into the actual suspension by a pharmacist. The
oral suspension is thus the actual dosage form ingested by
patients.
[0068] Azithromycin suspensions may contain, e.g., in addition to a
stabilized azithromycin composition, one or more thickening agents,
a buffer or pH-altering agent. Dispersing agents may also be used
to facilitate formation of a suspension.
[0069] Suitable thickening agents function as suspending agents and
include, for example, hydrocolloid gums known for such purpose,
examples of which include xanthan gum, guar gum, locust bean gum,
gum tragacanth, and the like. Alternatively, synthetic suspending
agents may be used such as sodium carboxymethylcellulose,
polyvinylpyrrolidone, hydroxypropylcellulose and the like.
Dispersing agents include colloidal silicon dioxide, available from
Cabot Corporation, Boston, Mass. under the trade designation
Cab-O-Sil.
[0070] A powder used to make a suspension may also contain
conventional optional ingredients such as (1) wetting agents such
as sorbitan monolaurate, polysorbate 80, and sodium lauryl sulfate;
(2) anti-foaming agents and (3) sweeteners and fillers such as
glucose. The powder may also contain a buffer to maintain a high pH
upon reconstitution, as discussed above. Suitable buffers and
pH-altering agents include tribasic sodium phosphate, anhydrous
sodium carbonate, glycine, and the like. Suitable preservatives are
well known, for example sodium benzoate and the like.
[0071] A stabilized azithromycin composition in accordance with the
present invention may be formulated in a unit dose packet dosage
form or sachet. Such a packet will typically contains a blend of
azithromycin and excipients which is thus reconstituted. In
addition to a stabilized azithromycin composition in accordance
with the present invention, the packet may contain, for example, a
dispersing agent which makes the sachet powder free flowing, for
example colloidal silicon dioxide such as Cab-O-Sil from Cabot. The
dispersing agent may also serve as a glidant. The formulation may
also optionally contain ingredients including (1) a filler or
sweetener (e.g. glucose); (2) a buffer (e.g. sodium phosphate); (3)
a wetting agent such as a surfactant, for example sodium lauryl
sulfate, and (4) flavors such as any of those enumerated herein,
and the like. The powder in the packet flows freely and disperses
quickly, essentially immediately upon stirring when
reconstituted.
EXAMPLES
[0072] Although the following examples illustrate the practice of
the present invention in some of its embodiments, the examples
should not be construed as limiting the scope of the invention.
Other embodiments will be apparent to one skilled in the art from
consideration of the specification and examples.
Example 1
[0073] Several azithromycin samples were analyzed using HPLC to
determine the level of impurities within each sample. The
analytical conditions of the HPLC were column of 150.times.4.6 mm;
packing material of Kromasil KR 100-5C18, 5.PHI.; and an eluent of
40% 0.05 M K.sub.2HPO.sub.4 adjusted to a pH of 8.2 and 60%
acetonitrile. The flow rate was 0.9 ml/min; the detector set at 210
nm; and column temperature of 30.degree. C. The samples were
injected into the HPLC and run for over 35 min. The impurities were
determined by their relative retention times (RRT) as compared to
azithromycin and were reported as a weight percent (versus
azithromycin) of the total composition. Additional impurities found
in the samples were reported under "other RRT" as a weight percent
of the azithromycin content. The results of the analytical tests is
summarized in Table A. Table A demonstrates a finding of the main
azithromycin degradation products where azithromycin batches have
been stored under uncontrolled temperature conditions (25.degree.
C. and higher) in regular packages (intimate package is LDPE and
exterior is aluminum laminate). The lowest row of the table sums up
each impurity content for all batches. The raw data reveals that
the main degradants of azithromycin upon storage are RRT 0.26,
0.34, 0.37, and 0.80. TABLE-US-00001 RRT (%) Other Total AZT Batch
0.16 0.18 0.23 0.26 0.34 0.37 0.40 0.49 0.60 0.80 0.88 RRT % %
Batch 1 ND <0.1 ND 0.13 0.45 0.14 ND ND ND 0.25 ND 0.45 1.7
Batch 2 ND <0.1 ND ND 0.32 <0.1 ND ND ND 0.24 ND 0.49 1.3
Batch 3 0.15 ND ND 0.16 0.64 0.32 ND ND ND <0.1 ND 0.64 1.5
Batch 4 ND ND ND <0.1 <0.1 <0.1 ND <0.1 ND <0.1 ND
0.00 0.0 Batch 5 ND ND ND <0.1 <0.1 <0.1 ND <0.1 ND
0.11 ND 0.11 0.2 Batch 6 ND <0.1 ND <0.1 ND <0.1 <0.1
<0.1 ND ND ND 0.00 0.0 Batch 7 ND <0.1 ND <0.1 <0.1
<0.1 ND ND ND ND ND 0.16 0.2 Batch 7 ND <0.1 ND 0.41 0.37
0.23 0.22 ND ND 0.20 ND 0.41 1.4 Batch 8 ND <0.1 ND 0.14 0.16
<0.1 ND ND ND ND ND 0.16 0.4 Batch 8 ND <0.1 ND 0.28 0.28
0.19 0.21 ND ND 0.14 ND 0.28 1.2 Batch 9 ND ND ND ND <0.1
<0.1 ND ND ND ND ND 0.00 0.0 Batch 9 ND ND ND 0.29 0.40 0.17 ND
<0.1 ND 0.12 ND 0.40 1.2 Batch 10 ND ND <0.1 ND 0.13 <0.1
ND ND ND <0.1 ND 0.13 0.2 Batch 10 ND ND ND <0.1 0.18 0.11 ND
0.10 ND <0.1 ND 0.18 0.5 Batch 11 ND ND ND <0.1 0.13 <0.1
ND <0.1 ND <0.1 ND 0.16 0.4 Batch 12 <0.1 ND <0.1 0.18
0.23 <0.1 <0.1 ND ND <0.1 ND 0.23 0.5 Sum of 0.15 0.00
0.00 1.59 3.29 1.16 0.43 0.10 0.00 1.06 0.00 impurities
Example 2
Storage Testing
[0074] Three samples of azithromycin were separately packaged in a
standard polyethylene bag, and then the polyethylene bags
containing azithromycin were separately packaged into aluminum bags
with silica gel. The stored azithromycin was submitted to stability
programs either long term or accelerated to determine the effect
upon azithromycin stability and the production of degradation
products. The longer term stability program comprised submitting
the sample to a temperature of about 25.degree. C..+-.2.degree. C.
at a relative humidity of 60%.+-.5%. The accelerated program
comprised submitting the sample to a temperature of about
40.degree. C..+-.2.degree. C. at a relative humidity of 75%+5%. The
samples were analyzed at regular intervals to determine the
impurity profiles as assayed by HPLC using the technique described
in Example 1. The water content was determined by Karl Fischer
methodology; and the ethanol content was determined by gas
chromatography. The results of these tests are summarized in Table
B, where "Any %" means any kind of impurity that gives the highest
content in azithromycin. TABLE-US-00002 TABLE B Azithromycin
Stability in polyethylene bag Impurities AZT Time Temp. Any Total %
% Batch (months) (.degree. C.) % % Water Ethanol Batch 0 0.12 0.33
2.99 2.2 No. 4 3.sup.a 25.degree. C. 0.55 2.14 2.97 2.2 1.sup.b
40.degree. C. 0.45 1.93 3.13 2.1 2.sup.b 0.65 3.10 2.65 1.8 3.sup.b
0.77 3.71 2.95 1.8 Batch 0 0.12 0.22 3.83 1.9 No. 5 3.sup.a
25.degree. C. 0.49 2.17 2.93 1.8 1.sup.b 40.degree. C. 0.43 1.77
3.22 1.8 2.sup.b 0.72 2.78 2.86 1.6 3.sup.b 1.11 5.07 3.27 1.5
Batch 0 <0.1% <0.1% 3.78 2.0 No. 6 3.sup.a 25.degree. C. 0.32
1.40 2.75 2.0 1.sup.b 40.degree. C. 0.44 1.71 3.21 1.9 2.sup.b 0.62
2.08 2.80 1.9 3.sup.b 0.81 3.94 3.12 1.7 .sup.aLong term program.
.sup.bAccelerated program.
[0075] Evaluation of results shown in Table B demonstrated that
more degradation products were produced at higher temperatures,
i.e. 40.degree. C., as compared to either the starting material or
at lower temperatures, i.e. 25.degree. C. Table C contains a
detailed presentation of the impurity profile for the tested
batches wherein the impurities were reported as by RRT and weight
percentage of the total composition. TABLE-US-00003 TABLE C
Extended Analytical Profile for Azithromycin AZT Time Temp
Impurities RRT (%) Batch (months) .degree. C. 0.26 0.35 0.38 0.40
0.82 Batch 0 <0.1 0.12 <0.1 <0.1 No. 4 3.sup.a 25 0.40
0.43 0.29 0.21 0.34 1.sup.b 40 0.45 0.42 0.28 0.22 0.31 2.sup.b
0.65 0.61 0.50 0.22 0.46 3.sup.b 0.72 0.77 0.50 0.37 0.61 3.sup.b
55 0.78 0.91 0.61 0.34 0.73 Batch 0 <0.1 <0.1 <0.1 <0.1
0.12 No. 5 3.sup.a 25 0.49 0.46 0.44 0.15 0.18 1.sup.b 40 0.39 0.43
0.23 0.25 0.25 2.sup.b 0.59 0.72 0.37 0.19 0.35 3.sup.b 1.41 0.76
0.72 0.19 0.52 3.sup.b 55 1.27 1.19 1.22 0.06 0.91 Batch 0 <0.1
<0.1 <0.1 <0.1 <0.1 No. 6 3.sup.a 25 0.31 0.32 0.3 0.1
0.12 1.sup.b 40 0.44 0.40 0.26 0.25 <0.1 2.sup.b 0.49 0.62 0.27
0.16 0.20 3.sup.b 0.74 0.71 0.67 0.19 0.47 3.sup.b 55 0.92 0.87
0.92 0.06 0.65 .sup.aLong term program. .sup.bAccelerated
program.
Example 3
Azithromycin Stability as a Function of Storage Temperature
[0076] Samples of azithromycin were placed in storage bags and each
batch sample was analyzed after storage at a variety of
temperatures using the analytical techniques as described in
Example 1. Each batch was packaged in a polyethylene bag and
subsequently, each bag was packaged in an aluminum bag with silica
gel. Table D summarizes the effects of storage temperature on the
production of azithromycin degradation products. The results
demonstrate that storing azithromycin at low temperatures
(+5.degree. C.) leads to inhibition of the production of
degradation products. TABLE-US-00004 TABLE D Azithromycin Stability
as a Function of Storage Temperature AZT Time RRT (%) Other Total
Batch (months) T.degree. C. 0.26 0.34 0.37 0.80 RRT % % Batch 0
<0.1 0.07 0.03 <0.1 <0.1 0.1 No. 4 3 2-8 0.07 0.12 0.06
0.06 0.12 0.3 3 25 0.36 0.41 0.26 0.32 0.41 1.5 Batch 0 <0.1
0.07 0.03 <0.1 <0.1 0.1 No. 5 3 2-8 0.10 0.15 0.07 0.08 0.15
0.4 3 25 0.44 0.62 0.39 0.43 0.62 1.9 Batch 0 <0.1 0.13 0.07
0.04 0.13 0.2 No. 6 3 2-8 0.07 0.17 0.11 0.03 0.17 0.4 3 25 0.39
0.57 0.32 0.34 0.57 1.8
Example 4
Azithromycin Stability as a Function of Layered Storage
Container
[0077] Five different samples of azithromycin were stored in a
variety of packages to determine the amount of degradation products
after a particular time and temperature. Using HPLC analytical
methodology as described in Example 1, the presence and amount of
degradation products for each package were determined. Each sample
was packaged directly into an aluminum laminate, or packaged in an
inner polyethylene (PE) bag and exterior aluminum laminate bag.
Each sample was stored at an elevated temperature for 6-7 days. The
results demonstrate that fewer azithromycin degradation products
were found in the aluminum laminate bags as compared to the
polyethylene/aluminum laminate double bag. Table E summarizes the
effect of different packaging on the stability of azithromycin.
TABLE-US-00005 TABLE E Azithromycin Stability as a Function of Time
RRT (%) AZT Time Other Batch Package (days) T.degree. C. 0.25 0.33
0.36 0.78 0.80 RRT % Batch 0 <0.1 0.12 <0.1 <0.1 <0.1
0.12 No. 4 direct in Al laminate 6 55 0.17 0.14 0.07 0.11 <0.1
0.17 PE bag in Al laminate 6 55 0.49 0.48 0.26 0.35 <0.1 0.49
Batch 0 0.09 0.08 0.03 <0.1 0.06 0.10 No. 5 direct in Al
laminate 6 55 0.13 0.10 0.03 0.08 0.07 0.13 PE bag in Al laminate 6
55 0.36 0.36 0.15 0.2 0.06 0.36 Batch 0 0.05 0.05 0.03 <0.1
<0.1 <0.1 No. 13 direct in Al laminate 6 55 0.14 0.12 0.05
0.05 <0.1 0.14 PE bag in Al laminate 6 55 0.42 0.44 0.19 0.27
<0.1 0.44 Batch 0 0.37 0.38 0.19 <0.1 0.22 0.38 No. 7 direct
in Al laminate 7 55 0.37 0.39 0.14 <0.1 0.22 0.39 PE bag in Al
laminate 7 55 0.49 0.51 0.26 <0.1 0.28 0.51 Batch 0 0.08 0.18
0.08 <0.1 <0.1 0.18 No. 10 direct in Al laminate 7 55 0.12
0.25 0.10 <0.1 0.06 0.25 PE bag in Al laminate 7 55 0.24 0.41
0.18 <0.1 0.15 0.41
Example 5
Double Aluminum Laminate Package Studies
[0078] Different batches of azithromycin were packaged in double
aluminum laminate bags under a variety of conditions. The storage
conditions included long term (2.degree. C. to 8.degree. C.); humid
long term (25.degree. C..+-.2.degree. C. at 60%.+-.5% relative
humidity); humid accelerated (25.degree. C..+-.2.degree. C. at
60%.+-.5% relative humidity); and high humidity accelerated
(40.degree. C. at 70%.+-.5% relative humidity). After a
predetermined amount of time, each sample was analyzed according to
the analytical technique described in Example 1. Table F summarizes
the test data. The decomposition of azithromycin in a double layer
of aluminum laminate packaging was significantly inhibited. Even at
a temperature of 40.degree. C., the impurity increase was very
moderate and close to the results at 25.degree. C. TABLE-US-00006
TABLE F Azithromycin Stability in Double Aluminum Bags. Impurities
AZT Time RRT (%) Other % % Batch (months) 0.26 0.34 0.37 0.78 RRT %
Total % Water EtOH Batch 0 0.29 0.40 0.17 0.12 0.40 1.30 3.22 2.1
No. 10 3.sup.a 0.24 0.32 0.16 0.15 0.32 0.98 3.40 2.1 3.sup.b 0.30
0.39 0.18 0.21 0.39 1.29 3.69 2.1 1.sup.c 0.29 0.40 0.20 0.22 0.40
1.22 2.90 2.2 2.sup.c 0.33 0.33 0.25 0.20 0.33 1.31 3.31 2.1
3.sup.c 0.30 0.39 0.18 0.21 0.39 1.29 3.69 2.1 1.sup.d 0.34 0.49
0.22 0.19 0.49 1.35 3.17 2.2 2.sup.d 0.40 0.37 0.35 0.24 0.40 1.57
3.11 2.2 3.sup.d 0.38 0.46 0.25 0.28 0.46 1.47 3.46 2.2 Batch 0
<0.10 0.18 0.11 <0.10 0.18 0.53 3.66 2.2 No. 11 3.sup.a
<0.10 0.15 <0.10 <0.10 0.15 0.26 3.90 2.1 3.sup.b <0.10
0.19 0.12 <0.10 0.19 0.54 3.75 2.1 1.sup.c <0.10 0.20
<0.10 <0.10 0.20 0.37 3.69 2.1 2.sup.c <0.10 0.16 0.12
<0.03 0.16 0.41 3.77 2.1 3.sup.c <0.10 0.19 0.12 <0.10
0.19 0.54 3.75 2.1 1.sup.d 0.12 0.24 0.12 <0.10 0.24 0.75 3.65
2.1 2.sup.d 0.15 0.18 0.18 <0.10 0.18 0.65 3.47 2.2 3.sup.d 0.21
0.31 0.15 0.11 0.31 0.90 3.84 2.1 Batch 0 <0.03 0.13 <0.10
<0.03 0.16 0.42 3.67 2.2 No. 12 3.sup.a <0.10 <0.10
<0.10 <0.10 0.14 0.25 3.69 2.1 3.sup.b <0.10 0.17 <0.10
<0.10 0.16 0.42 3.64 2.2 1.sup.c <0.10 0.17 <0.10 <0.10
0.17 0.30 3.51 2.1 2.sup.c <0.10 0.12 0.11 <0.10 0.13 0.57
3.64 2.1 3.sup.c <0.10 0.17 <0.10 <0.10 0.17 0.39 3.64 2.2
1.sup.d 0.13 0.26 <0.10 <0.10 0.26 0.52 3.63 2.1 2.sup.d 0.15
0.17 0.15 <0.10 0.17 0.60 3.44 2.2 3.sup.d 0.13 0.22 <0.10
<0.03 0.22 0.60 3.73 2.2 .sup.aLong term. .sup.bHumid long term.
.sup.cHumid accelerated. .sup.dHigh humidity accelerated.
Example 6
Year Long Azithromycin Study
[0079] Samples of azithromycin Form A were separately packaged into
polyethylene/aluminum laminate bags, and each polyethylene/aluminum
laminate bag was packaged into a second polyethylene/aluminum
laminate bag. Each bag was subjected to a stability program (a)
25.degree. C..+-.2.degree. C. at 60% relative humidity or (b)
40.degree. C..+-.2.degree. C. at 75% relative humidity. After one
year, each sample was analyzed as described in Example 1 to
determine the presence and amount of degradation products. The
impurity level for each sample was determined to be not more than
0.5%. Thus, each tested batch demonstrated the stability of
azithromycin of greater than 1 year. TABLE-US-00007 Storage Lot No.
Conditions Interval RRT = 0.26 RRT = 0.34 RRT = 0.37 RRT = 0.78
Total Lot 1 25.degree. C./60% RH 0 MT <0.10 0.18 0.11 <0.10
0.53 25.degree. C./60% RH 1 MT <0.10 0.20 <0.10 <0.10 0.37
25.degree. C./60% RH 2 MT <0.10 0.16 <0.03 <0.03 0.41
25.degree. C./60% RH 3 MT <0.10 0.19 <0.10 <0.10 0.54
25.degree. C./60% RH 6 MT 0.11 0.19 <0.10 <0.10 0.53
25.degree. C./60% RH 9 MT 0.13 0.19 <0.10 <0.10 0.60
25.degree. C./60% RH 12 MT 0.15 <0.10 <0.10 <0.10 0.60
25.degree. C./60% RH 18 MT 0.17 0.19 <0.10 <0.10 0.91 Lot 1
40.degree. C./75% RH 0 MT <0.10 0.18 0.11 <0.10 0.53
40.degree. C./75% RH 1 MT 0.12 0.24 0.12 <0.10 0.75 40.degree.
C./75% RH 2 MT 0.15 0.18 0.18 <0.10 0.65 40.degree. C./75% RH 3
MT 0.21 0.31 0.15 0.11 0.90 40.degree. C./75% RH 6 MT 0.34 0.34
0.22 0.12 1.30 Lot 2 25.degree. C./60% RH 0 MT <0.03 0.13
<0.10 <0.03 0.42 25.degree. C./60% RH 1 MT <0.10 0.17
<0.10 <0.10 0.30 25.degree. C./60% RH 2 MT <0.10 0.12 0.11
<0.10 0.57 25.degree. C./60% RH 3 MT <0.10 0.17 <0.10
<0.10 0.39 25.degree. C./60% RH 6 MT 0.1 0.15 0.10 <0.10 0.46
25.degree. C./60% RH 9 MT 0.16 0.16 0.14 <0.10 0.70 25.degree.
C./60% RH 12 MT 0.18 0.25 0.16 0.11 1.00 25.degree. C./60% RH 18 MT
0.15 0.26 <0.10 0.11 0.89 Lot 2 40.degree. C./75% RH 0 MT
<0.03 0.13 <0.10 <0.03 0.42 40.degree. C./75% RH 1 MT 0.13
0.26 <0.10 <0.10 0.52 40.degree. C./75% RH 2 MT 0.15 0.17
0.15 <0.10 0.60 40.degree. C./75% RH 3 MT 0.13 0.22 <0.10
<0.03 0.60 40.degree. C./75% RH 6 MT 0.16 <0.10 0.12 <0.10
0.56
The typical peak of azithromycin dihydrate in Form A is 13.2
degrees two-theta.
Example 7
Azithromycin Monohydrate Stability
[0080] A sample of azithromycin monohydrate is packaged into a
polyethylene/aluminum laminate bag. The storage conditions include
a temperature of about 25.degree. C. and/or 60% relative humidity.
After 3 months, the X-ray diffraction pattern shows that less than
about 5% of azithromycin monohydrate is transformed to the
dihydrate form.
General Disclosure with Respect to the Below Examples
[0081] The dibasic calcium phosphate dihydrate used was
Emcompress.RTM., which is available from Penwest Pharmaceuticals
Co., Cedar Rapids, Iowa. The sodium starch glycolate used was
Explotabg, which is also available from Penwest Pharmaceuticals.
Sodium lauryl sulfate was used as received from Cognis (Henkel).
The povidone used was povidone K-25 as received from ISP
Pharmaceuticals. The colloidal silicon dioxide used was either
Cab-O-Sil.RTM., available from Astro Chemicals Inc., Springfield,
Mass., or Aerosil 200.RTM., available from Degussa. The dibasic
calcium phosphate used was A-Tab, which is available from Rhodia
(Rhone Poulenc). The pregelatinized starch used was Starch
1500.RTM., which is available from Colorcon. The croscarmellose
sodium used was Ac-Di-Sol.RTM., which is available from Farma
International. The tablet coating used was Opadry.RTM., which is
available from Colorcon. The xanthan gum used is available from
Kelco.
Quantitation Method Used in Accelerated Stability Studies
[0082] The quantity of impurities present before and after
oxidative stress were quantified by high performance liquid
chromatography, employing the following conditions: [0083] Column:
RP18, 5.mu., 150.times.4.6 mm [0084] Eluent: 40% 0.05M of potassium
hydrogen phosphate (K.sub.2HPO.sub.4) adjusted to pH 8.2 with 20%
phosphoric acid; 60% acetonitrile [0085] Flow rate: 0.9 ml
min.sup.-1 [0086] Detection: UV, .lamda.=210 nm [0087] Column
Temp.: 30.degree. C.
[0088] Sample [0089] Volume: 50 .mu.l [0090] Diluent: Same as
Eluent
[0091] Sample solutions were freshly prepared from azithromycin and
injected on column. The percentages of impurities were calculated
from the integrator output.
Performance Evaluation
[0092] The performance of the HPLC system was tested using
standardized solutions of AZT and DMAZT.
Example 8
Admixtures of Azithromycin and BHT
[0093] Mixtures of azithromycin and BHT were prepared using various
methods of admixing to assess their effectiveness at inhibiting
degradation of azithromycin.
Preparative
Preparation 1 [CS Ex. 1: precipitated]
[0094] Technical grade azithromycin (10 g, 13 mmol) and BHT (0.18
g, 0.82 mmol, 6.1 mole %) were dissolved in absolute ethanol (30
ml) at 20.degree. C. in a 250 ml three-necked flat flanged jacketed
vessel equipped with a mechanical stirrer, a condenser and
thermometer. Water (3 ml) was added at 20.degree. C. and the
solution was heated at a constant 9.degree. C. h.sup.-1 temperature
gradient to 55.degree. C. over about 4 hours. More water (11 ml)
was slowly added to the vessel at between 35.degree. C. and
55.degree. C., which caused a precipitate to form. The resulting
suspension was maintained at 55.degree. C. for another two hours.
During this time interval more water (49 ml) was added to the
suspension. The suspension was then cooled at a constant
temperature gradient from 55.degree. C. to 20.degree. C. over 2
hours and filtered at 20.degree. C. After drying, a stable dry
product (9 g, 90%) was obtained.
Preparation 2 [CS Ex. 2: Added at Cloudiness]
[0095] Technical grade azithromycin (10 g, 13.35 mmol) was
dissolved in absolute ethanol (30 ml) at 20.degree. C. in a 250 ml
three-necked flat flanged jacketed vessel equipped with a
mechanical stirrer, a condenser and thermometer. Water (3 ml) was
added at 20.degree. C. and the solution was heated at a constant
9.degree. C. h.sup.-1 temperature gradient to 55.degree. C. over
about 4 hours. More water (11 ml) was slowly added to the vessel at
between 35.degree. C. and 55.degree. C. Azithromycin began to
precipitate from the solution at 46.degree. C. BHT (0.18 g, 0.82
mmol, 6.1 mole %) was added at the first sign of cloudiness. After
reaching 55.degree. C., the suspension was maintained at that
temperature for another two hours, over which time more water (49
ml) was added. The suspension was then cooled at a constant
18.degree. C. h-1 temperature gradient from 55.degree. C. to
20.degree. C. over about 2 hours and then filtered at 20.degree. C.
A stable dry product (9 g, 90%) was obtained after drying.
Preparation 3 [CS Ex. 3: Portion Evaporated Portion Added at
Cloudiness]
[0096] Technical grade azithromycin (10 g, 13 mmol), and BHT (0.12
g, 0.54 mmol, 4.1 mole %) were dissolved in absolute ethanol (30
ml) at 20.degree. C. in a 250 ml three-necked flat flanged jacketed
vessel equipped with a mechanical stirrer, a condenser and
thermometer. The ethanol was evaporated and the dry residue was
taken up in fresh absolute ethanol (20 ml). Water (3 ml) was added
at 20.degree. C. and the solution was heated at a constant
9.degree. C. h.sup.-1 temperature gradient to 55.degree. C. over
about 4 hours. More water (11 ml) was slowly added to the vessel at
between 35.degree. C. and 55.degree. C. Azithromycin began to
precipitate from the solution at 46.degree. C. BHT (180 mg, 0.82
mmol, 6.1 mole %) was added at the first sign of cloudiness. After
reaching 55.degree. C., the suspension was maintained at that
temperature for another two hours, over which time more water (49
ml) was added. The suspension was cooled at a constant temperature
gradient of 18.degree. C. h.sup.-1 from 55..degree. C. to
20.degree. C. over about 2 hours and then filtered at 20.degree. C.
A stable dry product (9 g, 90%) was obtained after drying.
Preparation 4 [Milling]
[0097] Azithromycin (1 g, 1.3 mmol) was weighed out and set aside.
BHT (12 mg, 0.054 mmol, 4.1 mole %) was finely milled with a mortar
and pestle. The azithromycin was added portionwise to the BHT. Each
portion was thoroughly milled with the BHT using the mortar and
pestle.
Preparation 5 [Comparative]
[0098] In this example, no antioxidant was used. In other respects,
the azithromycin was processed according to Preparation 1 and the
resulting product was used as a control sample against which to
compare the degradation rates of stabilized azithromycin
compositions.
Methodology
[0099] Samples of azithromycin admixtures prepared according to
preparations 1-5 were analyzed by HPLC for impurity content
immediately after their preparation by mixing with an appropriate
quantity of eluent to give an approximately 4 mg/ml clear solution.
Another sample of each of the preparations was stored at 55.degree.
C. The vial contents were analyzed by HPLC seven days after being
placed in the oven.
Results
[0100] The results of the accelerated stability study on stabilized
azithromycin are recorded in Table 1. TABLE-US-00008 TABLE 1
Comparison of Degradation of Azithromycin stabilized with BHT and
without Stabilization Upon Exposure to 55.degree. C. Total
Impurities Total Impurities Exposure After BHT Before Exposure Time
Exposure Percent Preparation (mole %) (% Area) (Days) (% Area)
Change Method of Admixing 1 6.1 0.66 7 1.16 0.50 AZT and BHT
co-precipitated from solution 2 6.1 0.88 7 0.98 0.10 Precipitation
of AZT from a suspension of BHT 3 4.1 0.66 7 0.86 0.20
Co-precipitation of AZT and BHT from a suspension of BHT 4 4.1 0.25
16 1.03 0.78 Milling 5 -- 0.27 7 3.76 3.49 No BHT was used
[0101] The four different techniques of intimately admixing
azithromycin and BHT used in Preparations 1-4 led to a significant
reduction in impurity content, relative to the control, after the
admixture was subjected to oxidative stress. The stability results
suggest that degradation occurs by an oxidation pathway because of
the general inhibition achieved by adding the free radical
inhibitor BHT. The degrees of inhibition observed using the
different techniques of admixing are significantly different.
Comparison of the results from Preparations 1 and 2 shows that
oxidation is inhibited somewhat more effectively by adding the
stabilizer as soon as the azithromycin begins to precipitate from
the ethanolic solution, rather than before, but that both
techniques are highly effective. It is believed that addition of
the stabilizer at the time that the azithromycin begins to
precipitate from the solution may be more effective relative to
addition of the stabilizer before precipitation because the
stabilizer or antioxidant (such as BHT) is more effectively
entrapped within the already formed crystals and consequently has
increased protective activity. If the crystals are not yet formed,
the stabilizer or antioxidant is more easily washed out by the
solvent. Comparison of the results from Preparations 2 and 3 shows
that the anti-oxidant inhibiting effect of BHT did not diminish
over time. The best results of azithromycin stabilization were
achieved by forming a stabilized azithromycin composition by
co-milling of azitbromycin and an antioxidant such as BHT.
Example 9
Admixtures of Azithromycin and Food Grade Antioxidants
[0102] The inhibiting effect of food grade antioxidants was
explored at yet lower concentrations and with other mixing
methods.
Preparative
Preparation 6 [M 2206]
[0103] Technical grade azithromycin was recrystallized from
ethanol. No anti-oxidants were added.
Preparation 7 [T 582-02]
[0104] Technical grade azithromycin (300 g, 400 mmol) was
recrystallized from ethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) was
dissolved in ethanol and the solution was sprayed onto the
azithromycin with thorough mixing.
Preparation 8 [T 592-03]
[0105] Technical grade azithromycin (300 g, 400 mmol) was
recrystallized from ethanol. BHT (1.2 g, 5.4 mmol, 1.4 mole %) and
PG (1.2 g, 5.7 mmol, 1.4 mole %) were dissolved in ethanol and the
solution was sprayed onto the azithromycin with thorough
mixing.
Preparation 9 [T 582-04]
[0106] Technical grade azithromycin (300 g, 400 mmol) was dissolved
in ethanol and a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) in
ethanol was combined with the azithromycin solution. The ethanol
was then evaporated leaving a residue of azithromycin and BHT in
intimate admixture.
Preparation 10 [T 582-05]
[0107] Technical grade azithromycin (300 g, 400 mmol) was dissolved
in ethanol and a solution of BHT (1.2 g, 5.4 mmol, 1.4 mole %) and
PG (1.2 g, 5.7 mmol, 1.4 mole %) was combined with the azithromycin
solution. The ethanol was then evaporated leaving a residue of
azithromycin, BHT and PG in intimate admixture.
Methodology
[0108] Preparations 6-10 were incubated at 25.degree. C. and
50.degree. C. for 20 hours under open cap conditions.
Results
[0109] The results of the accelerated stability study comparing
azithromycin stabilized by co-precipitation with an antioxidant and
granulation with an antioxidant-containing solution are reported in
Table 2. TABLE-US-00009 TABLE 2 Comparison of Degradation of
Unstabilized Azithromycin, Azithromycin Stabilized by Wet
Granulation with Antioxidant and Azithromycin Stabilized by
Co-precipitation with an Antioxidant After Twenty Hours at Ambient
or Elevated Temperature Temp Antioxidant % Impurity 1 % Impurity 2
% Impurity 3 % Impurity 4 Total Preparation (.degree. C.) (mole %)
(RRT.sup.a .apprxeq.0.23) (RRT.sup.a .apprxeq.0.30) (RRT.sup.a
.apprxeq.0.34) (RRT.sup.a .apprxeq.0.76) Impurity Method of Mixing
.sup. 6.sup.b 25 -- 0.07 0.19 0.09 0.03 0.38 Antioxidant was not
added. unstabilized 50 0.30 0.50 0.16 0.16 1.12 7 25 BHT
(1.4.sup.b) 0.07 0.24 0.08 0.05 0.44 Azithromycin granulated with
an 50 0.32 0.52 0.22 0.16 1.22 ethanolic solution of antioxidant. 8
25 BHT (1.4) 0.06 0.21 0.06 0.04 0.37 Azithromycin granulated with
an 50 & PG (1.4) 0.28 0.38 0.27 0.15 1.08 ethanolic solution of
antioxidant. 9 25 BHT (1.4) 0.09 0.22 0.07 0.03 0.41
Co-precipitation of AZT and 50 0.08 0.22 0.08 0.06 0.44 antioxidant
10 25 BHT (1.4) 0.08 0.20 0.08 0.03 0.39 Co-precipitation of AZT
and 50 & PG (1.4) 0.08 0.22 0.08 0.06 0.44 antioxidant
.sup.aRRT = relative retention time .sup.b1.4 mole % corresponds to
approximately 0.4 weight percent for both BHT and PG
[0110] As can be seen by comparison of the results obtained from
Preparations 9 and 10 with those obtained from Preparations 6 and
7, the use of antioxidants resulted in less degradation when the
antioxidants were co-precipitated with azithromycin versus
granulating azithromycin with an ethanolic solution containing the
antioxidants. Degradation of the untreated azithromycin was most
significant at elevated temperature, yet elevated temperature had
little effect upon the degradation rate of azithromycin that was
coprecipitated with an antioxidant (Preparations 9 and 10). In
addition, the mode of application of the antioxidant is more
important to achieving the inhibiting effect than the amount of
antioxidant used (compare the total impurity content of
Preparations 8, 9 and 10 after twenty hours at 50.degree. C.).
Example 10
Wet Granulated Tablet of Stabilized Azithromycin
[0111] In addition to studying the stability of mixtures highly
concentrated in azithromycin (Le., mixtures of azithromycin and an
antioxidant), we studied the stability of azithromycin in
representative pharmaceutical compositions and dosage forms
containing antioxidant mixed with AZT in various ways.
Formulations
Formulation 1 [T 582-02]
[0112] Stabilized azithromycin resulting from Preparation 7 was
formulated into a wet granulated tablet following the stepwise
procedure below using the components in Table 3. TABLE-US-00010
TABLE 3 Per mg/ Wt. Batch No Components Tablet % (g) 1 Preparation
7 (AZT granulated 270 58.35% 219.12 with BHT soln.) 2 Dibasic
Calcium phosphate 30 6.48 24.28 dihydrate 3 Sodium starch glycolate
9.4 2.03 7.61 4 Sodium lauryl sulfate (SLS) 3.13 0.68 2.54 5
Povidone K-25 (PVP) 19 4.11 15.36 6 Dibasic Calcium Phosphate 115
24.90 92.95 Dihydrate 7 Sodium starch glycolate (SSG) 9.4 2.03 7.61
8 Magnesium stearate 4.75 1.03 3.82 9 Colloidal silicon dioxide
2.09 0.45 1.69 (Cab-O-Sil .RTM.) Total 462.7 100.00 347.98 10 BHT
in Azithromycin: 1.08 0.23 0.88 11 Alcohol 2A (removed in 40
processing)
1. A solution of SLS (2.54 g) and PVP K-25 (15.36 g) was prepared
in denatured alcohol formula 2A (40 g) (see USP). 2. Preparation 7
(220.0 g) was mixed in a polyethylene bag with dibasic calcium
phosphate dihydrate and sodium starch glycolate. 3. The product of
step 2 was transferred into a Hobart planetary mixer and granulated
with the PVP-SLS solution of step 1 at low speed for 1 minute. 4.
The granulate was passed through a hand screen (#8 mesh) and dried
at 45.degree. C. for 6 hours in a forced air oven. 5. The dried
granulate of step 4 was passed through a hand screen (# 16 mesh).
The loss on drying (LOD) of the granulate was 2.9% (90.degree. C.).
6. The screened granulate was additionally dried at 50.degree. C.
for 50 minutes at which point LOD=1.6-1.9%. 7. The dried
granulation of step 6 was mixed with the dibasic calcium phosphate
dihydrate and SSG in a polyethylene bag for 2 minutes. 8. In a
separate bag colloidal silicon dioxide was mixed with about 100 g
of the granulate of step 7 and then passed through a hand screen (#
16 mesh) and then combined with the remaining quantity of the
granulate of step 7 and mixed for 1 minute in a polyethylene bag.
9. The magnesium stearate was combined with about 100 g of the
granulate of step 8, passed through a hand screen (#16 mesh) and
then combined with remaining quantity of step 8 and mixed for 1
minute in polyethylene bag.
[0113] Capsule-shape tablets were prepared from the granulate
obtained after step 9 using 0.248.times.0.560 inch punches on a B3B
Manesty tablet press.
Formulation 2 [T 582-03]
[0114] Formulation 2 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 8 containing AZT granulated with an ethanolic solution
containing 1.4 mole % of BHT and PG for Preparation 7. The
formulation thus contained 0.23 wt. % of each of BHT and PG.
Formulation 3 [T 582-04]
[0115] Formulation 3 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 9, a co-precipitate of AZT and 1.4 mole % BHT from an
ethanolic solution, for Preparation 7. The formulation thus
contained 0.23 wt. % of BHT.
Formulation 4 [T 582-05]
[0116] Formulation 4 was prepared using the same inactive
ingredients and processing as per Formulation 1 but substituting
Preparation 110, a co-precipitate of AZT, 1.4 mole % BHT, and 1.4
mole % PG, from an ethanolic solution, for Preparation 7. The
formulation thus contained 0.23 wt. % of BHT and PG.
Methodology
[0117] All tablets were stressed under "open cap" conditions at
50.degree. C. for 184 h.
Results
[0118] The results of the accelerated stability study on tablets
formulated with stabilized azithromycin are reported in Table 4.
TABLE-US-00011 TABLE 4 Comparison of Stability of Wet-Granulated
Tablets Containing 250 mg Stabilized Azithromycin Prepared by
Different Methods of Admixing The Azithromycin and Antioxidant Upon
Exposure to 50.degree. C. Total Impurities (%) Antioxidant Before
Percent Change Formulation Preparation (Wt. % of Tablet) Exposure
66 h 184 h 66 h 184 h Method of Admixing 1 7 BHT (0.23%) 0.47 1.51
2.55 1.04 2.08 AZT granulated with ethanolic solution containing
antioxidant. 2 8 BHT (0.23%) 0.37 1.20 2.10 0.83 1.73 AZT
granulated with ethanolic PG (0.23%) solution containing
antioxidant. 3 9 BHT (0.23%) 0.38 0.71 1.17 0.33 0.79
Co-precipitation of AZT and antioxidant. 4 10 BHT (0.23%) 0.34 0.40
0.58 0.20 0.24 Co-precipitation of AZT and PG (0.23%)
antioxidant.
[0119] The results recorded in Table 4 show that an intimate
admixture of AZT and antioxidant obtained by co-precipitation is
more effective at inhibiting degradation in a wet granulated tablet
formulation than the application of the antioxidant during wet
granulation of the AZT with other excipients.
Example 11
Azithromycin Tablet Prepared by Dry Granulation
[0120] The stability of dry granulated tablet formulations of
azithromycin that were pre-compressed by roller compaction was also
assessed in formulations with and without an added food grade
antioxidant.
Formulations
[0121] Azithromycin was formulated into dry granulated 500 mg
tablets following the stepwise procedure below using the excipients
in Table 5. TABLE-US-00012 TABLE 5 Formulations (mg/Tablet) Stage
Ingredients 5 6 7 8 9 Part I Azithromycin 525.3* 525.3* 525.3*
525.3* 525.3* Colloidal SiO.sub.2 (Aerosil 200 .RTM.) 8.0 8.0 8.0
8.0 8.0 Propyl Gallate -- 0.8 -- -- -- BHT -- 0.8 -- 0.4 0.8 Sodium
Ascorbate -- -- 1.6 -- -- Part II Dibasic Calcium Phosphate 90.7
89.1 89.1 90.3 89.9 Pregelatinized Starch 55.0 55.0 55.0 55.0 55.0
Croscarmellose Sodium 18.0 18.0 18.0 18.0 18.0 Talc 32.0 32.0 32.0
32.0 32.0 Magnesium Stearate 2.0 2.0 2.0 2.0 2.0 Part III Colloidal
SiO.sub.2 (Aerosil 200 .RTM.) 10.0 10.0 10.0 10.0 10.0 Sodium
Lauryl Sulfate 2.4 2.4 2.4 2.4 2.4 Croscarmellose Sodium 28.0 28.0
28.0 28.0 28.0 Talc 13.6 13.6 13.6 13.6 13.6 Magnesium Stearate
15.0 15.0 15.0 15.0 15.0 Coating Opadry .RTM. 24.0 24.0 24.0 24.0
24.0 Theoretical End Weight 824.0 824.0 824.0 824.0 824.0 *525.3 mg
of Azithromycin solvate is equivalent to 500 mg Azithromycin (based
on the specific APl potency of the particular lot used)
Formulation 5 [K-28201] 1. Part I materials were blended in a
polyethylene bag and passed through an oscillating granulator
(Frewitt.RTM.) equipped with a 1 mm aperture screen and loaded into
a twin shelled Y-cone dry blender. 2. Part II materials were added
to the Y-cone blender and mixed. 3. The mix was passed through a
roller compactor. 4. The compact was twice passed through the
oscillating granulator. In the first pass, the granulator was
equipped with a 2 mm aperture screen. In the second pass, the
granulator was equipped with a 1 mm aperture screen. The milled
granulate was loaded into a Y-cone blender. 5. The Part III
materials were added to the Y-cone blender and mixed. 6. Oval
tablets 9.times.17 mm were pressed from the mixture on a Kilian RLS
rotary tablet press. 7. A portion of the compressed tablets were
coated with Opadry.RTM. II White. This formulation did not contain
stabilizers. Formulation 6 [K-28202]
[0122] Formulation 6 was processed using the same inactive
ingredients and processing as per Formulation 5 except that 0.8
mg/tablet BHT and 0.8 mg/tablet PG were added in Step 1 and the
amount of dibasic calcium phosphate used was reduced to give a
tablet of identical theoretical end weight. Formulation 6 contained
0.1 wt. % BHT and 0.1 wt. % Propyl Gallate.
Formulation 7 [K-28483]
1. Part I materials were blended in a Diosna.RTM. P-10 high shear
mixer.
2. Part II materials were added to the mixer and mixed.
3. The mix was passed through a roller compactor.
[0123] 4. The compact was twice passed through a Frewitt. In the
first pass, the Frewitt was equipped with a 2 mm aperture screen.
In the second pass, the Frewitt was equipped with a 1 mm aperture
screen. The milled granulate was loaded into a Y-cone blender.
5. The Part III materials were added to the Y-cone blender and
mixed.
6. Oval tablets 9.times.17 mm were pressed from the mixture on a
Kilian RLS rotary tablet press.
7. A portion of the compressed tablets were coated with Opadry.RTM.
II White. The formulation contained 0.2 wt. % of Sodium
Ascorbate.
Formulation 8 [K-28484]
[0124] Formulation 8 was processed using the same inactive
ingredients and processing as per Formulation 7 except that 0.4
mg/tablet BHT was added to the Part I materials in lieu of 1.6
mg/tablet sodium ascorbate and the amount of dibasic calcium
phosphate was adjusted to yield a tablet of identical weight.
Formulation 8 contained 0.05 wt. % of BHT.
Formulation 9 [K-28485]
[0125] Formulation 9 was processed using the same inactive
ingredients and processing as per Formulation 8 except that 0.8
mg/tablet BHT was added in Step I and the amount of dibasic calcium
phosphate was reduced by 0.4 mg/tablet. Formulation 9 contained 0.1
wt. % of BHT.
Methodology
[0126] Tablets were stressed under a variety of storage conditions:
in blister packs, in high density polyethylene (HDPE) bottles, and
in aluminum laminated bags. The containers were filled and then
sealed under ordinary atmosphere. The tablets were stored for five
or seven days at 55.degree. C.
Results
[0127] The results of the accelerated stability study on tablets
prepared by dry granulation with pre-compression by roller
compaction are reported in Table 6. TABLE-US-00013 TABLE 6
Stability of Dry-Granulated 500 mg Azithromycin Tablets
Pre-Compressed by Roller Compaction to Storage at 55.degree. C. in
Conventional Pharmaceutical Packaging and with or Without Different
Food Grade Antioxidants Formulated in the Tablets Total Impurities
By HPLC (% Area) Storage Stabilizer Exposure Time Before After
Formulation Conditions (Wt. % of Tablet) (Days) Exposure Exposure
Change 5(coated) Blister Pack -- 5 0.7 1.3 0.6 5(coated) HDPE
Bottle -- 5 0.7 1.9 1.2 6(coated) Blister Pack BHT (0.1) & PG
(0.1) 5 0.4 0.6 0.2 6(coated) HDPE Bottle BHT (0.1) & PG (0.1)
5 0.4 0.6 0.2 7 (coated) Aluminum Laminate Bag SA (0.2) 7 0.3 0.8
0.5 7 (uncoated) Aluminum Laminate Bag SA (0.2) 7 0.6 0.9 0.3 8
(coated) Aluminum Laminate Bag BHT (0.05) 7 0.2 0.6 0.4 8
(uncoated) Aluminum Laminate Bag BHT (0.05) 7 0.4 0.7 0.3 9
(coated) Aluminum Laminate Bag BHT (0.1) 7 0.2 0.5 0.3 9 (uncoated)
Aluminum Laminate Bag BHT (0.1) 7 0.3 0.5 0.2
[0128] A significant reduction in the degradation rate of tablets
stored in blister packs and HDPE bottles was observed when 0.2 wt.
percent antioxidant was included in the formulation (compare the
results for Formulations 5 and 6). BHT (alone) and mixtures of BHT
and PG were more effective at inhibiting degradation than SA, but
all three antioxidants provide an inhibiting effect relative to
untreated azithromycin.
Example 12
Azithromycin Tablet Prepared by Dry Granulation--Slugging
[0129] The stability of dry granulated tablet formulations of
azithromycin that were pre-compressed by slugging was also assessed
with and without adding a food grade antioxidant to the
formulation.
Formulations
Formulation 10 [T 582-08]
[0130] Formulation 10 was prepared using the same inactive
ingredients as Formulation 5.
1. Part I materials were blended in a polyethylene bag and passed
through an oscillating granulator (Frewitt.RTM.) equipped with a 1
mm aperture screen into a twin shelled Y-cone dry blender.
2. Part II materials were added to the Y-cone blender and
mixed.
3. The mix was slugged into slugs using a Manesty B3B tablet
press.
4. The slugs were milled in the granulator, which was equipped with
a #16 mesh screen and passed into the Y-cone blender.
5. The Part III materials were added to the Y-cone blender and
mixed.
6. Oval tablets 9.times.19 mm were pressed from the mixture on a
Manesty B3B rotary tablet press.
[0131] 7. A portion of the compressed tablets were coated with
Opadry.RTM. II White. Coating was performed by top spraying a
suspension of Opadry II.RTM. White in a Fluidized Bed
(Uniglatt.RTM.). The inlet temperature was 60.degree. C.; the
outlet temperature was 40.degree. C. Formulation 10 did not contain
an antioxidant.
Formulation 11 [T 582-09]
[0132] Formulation 11 used the same inactive ingredients as
Formulation 6 and was processed as per Formulation 10. Formulation
11 contained 0.1 wt. % BHT and 0.1 wt. % Propyl Gallate.
Methodology
[0133] Stabilized and unstabilized azithromycin tablets prepared by
dry granulation with slugging were stored at 60.degree. C. in
sealed amber glass bottles for 114 h. Another bottle of stabilized
azithromycin tablets was stored "open cap" under identical
conditions. Stabilized azithromycin tablets were also studied at
55.degree. C. in polypropylene (PP) and amber glass bottles.
Results
[0134] The results of the accelerated stability study on tablets
formulated by dry granulation with pre-compression by slugging are
recorded in Table 7. TABLE-US-00014 TABLE 7 Comparison of
Degradation of Dry-Granulated Azithromycin Tablets with And Without
0.1 Wt. % BHT and 0.1 Wt. % PG at Elevated Temperatures Storage
Condition Total Impurities Detected by HPLC (% Area) Formulation
Storage Container Temp. (.degree. C.) Time (h) Before Exposure
After Exposure Change 10 Amber glass bottle 60 114 0.66 3.86 3.20
(unstabilized) (closed cap) 11 Amber glass bottle (open cap) 60 114
0.48 1.85 1.37 11 Amber glass bottle (closed cap) 60 114 0.48 1.44
0.96 11 PP bottle 55 5 0.42 0.55 0.13 (closed cap with small
headspace).sup.1 11 PP bottle 55 5 0.42 1.16 0.74 (closed cap with
large headspace).sup.2 11 amber glass bottle 55 5 0.42 0.49 0.07
(closed cap with small headspace).sup.1 .sup.1The bottle was filled
with tablets. .sup.2Two Tablets were added per bottle.
[0135] The results recorded in Table 7 show that including 0.1 wt.
% BHT and 0.1 wt. % PG in the formulation was effective at
inhibiting degradation of azithromycin tablets prepared by dry
granulation with slugging. The stabilized tablets showed a three
fold reduction in degradation compared to unstabilized tablets at
60.degree. C. under identical closed capped conditions. Even under
open cap conditions, the stabilized tablets underwent less than
half the degradation than unstabilized tablets stored in a sealed
bottled.
Example 13
Powder Suitable for Preparing a Liquid Suspension Dosage Form
[0136] The stability of powder formulations suitable for making
liquid dosage forms like suspensions, syrups and elixirs also was
assessed with and without adding a food grade antioxidant to the
formulation.
Formulations
[0137] Azithromycin was formulated into a powder that can be
constituted as a liquid oral dosage form following the stepwise
procedure below using the excipients in Table 8. TABLE-US-00015
TABLE 8 Formulation 12 Formulation 13 Stage Ingredients (mg per
dose) (mg per dose) Part I Azithromycin 210.12* 210.12* Aerosil 200
20.00 20.00 BHT -- 0.40 Part II Xanthan Gum 6.50 6.50 Klucel LF
5.00 5.00 Sodium Phosphate Tribasic 20.00 20.00 Part III Sucrose
3850.00 3850.00 Theoretical End Weight 4111.60 4112.00 *210.12 mg
Azithromycin is equivalent to 200 mg Azithromycin base, based on
the specific API batch potency.
Formulation 12 [K-28527] 1. Part I materials were passed through an
18 mesh screen and blended in a Y cone blender. 2. Part II
materials were added to the Y-cone blender and mixed. 3. Sucrose
(milled 0.8 mm screen) was added to the Y-cone blender and mixed.
4. The blend was passed through Frewitt 0.8 mm screen and blended
for 5 minutes. Formulation 12 did not contain an antioxidant.
Formulation 13 [K-28528]
[0138] Formulation 13 was prepared using the same inactive
ingredients and processing as Formulation 12, except that 0.01 wt.
% BHT was added in Step 1.
Methodology
[0139] The stability of the powder blend was studied by placing the
powder in open capped amber bottles and storing them in a vented
over for seven days. The powder also was constituted at 40 mg/ml in
water in amber bottles. The bottles were capped and stored at room
temperature for seven days.
Results.
[0140] The results of the accelerated stability study on the dry
powder and the (unaccelerated) stability study on the solution are
recorded in Table 9. TABLE-US-00016 TABLE 9 Comparison of
Degradation of Azithromycin Powder Formulation for Preparing Liquid
Dosage Forms with And Without 0.01 Wt. % BHT RRT RRT RRT RRT Total
Antioxidants Time T 0.28 0.36 0.38 0.83 Impurity Formulation (Wt.
%) (days) (.degree. C.) (%) (%) (%) (%) (%) 12 -- 0 -- 0.15 0.24
0.11 <0.1 0.50 12 (dry powder) -- 7 55 0.42 0.65 0.28 0.31 1.66
% Change 0.27 0.41 0.17 0.31 1.16 12 (Constituted) -- 7 RT 0.10
0.19 <0.1 <0.1 0.50 % Change.sup.a .about.0.sup.a
.about.0.sup.a .about.0.sup.a .about.0.sup.a .about.0.sup.a 13 -- 0
-- 0.10 0.19 <0.1 <0.1 0.29 13 (dry powder) BHT (0.01) 7 55
0.34 0.55 0.23 0.33 1.45 % Change 0.24 0.36 0.23 0.33 1.16 13
(Constituted) BHT (0.01) 7 RT 0.12 0.20 <0.1 <0.1 0.3 %
Change 0.02 0.01 0.00 0.00 0.03 .sup.aThe impurity (identified by
RRT in the above table) percentage values at 0 days and after 7
days (reconstituted) were of negligible difference, indicating that
essentially no degradation occurred during storage of the
reconstituted formulation for 7 days.
[0141] The data shows that the addition of 0.01 wt. % BHT to the
powder formulation for making liquid dosage forms did not improve
the stability of azithromycin in the powder when held at 55.degree.
C. for seven days. The results of Formulations 12 and 13 show that,
in general, no additional stability is achieved when the
antioxidant is combined with the azithromycin by simple powder
mixing of the two, in contrast to forming an intimate admixture of
the azithromycin and antioxidant by, e.g., co-precipitation or
co-milling as described hereinabove.
* * * * *