U.S. patent application number 11/212332 was filed with the patent office on 2006-02-02 for directly compressible formulations of azithromycin.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Steven W. Collier, Barbara A. Johnson, Brendan Murphy, Ernest Quan.
Application Number | 20060024363 11/212332 |
Document ID | / |
Family ID | 23346277 |
Filed Date | 2006-02-02 |
United States Patent
Application |
20060024363 |
Kind Code |
A1 |
Murphy; Brendan ; et
al. |
February 2, 2006 |
Directly compressible formulations of azithromycin
Abstract
The present invention relates to a dry blend, used for forming
azithromycin tablets by direct compression, comprising
non-dihydrate azithromycin and at least one pharmaceutically
acceptable excipient. This invention also relates to an
azithromycin tablet comprising non-dihydrate azithromycin and at
least one pharmaceutically acceptable excipient. Preferably, the
azithromycin tablet is formed by directly compressing the dry
blend, of the present invention, to form said azithromycin tablet.
Preferably, the azithromycin tablet, of the present invention,
contains a dosage of 250 mgA, 500 mgA or 600 mgA of azithromycin.
This invention further relates to an azithromycin tablet which is
produced by forming a dry blend of a non-granulated azithromycin
form A and at least one pharmaceutically acceptable excipient. The
azithromycin tablet is then formed by directly compressing the dry
blend.
Inventors: |
Murphy; Brendan; (Mystic,
CT) ; Collier; Steven W.; (Berkeley, CA) ;
Quan; Ernest; (East Lyme, CT) ; Johnson; Barbara
A.; (Niantic, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
23346277 |
Appl. No.: |
11/212332 |
Filed: |
August 26, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10327459 |
Dec 20, 2002 |
|
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11212332 |
Aug 26, 2005 |
|
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60343480 |
Dec 21, 2001 |
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Current U.S.
Class: |
424/464 ;
514/28 |
Current CPC
Class: |
A61K 31/7052 20130101;
A61K 9/2018 20130101; A61P 31/00 20180101; A61K 9/2095 20130101;
A61K 9/2054 20130101 |
Class at
Publication: |
424/464 ;
514/028 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/7052 20060101 A61K031/7052 |
Claims
1. A dry blend, used for forming azithromycin tablets by direct
compression, comprising: (a) about 1-80%, by weight non-dihydrate
azithromycin; and (b) at least one pharmaceutically acceptable
excipient; wherein the Carr's Compressibility Index, of the dry
blend, is less than about 34%; wherein said non-dihydrate
azithromycin is azithromycin monohydrate hemi-ethanol solvate,
azithromycin monohydrate hemi-isopropanol solvate, azithromycin
monohydrate hemi-n-propanol solvate or azithromycin
sesquihydrate.
2-4. (canceled)
5. A dry blend of claim 1 wherein the non-dihydrate azithromycin is
non-granulated.
6. (canceled)
7. A dry blend of claim 1 further comprising about 0. 1-85%, by
weight, of a diluent.
8. A dry blend of claim 7 wherein said diluent is from 20-70%, by
weight.
9-10. (canceled)
11. A dry blend of claim 8 wherein the Carr's Compressibility
Index, of the dry blend, is less than about 31%.
12. A dry blend of claim 8 wherein the Carr's Compressibility
Index, of the dry blend, is less than about 28%.
13. A dry blend of claim 1 further comprising from about 2-15%, by
weight, of a disintegrant.
14. A dry blend of claim 13 further comprising: (a) about 2-10%, by
weight, of the disintegrant; and (b) about 0.5-8%, by weight, of a
lubricant.
15. A dry blend of claim 1 further comprising from about 0.25-10%,
by weight, of a lubricant.
16. A dry blend of claim 15 wherein said lubricant is from about
0.5-3%, by weight.
17-24. (canceled)
25. A dry blend of claim 1 wherein the Carr's Compressibility
Index, of the dry blend, is less than about 31%.
26. A dry blend of claim 1 wherein the Carr's Compressibility
Index, of the dry blend, is less than about 28%.
27. A dry blend of claim 1 wherein the internal angle of friction,
of the dry blend, is less than about 34.degree..
28. (canceled)
29. A dry blend of claim 1 wherein the internal angle of friction,
of the dry blend, is less than about 31.degree..
30-83. (canceled)
84. A directly compressible dry blend comprising: (a) azithromycin
monohydrate hemi-ethanol solvate, azithromycin monohydrate
hemi-isopropanol solvate, azithromycin monohydrate hemi-n-propanol
solvate or azithromycin sesquihydrate; and (b) at least one
pharmaceutically acceptable excipient;
85. The dry blend of claim 84 wherein the Carr's Compressibility
Index, of the dry blend, is less than about 34%.
Description
[0001] This application is a continuation of U.S. Ser. No.
10/327,459, filed Dec. 20, 2002, which is a non provisional of
Provisional Applications 60/343,480, filed Dec. 21, 2001.
BACKGROUND OF THE INVENTION
[0002] Direct compression is a tableting process in which tablets
are compressed directly from powder blends containing an active
ingredient. In direct compression, all the ingredients required for
tableting, including the active ingredient and processing aids, are
incorporated into a free flowing blend which is then tableted. The
active ingredient, excipients, and other substances are blended and
then compressed into tablets.
[0003] Tablets are typically formed by pressure being applied to a
material in a tablet press.
[0004] There are a number of tablet presses, each varying in
productivity and design but similar in basic function and
operation. All compress a tablet formulation within a die cavity by
pressure exerted between two steel punches, a lower punch and an
upper punch.
[0005] Pharmaceutical manufacturers prefer the use of direct
compression, over wet and dry granulation processes, because of its
shorter processing times and cost advantages. However, direct
compression is generally limited to those situations in which the
active ingredient has physical characteristics suitable for forming
pharmaceutically acceptable tablets.
[0006] Some active ingredients, which are generally unsuitable for
direct compression, can be formed into a directly compressible
formulation by incorporating one or more excipients before
compressing. The addition of excipients to the formulation,
however, will increase the tablet size of the final product. As
tablet size must be within certain parameters to function as a
suitable dosage form, there is a limit beyond which increasing
tablet size to accommodate increasing amounts of excipients to
enhance compactability is not practical. As a result, manufacturers
are often limited to using the direct compression method for
formulations containing a low dose of the active ingredient per
compressed tablet such that the formulation may accommodate
sufficient levels of excipient to make direct compression
practical.
[0007] In the development of pharmaceutical dosage forms, it is
important to balance several different objectives. Preparation of a
pharmaceutical dosage form should be economical. Also, the dosage
form should be easy to swallow. Further, smaller dosage forms are
more acceptable to patients and result in improved patient
compliance.
[0008] It is known that, to form a tablet from a given formulation,
the formulation must have good flow properties for precise
volumetric feeding of the material to the die cavity and suitable
compressibility, compactability, and ejection properties to form a
tablet. The flow properties of powders are critical for efficient
tableting operation. The ability of the material to flow freely
into the die is important to ensure that there is uniform filling
of the die and a continuous movement of the material from its
source. Poor flow properties of the material will affect the
weight, hardness and friability of the tablets. Good flow of
powders, to be compressed, is necessary to assure efficient mixing
and acceptable weight uniformity for the compressed tablets.
[0009] Azithromycin, which is also named
9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, generally, is not
considered to be amenable to the production of directly
compressible tablets of azithromycin formulations.
[0010] It would be desirable to develop an azithromycin formulation
that is amenable to direct compression and that produces tablets
having acceptable hardness and friability.
SUMMARY OF THE INVENTION
[0011] The present invention relates to a dry blend, used for
forming azithromycin tablets by direct compression, comprising
non-dihydrate azithromycin and at least one pharmaceutically
acceptable excipient.
[0012] This invention also relates to an azithromycin tablet
comprising non-dihydrate azithromycin and at least one
pharmaceutically acceptable excipient. Preferably, the azithromycin
tablet is formed by directly compressing the dry blend, of the
present invention, to form said azithromycin tablet.
[0013] Preferably, the azithromycin tablet, of the present
invention, contains a dosage of 250 mgA, 500 mgA or 600 mgA of
azithromycin.
[0014] This invention further relates to an azithromycin tablet
which is produced by forming a dry blend of a non-granulated
azithromycin form A and at least one pharmaceutically acceptable
excipient. The azithromycin tablet is then formed by directly
compressing the dry blend.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a plot of the bulk particle size distribution of
azithromycin for azithromycin lots 1 through 11 by light scattering
analysis (Malvern Mastersizer S, Malvem Instruments,
Worcestershire, UK).
[0016] As used in FIG. 1:
[0017] The -.DELTA.- symbol represents the particle size
distribution of bulk lot 1
[0018] The -x- symbol represents the particle size distribution of
bulk lot 2
[0019] The -.diamond-solid.- symbol represents the particle size
distribution of bulk lot 3
[0020] The -.diamond.- symbol represents the particle size
distribution of bulk lot 4
[0021] The -.box-solid.- symbol represents the particle size
distribution of bulk lot 5
[0022] The -.tangle-solidup.- symbol represents the particle size
distribution of bulk lot 6
[0023] The .....diamond..... symbol represents the particle size
distribution of bulk lot 7
[0024] The .....DELTA..... symbol represents the particle size
distribution of bulk lot 8
[0025] The .... .... symbol represents the particle size
distribution of bulk lot 9
[0026] The ....smallcircle.... symbol represents the particle size
distribution of bulk lot 10
[0027] The ....circle-solid.... symbol represents the particle size
distribution of bulk lot 11
DETAILED DESCRIPTION
[0028] In the specification and claims that follow, reference will
be made to a number of terms which shall be defined to have the
following meaning.
[0029] The term "dry blend", as used herein, means a generally
homogeneous mixture of two or more materials in particle form. The
particles may be in powdered form or, alternatively, larger
aggregated or agglomerated particles.
[0030] The term "azithromycin" as used herein includes all
crystalline and amorphous forms of azithromycin, including all
polymorphs, isomorphs, clathrates, salts, solvates and hydrates of
azithromycin, unless specifically stated. Azithromycin forms
include the dihydrate form and various non-dihydrate forms.
[0031] The stable dihydrate of azithromycin, which is essentially
non-hygroscopic under conditions of relative humidity conducive to
formulation of azithromycin and is disclosed in U.S. Pat. No.
6,268,489, is designated herein as "form A". The form is a
crystalline dihydrate, prepared by crystallization from
tetrahydrofuran and an aliphatic (C.sub.5-C.sub.7)hydrocarbon in
the presence of at least two molar equivalents of water.
[0032] "Non-dihydrate azithromycin" means all amorphous and
crystalline forms of azithromycin including all polymorphs,
isomorphs, clathrates, salts, solvates and hydrates of azithromycin
other than form A, the dihydrate form of azithromycin (azithromycin
dihydrate).
[0033] Non-dihydrate azithromycin includes a hygroscopic hydrate of
azithromycin, as disclosed in U.S. Pat. No. 4,474,768, which is
designated herein as "form B".
[0034] Azithromycin may be present in several alternate crystalline
non-dihydrate forms, including forms D, E, F, G, H, J, M, N, O, P,
Q and R, which are disclosed in U.S. patent application Ser. No.
10/152,106, filed 21 May 2002, the teachings of which are
incorporated herein, by reference, in their entirety.
[0035] Both Family I and Family II isomorphs are hydrates and/or
solvates of azithromycin. The solvent molecules in the cavities
have a tendency to exchange between solvent and water under
specific conditions. Therefore, the solvent/water content of the
isomorphs may vary to a certain extent. Forms B, F, G, H, J, M, N,
O, and P belong to Family I azithromycin and belong to a monoclinic
P2.sub.1 space group with cell dimensions of a=16.3.+-.0.3 .ANG.,
b=16.2.+-.0.3 .ANG., c=18.4.+-.0.3 .ANG.and beta=109.+-.2.degree..
Forms D, E and R belong to Family II azithromycin and belong to an
orthorhombic P2.sub.12.sub.12.sub.1 space group with cell
dimensions of a=8.9.+-.0.4 .ANG., b=12.3.+-.0.5 .ANG. and
c=45.8.+-.0.5 .ANG.. Form Q is distinct from Families I and II.
[0036] Form D azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.C.sub.6H.sub.12 in its
single crystal structure, being azithromycin monohydrate
monocyclohexane solvate. Form D is further characterized as
containing 2-6% water and 3-12% cyclohexane by weight in powder
samples. From single crystal data, the calculated water and
cyclohexane content of form D is 2.1 and 9.9%, respectively.
[0037] Form E azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.C.sub.4H.sub.8O being
azithromycin monohydrate mono-tetrahydrofuran solvate. Form E is a
monohydrate and mono-THF solvate by single crystal analysis.
[0038] Form G azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.1.5H.sub.2O in the single crystal
structure, being azithromycin sesquihydrate. Form G is further
characterized as containing 2.5-6% water and <1% organic
solvent(s) by weight in powder samples. The single crystal
structure of form G consists of two azithromycin molecules and
three water molecules per asymmetric unit. This corresponds to a
sesquihydrate with a theoretical water content of 3.5%. The water
content of powder samples of form G ranges from about 2.5 to about
6%. The total residual organic solvent is less than 1% of the
corresponding solvent used for crystallization. azithromycin
monohydrate hemi-1,2 propanediol solvate. Form H is a
monohydrate/hemi-propylene glycol solvate of azithromycin free
base.
[0039] Form J azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.0.5C.sub.3H.sub.7OH in the
single crystal structure, being azithromycin monohydrate
hemi-n-propanol solvate. Form J is further characterized as
containing 2-5% water and 1-5% 1-propanol by weight in powder
samples. The calculated solvent content is about 3.8% n-propanol
and about 2.3% water.
[0040] Form M azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.0.5C.sub.3H.sub.7OH, being
azithromycin monohydrate hemi-isopropanol solvate. Form M is
further characterized as containing 2-5% water and 1-4% 2-propanol
by weight in powder samples. The single crystal structure of form M
would be a monohydrate/hemi-isopropranolate.
[0041] Form N azithromycin is a mixture of isomorphs of Family I.
The mixture may contain variable percentages of isomorphs, F, G, H,
J, M and others, and variable amounts of water and organic
solvents, such as ethanol, isopropanol, n-propanol, propylene
glycol, acetone, acetonitrile, butanol, pentanol, etc. The weight
percent of water can range from 1-5.3% and the total weight percent
of organic solvents can be 2-5% with each solvent content of 0.5 to
4%.
[0042] Form O azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.0.5H.sub.2O.0.5C.sub.4H.sub.9OH,
being a hemihydrate hemi-n-butanol solvate of azithromycin free
base by single crystal structural data.
[0043] Form P azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.0.5C.sub.5H.sub.12O being
azithromycin monohydrate hemi-n-pentanol solvate.
[0044] Form Q azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2.0.5C.sub.4H.sub.8O being
azithromycin monohydrate hemi-tetrahydrofuran solvate. It contains
about 4% water and about 4.5% THF.
[0045] Form R azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.C.sub.5H.sub.12O being
azithromycin monohydrate mono-methyl tert-butyl ether solvate. Form
R has a theoretical water content of 2.1 weight % and a theoretical
methyl tert-butyl ether content of 10.3 weight %.
[0046] Form F azithromycin is of the formula
C.sub.38H.sub.72N.sub.2O.sub.12.H.sub.2O.0.5C.sub.2H.sub.5OH in the
single crystal structure, being azithromycin monohydrate
hemi-ethanol solvate. Form F is further characterized as containing
2-5% water and 1-4% ethanol by weight in powder samples.
[0047] The single crystal of form F is crystallized in a monoclinic
space group, P2.sub.1, with the asymmetric unit containing two
azithromycins, two waters, and one ethanol, as a
monohydrate/hemi-ethanolate. It is isomorphic to all Family I
azithromycin crystalline forms. The theoretical water and ethanol
contents are 2.3 and 2.9%, respectively.
[0048] The term "non-granulated" azithromycin, as used herein,
means that the azithromycin is not dry granulated, such as by
slugging or roller compaction, or wet granulated.
[0049] "Bulk azithromcyin", as used herein, means azithromycin
particles without added excipients.
[0050] The term "pharmaceutically acceptable" means that which is
generally safe, non-toxic and neither biologically nor otherwise
undesirable and includes that which are acceptable for veterinary
use as well as human pharmaceutical use.
[0051] The phrase "directly compressible formulation" means a
formulation which can be compressed into a pharmaceutically
acceptable tablet without a prior granulation step.
[0052] The term "compressibility" means the degree to which a
formulation decreases in volume when air is removed.
[0053] The term "compactibility" means the ease with which a
formulation is compressed into tablets possessing acceptable
hardness properties.
[0054] The term "free flowing" as used herein means the ability of
material to flow without mechanical agitation on standard tableting
equipment utilizing gravity to induce flow, such as an F-press.
Good flowing materials result in dosage forms with good weight
uniformity as evidenced by low relative standard deviation (% RSD)
or coefficient of variation (% CV) of dosage form weight.
[0055] The term "fines" as used herein refers to particles with a
diameter of less than about 44 microns, as measured by the Malvern
method.
[0056] The term "F-press" as used herein refers to a MANESTY
F-PRESS (Manesty Machines Ltd., UK).
[0057] The term "mgA" refers to milligrams of the free base of
azithromycin.
[0058] In the method of the present invention, the azithromycin
used may be milled or unmilled bulk drug.
[0059] The dry blend, of the present invention, is used to produce
non-dihydrate azithromycin tablets by direct compression.
Typically, the dry blend contains from about 1% to about 80% of
non-dihydrate azithromycin. Preferably, the azithromycin, in the
dry blend, is non-granulated.
[0060] It is also preferred that the azithromycin in the dry blend
comprise a form of non-dihydrate azithromycin selected from forms
B, D, E, F, G, H, J, M, N, O, P, Q, R, or mixtures thereof.
[0061] In addition to the non-dihydrate azithromycin, the dry blend
of the present invention, also includes at least one
pharmaceutically acceptable suitable excipient. The excipients may
include processing aids that improve the direct compression
tablet-forming properties of the dry blend.
[0062] In one embodiment of the present invention, the dry blend is
suitable for use in forming azithromycin tablets through
gravity-fed, direct compression tableting.
[0063] To be suitable for direct compression on a gravity fed
tableting press, particularly at higher azithromycin loadings, such
as 45% or more, the particle size profile of azithromycin, is
critical. As azithromycin loading increases, the fines in the bulk
azithromycin tend to further degrade the flow properties of the dry
blend as they constitute a higher percentage of the total particles
within the dry blend. Therefore, it is necessary to reduce the
amount of azithromycin fines within the dry blend to obtain
acceptable flow on a gravity fed tableting press and make a tablet
having acceptable friability.
[0064] By "gravity fed tableting press" it is meant that a
pharmaceutical formulation is not force fed into a die, and that
the flow of the pharmaceutical formulation is induced by gravity.
An example of a gravity fed tableting press is the Manesty
F-press.
[0065] In this embodiment of the present invention, the particle
size distribution was determined using a Malvern Mastersizer S
(Malvern Instruments, Worcestershire, UK) with a MS-1-Small Volume
Sample Dispersion Unit. This unit allowed for particle size
analysis through a wet sample dispersion step and subsequent
particle size measurements using laser diffraction.
[0066] In this embodiment of the present invention, to achieve
suitable flow properties for the dry blend, particularly at higher
azithromycin loadings, typically, less than about 20% of the
azithromycin particles, by volume, in the dry blend, should have a
diameter of 44 .mu.m or less. Preferably, less than about 14% of
the azithromycin particles should have a diameter of 44 .mu.m or
less.
[0067] Likewise, in the present dry blend, it is preferred that
less than about 27% of the azithromycin particles should have a
diameter of 74 .mu.m or less.
[0068] Further, in the present dry blend, it is preferred that less
than about 60% of the azithromycin particles should have a diameter
of 105 .mu.m or less. More preferably less than about 50% of the
azithromycin particles should have a diameter of 105 .mu.m or
less.
[0069] Even more preferably, less than about 6% of the azithromycin
particles should have a diameter of 16 .mu.m or less.
[0070] In a more preferred embodiment of the present invention, the
dry blend contains less than about 6% of the azithromycin
particles, by volume, with a diameter of about 16 .mu.m or less,
and less than about 20% of the azithromycin particles, by volume,
with a diameter of about 44 .mu.m or less. Even more preferably,
less than about 14% of the azithromycin particles should have a
diameter of 44 .mu.m or less.
[0071] In an even more preferred embodiment, the dry blend contains
less than about 6% of the azithromycin particles, by volume, with a
diameter of about 16 .mu.m, or less, less than about 20% of the
azithromycin particles, by volume, with a diameter of about 44
.mu.m, or less, and less than about 27% of the azithromycin
particles, by volume, with a diameter of about 74 .mu.m or less.
Even more preferably, less than about 14% of the azithromycin
particles should have a diameter of 44 .mu.m or less.
[0072] In yet an even more preferred embodiment, the dry blend
contains less than about 6% of the azithromycin particles, by
volume, with a diameter of about 16 .mu.m, or less, less than about
20% of the azithromycin particles, by volume, with a diameter of
about 44 .mu.m, or less, less than about 27% of the azithromycin
particles, by volume, with a diameter of about 74 .mu.m, or less,
and less than about 60% of the azithromycin particles, by volume,
with a diameter of about 105 .mu.m or less. Even more preferably,
less than about 14% of the azithromycin particles should have a
diameter of 44 .mu.m, or less, and less than about 50% of the
azithromycin particles should have a diameter of 105 .mu.m or
less.
[0073] The flow properties of a dry blend may be evaluated by a
number of methods known in the art. One way of characterizing
formulation properties of a powdered material is by bulk density
measurements. A simple method to provide a description of flow
characteristics by bulk density measurement is Carr's
Compressibility Index (Carr's Index).
[0074] Carr's Compressibility Index is a simple test to evaluate
flowability by comparing both the initial and final (tapped)
densities and the rate of packing down. A useful empirical guide to
flow is given by Carr's compressibility index: Compressibility
Index(%)=[(tapped density-initial density)/tapped
density].times.100 In the present invention, it was found that the
Carr's Compressibility Index of the dry blend provided a good
indication of the flow characteristics and thus, the suitability
for using the dry blend to prepare tablets through gravity-fed,
direct compression tableting. Generally, it was observed that
formulations with Carr's Compressibility Index values of less than
about 34% resulted in acceptable flow and tabletability on an
F-press, whereas formulations with values of 34%, or more, resulted
in poor flow and an inability to form suitable tablets on an
F-press. Therefore, in the present invention, the dry blend should
have a Carr's Compressibility Index less than about 34%, more
preferably less than about 31%, and even more preferably less than
about 28%.
[0075] Another measurement of particle flow is the internal angle
of friction that may be determined by shear cell experiments. The
primary difference in the flow behavior of liquids and powders is
in their internal friction. The lack of internal friction of
liquids allows them to form level surfaces at rest, while internal
friction in powders allows the formation of heaps or other
non-level surfaces.
[0076] Internal friction of powders is typically characterized
using a shear cell, which is a device that places a powder sample
under known physical stress conditions and measures its response to
those stresses, as disclosed in "Some Measurements of Friction in
Simple Powder Beds", Heistand, E. N. and Wilcox, C. J. (J. Pharm.
Sci. 57 (1968) 1421), incorporated herein by reference. The
response is reported as an angle of internal friction. This
parameter is a characteristic of the powders measured and varies
between materials. The lower the value of the angle of internal
friction, the better flowing the powder is. This parameter may be
used as a predictor of tablet weight variation during tableting
operations, since the powder fill weight, and therefore the tablet
weight, is dependent on the ability of the powder to quickly flow
into the tableting die. In the present invention, dry blends,
suitable for use in the preparation of tablets by direct
compression, had angles of internal friction of less than about
34.degree., and more preferably less than about 31.degree..
[0077] Even more preferably, dry blends of the present invention
have a Carr's Compressibility Index of less than about 34% and an
internal angle of friction of less than about 34.degree..
[0078] Most preferably, dry blends of the present invention have a
Carr's Compressibility Index of less than about 28% and an internal
angle of friction of less than about 31.degree..
[0079] A dry blend, having properties within the aforementioned
ranges, may be achieved by methods including, but not limited to,
providing suitable excipients, by increasing particle size, or by
modifying processing conditions. Typically, addition of excipients
provides a means to modify the flow profile of a low dose
pharmaceutical formulation, as commercially available excipients
have good flow properties. For dry blends, having higher
azithromycin loadings, Carr's Compressibility Index and/or internal
angles of friction with the aforementioned ranges may be achieved
by obtaining the azithromycin particle size distribution discussed
above.
[0080] Accordingly, the particle size profile of the azithromycin
should be evaluated, and if necessary, the azithromycin should be
processed to achieve the particle size profile.
[0081] To produce azithromycin particles having the desired
particle size distribution, the bulk azithromycin may be further
processed by methods including, but not limited to, 1) milling 2)
screening 3) recrystallization and 4) granulation, including dry
and wet granulation. The aforementioned further processing methods
may be used alone or in combination.
[0082] Milling involves subjecting the drug to a shear force such
that the particle size of the drug is reduced. The milling may be
an aggressive process where the particle size is reduced
significantly, or it may be a non-aggressive process where the
particle size is not reduced significantly, but merely done to
delump or break up larger clumps of drug formed in the bulk
drug.
[0083] In the pharmaceutical industry, milling is often used to
reduce the particle size of solid materials. Many types of mills
are available including pin mills, hammer mills and jet mills. One
of the most commonly used types of mill is the hammer mill. The
hammer mill utilizes a high-speed rotor to which a number of fixed
or swinging hammers are attached. The hammers can be attached such
that either the knife face or the hammer face contacts the
material. As material is fed into the mill, it impacts on the
rotating hammers and breaks up into smaller particles. A screen is
located below the hammers, which allows the smaller particles to
pass through the openings in the screen. Larger particles are
retained in the mill and continue to be broken up by the hammers
until the azithromycin particles are fine enough to flow through
the screen.
[0084] The azithromycin particles may optionally be screened. In
screening, bulk drug is placed through a mesh screen or series of
mesh screens to obtain the desired particle size for the bulk
drug.
[0085] Several methods are known for increasing the particle size
of drugs, including, but not limited to, granulation and
recrystallization. Wet granulation, for example, involves the use
of a granulating liquid that causes the azithromycin particles to
agglomerate and thus increase the particle size. Suitable wet
granulation methods for the preparation of azithromycin particles
are disclosed in copending U.S. Provisional Application Ser. No.
60/343,469, titled "Methods for Wet Granulating Azithromycin",
filed Dec. 21, 2001 and in copending International. Application
Docket Number PC23065A titled "Methods for Wet Granulating
Azithromycin". Suitable methods for dry granulating azithromycin
particles are disclosed in copending U.S. Provisional Application
Ser. No. 60/354.041, titled "Dry Granulated Formulations of
Azithromycin", filed Feb. 1, 2002.
[0086] In the present invention, wet granulation of the bulk drug
without the use of additional excipients may be used to increase
the particle size of the material
[0087] Recrystallization involves dissolving a bulk drug and
allowing it to reform as new crystals which are adequate in
particle size for the use in an azithromycin direct compression
tablet.
[0088] Another method to increase the particle size is to sieve the
bulk drug to remove the smaller particles.
[0089] While it was found that the azithromycin particle size
distribution was important for achieving acceptable flow properties
on gravity fed tableting equipment, dry blends with lower
azithromycin loadings or with an undesirable amount of fines may
still be directly compressed to form tablets by adjusting the
processing conditions, equipment and/or excipients as
necessary.
[0090] For example, a dry blend with a higher amount of fines may
be tableted, by direct compression, through using forced fed
tableting equipment. Methods of assisting flow, or force feeding,
are well known in the art.
[0091] Thus, in an alternative embodiment of the present invention,
a non-dihydrate azithromycin dry blend can be mechanically
processed in a manner to compensate for poor flow properties. For
example, the material may be introduced into the die using a
mechanical force feeder. A mechanical force feeder might be used
when poor weight control is obtained using a pharmaceutical
formulation.
[0092] Further, the flow properties of a dry blend may also be
modified by decreasing the percentage of bulk azithromycin in the
dry blend.
[0093] The amount of azithromycin and of the additional excipients
and processing aids may be varied provided suitable direct
compressibility properties of the pharmaceutical formulation are
achieved, as defined by flow measurements such as Carr's
Compressibility Index and internal angle of friction as described
herein.
[0094] Any additional excipients, such as diluent or dry binder
should preferably have good flow characteristics and
compactibility. Excipients having good flow properties are readily
available.
[0095] In the dry blend, of the present invention, excipients
suitable for use in direct compression include, but are not limited
to, binders, diluents, disintegrants, lubricants, fillers,
carriers, and the like.
[0096] Binders are used to impart cohesive qualities to a tablet
formulation, and thus ensure that a tablet remains intact after
compaction. Suitable binder materials include, but are not limited
to, microcrystalline cellulose, gelatin, sugars (including sucrose,
glucose, dextrose and maltodextrin), polyethylene glycol, waxes,
natural and synthetic gums, polyvinylpyrrolidone, cellulosic
polymers (including hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methyl cellulose, hydroxyethyl cellulose, and the
like).
[0097] Lubricants can be employed herein in the manufacture of
certain dosage forms, and will usually be employed when producing
tablets. In the present invention, a lubricant is added just before
the tableting step, and is mixed with the formulation for a minimum
period of time to obtain good dispersal. The lubricant employed in
a composition of the present invention may be one or more
compounds. Examples of suitable lubricants include, but are not
limited to, magnesium stearate, calcium stearate, zinc stearate,
stearic acid, talc, glyceryl behenate, polyethylene glycol,
polyethylene oxide polymers (for example, available under the
registered trademarks of Carbowax.TM. for polyethylene glycol and
Polyox.TM. for polyethylene oxide from Dow Chemical Company,
Midland, Mich.), 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, caIcium stearate, zinc stearate and mixtures of
magnesium stearate with sodium lauryl sulfate. Lubricants may
comprise from about 0.25% to about 10% of the tablet weight, more
preferably from about 0.5% to about 3%.
[0098] Disintegrants are used to facilitate tablet disintegration
or "breakup" after administration, and are generally starches,
clays, celluloses, algins, gums or crosslinked polymers. Suitable
disintegrants include, but are not limited to, crosslinked
polyvinylpyrrolidone (PVP-XL), sodium starch glycolate, and
croscarmellose sodium. If desired, the pharmaceutical formulation
may also contain minor amounts of nontoxic auxiliary substances
such as wetting or emulsifying agents, pH buffering agents and the
like, for example, sodium acetate, sorbitan monolaurate,
triethanolamine sodium acetate, triethanolamine oleate, sodium
lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene
sorbitan fatty acid esters, etc.
[0099] The diluent employed in a composition of the present
invention may be one or more compounds which are capable of
providing compactibility and good flow. A variety of materials may
be used as fillers or diluents. Suitable diluents or fillers
include, but are not limited to, lactose (monohydrate, spray-dried
monohydrate, anhydrous and the like), sucrose, dextrose, mannitol,
sorbitol, starch, cellulose (e.g. microcrystalline cellulose;
Avicel.RTM., FMC Biopolymer, Philadelphia, Pa.), dihydrated or
anhydrous dibasic calcium phosphate, calcium carbonate, calcium
sulfate, and others as known in the art. More preferably,
free-flowing diluents which can improve blend flow are: spray-dried
lactose monohydrate (such as 316 Fast Flo.RTM., Foremost Farms,
Baraboo, Wis. and Phamatose.RTM. DCL 11, DMV International Pharma,
Veghel, The Netherlands), agglomerated free-flowing lactose
monohydrate (such as Tablettose.RTM., Meggle GMBH, Wasserburg,
Germany), granulated lactose monohydrate (such as Pharmatose.RTM.
DCL 15, DMV International Pharma, Veghel, The Netherlands), roller
dried lactose monohydrate (such as Pharmatose.RTM. DCL 21, DMV
International Pharma, Veghel, The Netherlands), direct compression
lactose, anhydrous (such as Pharmatose.RTM. DCL 40, DMV
International Pharma, Veghel, The Netherlands and Anhydrous DT
Lactose, Quest International Inc., Hoffman Estates, Ill.),
spray-dried lactose with microcrystalline cellulose (MicroLac.RTM.
100, Meggle GMBH, Wasserburg, Germany), spray-dried lactose with
cellulose (Cellactose.RTM., Meggle GMBH, Wasserburg, Germany),
direct compression sucrose (such as Sugartab.RTM., Penwest
Pharmaceuticals Co., Patterson, N.Y. and Nu-Tab.RTM., DMV
International Pharma, Veghel, The Netherlands), co-crystallized
sucrose and modified dextrins (Di-Pac(.RTM., DominoSpecialty
Ingredients, Baltimore, Md.), spray-dried dextrates (Emdex.RTM.,
Penwest Pharmaceuticals Co., Patterson, N.Y.), coarse dextrose
(such as Cerelose.RTM. Coarse Dextrose 2037, Corn Products
International, Inc., Westchester, Ill.), agglomerated dextrose
(such as Unidex.RTM. 2034, Corn Products International, Inc.,
Westchester, Ill.), spray-dried maltodextrin (such as Maltrin.RTM.
M 510, Grain Processing Corp., Muscatine, Iowa), fine granular
maltodextrin (such as Maltrin.RTM. M 150, Grain Processing Corp.,
Muscatine, Iowa), spray-dried maltose (Advantose.TM. 100 Maltose
Powder, SPI Pharma, New Castle, Del.), spray-dried mannitol (such
as Mannogem.TM. EZ Spray Dried Mannitol, SPI Pharma, New Castle,
Del. and Parteck.TM. M, EM Industries, Inc., Hawthorne, N.Y.),
granular mannitol (such as Mannitol Granular 2080, SPI Pharma, New
Castle, Del. and Mannitol Granular, SPI Pharma, New Castle, Del.),
spray-dried sorbitol (such as Parteck.TM.SI[Sorbitol Instant.TM.],
EM Industries, Inc., Hawthorne, N.Y.), coarse sorbitol (such as
grades 834, 2016 and 1162 Crystalline Sorbitol, SPI Pharma, New
Castle, Del.), direct compression fructose co-dried with starch
(Advantose.TM. FS95 Fructose, SPI Pharma, New Castle, Del.),
pregelatinized corn starch (such as Spress.RTM. B820, Grain
Processing Corp., Muscatine, Iowa and Starch 1500.RTM., Colorcon
Inc., West Point, Pa.), high density microcrystalline cellulose
(such as Avicel.RTM. PH-302, FMC Biopolymer, Philadelphia, Pa.,
Pharmacel.RTM. 200, DMV International Pharma, Veghel, The
Netherlands and Emcocel.RTM. HD90, Penwest Pharmaceuticals Co.,
Patterson, N.Y.), direct compression microcrystalline cellulose
(such as Avicel.RTM. PH-200, FMC Biopolymer, Philadelphia, Pa.,
Pharmacel.RTM. 102, DMV International Pharma, Veghel, The
Netherlands and Emcocel.RTM. 90M and Emcocel.RTM. LP200, Penwest
Pharmaceuticals Co., Patterson, N.Y.), direct compression
silicified microcrystalline cellulose (such as Prosolv SMCC.TM. 90,
Penwest Pharmaceuticals Co., Patterson, N.Y.), free-flowing grades
of dibasic calcium phosphate, dihydrate (such as Emcompress.RTM.,
Penwest Pharmaceuticals Co., Patterson, N.Y. and Di-Tab.RTM.,
Rhodia Inc, Cranbury, N.J.) and free-flowing grades of dibasic
calcium phosphate, anhydrous (such as Anhydrous Emcompress.RTM.,
Penwest Pharmaceuticals Co., Patterson, N.Y. and A-Tab.RTM., Rhodia
Inc, Cranbury, N.J.). Most preferred free-flowing diluents are
spray-dried lactose and free-flowing lactose monohydrate grades,
high density and direct compression grades of microcrystalline
cellulose and silicified microcrystalline cellulose, spray-dried
dextrates, spray-dried and granular mannitol, spray-dried and
coarse sorbitol and free-flowing grades of dibasic calcium
phosphate, dihydrate.
[0100] In the present invention, it is more preferred that these
diluents be used to reduce the Carr's index and to reduce the angle
of internal friction for azithromycin formulations, particularly in
dry blends containing an azithromycin drug loading of about 30% or
more. The use of these diluents is even more particularly preferred
when about 20% or more of the azithromycin particles have a
diameter of about 44 microns or less.
[0101] 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.
[0102] For sachets and powders for suspension, the preferred
flavoring comprises a combination of cherry, banana and vanilla
flavors as further described in Table XIII of U.S. Pat. No.
5,605,889. The teachings of U.S. Pat. No. 5,605,889, in their
entirety, are incorporated herein by reference.
[0103] Other excipients and coloring agents may also be added to
azithromycin tablets. Coloring agents include, but are not limited
to, titanium dioxide and/or dyes suitable for food such as those
known as F. D. & C, dyes, aluminum lakes 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.
[0104] Dry blends, that are suitable for direct compression
tableting, in the present invention, include up to about 80 weight
percent non-dihydrate azithromycin, from about 10 wt % to about 90
wt % binder, from 0 wt % to about 85 wt % diluent, from 2 wt % to
about 15 wt % disintegrant; and from about 0.25 wt % to about 10 wt
% lubricant.
[0105] In a further embodiment, the dry blend contains up to about
80 wt % azithromycin, from about 2 wt % to about 10 wt %
disintegrant, from about 0.5 wt % to about 8 wt % lubricant; and
from about 0 wt % to about 85 wt % diluent.
[0106] To prepare the dry blend, the various components may be
weighed, delumped and combined except for the lubricating agent.
The mixing may be carried out for a sufficient period of time to
produce a homogeneous blend, and then the lubricant may be added.
Afterwards, the final mixing may be carried out. The dry blend may
be stored for later use or tableted on suitable equipment.
[0107] The components of the dry blend, including the azithromycin
and at least one excipient, may be combined by blending, mixing,
stirring, shaking, tumbling, rolling or by any other methods of
combining the formulation components to achieve a homogeneous
blend. It is preferable that the azithromycin and excipients are
combined under low shear conditions in a suitable apparatus, such
as a V-blender, tote blender, double cone blender or any other
apparatus capable of functioning under preferred low shear
conditions. Lubricant is typically added in the last step.
[0108] The invention should not be considered limited to these
particular conditions for combining the components and it will be
understood, based on this disclosure that the advantageous
properties can be achieved through other conditions provided the
components retain their basic properties and substantial
homogeneity of the blended formulation components of the
formulation is otherwise achieved without any significant
segregation.
[0109] In one embodiment, for preparing the dry blend, the
components are weighed and placed, except for the lubricant, into a
blending container. Blending is performed for a period of time to
produce a homogenous blend using suitable mixing equipment. The dry
blend may be passed through a mesh screen to delump the dry blend.
The screened dry blend may be returned to the blending container
and blended for an additional period of time. The lubricant, such
as magnesium stearate, may then be added and the dry blend may be
mixed for an additional period of time.
[0110] The dry blend is typically free flowing and may be employed
in the preparation of a tablet in standard tableting equipment, or
stored for later use.
[0111] Direct compression tablets provided by this invention are
solid, intended for oral use, of uniform appearance and with
sufficient mechanical strength to withstand possible damage from
storage and transport or a subsequent coating process. In order to
prepare a tablet having suitable properties by direct compression
methods, the dry blend must have good flow properties, good
compactability and other suitable physical characteristics.
[0112] The dry blend of the present invention may be employed in
the preparation of a tablet using tableting means, such as,
standard tableting equipment known in the industry for gravity fed
tableting processes and for equipment having means to force feed
the pharmaceutical formulation. In one embodiment, the dry blend is
used to prepare tablets on a single station tableting press.
Tablets comprising azithromycin are useful for the treatment of
bacterial and protozoal infections.
[0113] In a further aspect of the present invention, an
azithromycin tablet is made according to the following steps.
First, azithromycin and at least one excipient are blended to form
a dry blend. A lubricant may be added to the dry blend during, or
subsequent to, the blending of the azithromycin and other
excipients. The lubricated dry blend is then compacted to produce a
direct compression tablet.
[0114] Optionally, the dry blend may be subjected to a delumping
process after initial blending. In addition, the lubricated blend
may first be subjected to a precompression step on a rotary tablet
press prior to the final compression step for tablet formation. The
lubricated blend may optionally be force fed into a die prior to
compression.
[0115] Suitable dry blends, prior to being lubricated, may comprise
up to about 80% by weight of azithromycin, from about 10% to about
90% binder, from 0% to about 85% filler, from 2% to about 15%
disintegrant.
[0116] The lubricated blend may comprise from about 0.25% to about
10% lubricant more preferably from about 0.5% to about 3% of
lubricant. The particular amount of lubricant needed will depend,
in part, on the particular lubricant chosen. More preferably, a
suitable lubricated dry blend comprises from about 30% to about 60%
azithromycin.
[0117] In one embodiment, the direct compression tablet may
comprise an amount of lubricant that is greater than about 1% by
weight, based on the tablet weight, and less than about 6% by
weight, based on the tablet weight. In a further embodiment, the
direct compression tablet may comprise an amount of lubricant that
is greater than or equal to about 2% by weight, based on the tablet
weight, and less than or equal to about 5% by weight, based on the
tablet weight. In an even further embodiment, the direct
compression tablet may comprise an amount of lubricant that is
greater than or equal to about 3% by weight, based on the tablet
weight, and less than or equal to about 5% by weight, based on the
tablet weight.
[0118] In one embodiment, the direct compression tablet may
comprise an amount of glidant that is less than about 3% by weight,
based on the tablet weight. In a further embodiment, the direct
compression tablet may comprise an amount of glidant that is less
than about 1% by weight, based on the tablet weight. In an even
further embodiment, the tablet may comprise an amount of glidant
that is less than about 0.5% by weight, based on the weight of the
glidant. Suitable glidants include magnesium trisilicate, powdered
cellulose, starch, talc, tribasic calcium phosphate, stearate salts
and colloidal silicon dioxide. Most preferred glidants are talc,
magnesium stearate and colloidal silicon dioxide.
[0119] Typical compacting techniques for the preparation of a
tablet by direct compression utilize a piston like device with
three stages in each cycle 1) filling (adding the constituents of
the tablet to the compression chamber) 2) compaction (forming the
tablet) and 3) ejection (removing the tablet). The cycle is then
repeated. A representative tablet press is a Manesty Express 20
rotary press, manufactured by Manesty Machines Ltd., Liverpool,
England, and many others are available. The equipment may be
gravity fed or it may utilize means to force feed the lubricated
blend into the die. One common method is to use a feed frame, which
is equipped with moving paddles to aid in feeding the blend into
the die cavities. It should be understood that compacting methods
and techniques as described in the present specification are not
limited to any particular equipment.
[0120] In one embodiment, a high speed tablet press may be used. In
a further embodiment, a single station tableting press may be used.
Flow of the blend on high speed tablet presses is very important to
good weight control of the tablet. The use of a force feeder often
improves tablet weight control for poorer flowing blends. Another
common feature of high speed tablet presses is the ability to use
precompression. Precompression taps the blend when the die is full
with blend before the final compression step forms the tablet.
[0121] The tablets may be any shape as long as the tablet is in a
form that it may be administered orally and is not prone to capping
or exceeds the desired friability. The tablets may be round,
oblong, thick or thin, large or small in diameter, flat or convex,
scored or unscored, and imprinted. In one embodiment, the tablets
are round, in a further embodiment, the tablets are modified oval
or modified capsule shaped.
[0122] In one embodiment, the tablet may be a modified capsule
shape containing about 250 mgA, about 450 mg total weight. In one
embodiment, the dimensions of the aforementioned tablet are
0.26''.times.0.53''. In a further embodiment, the tablet may be a
modified oval shape containing about 500 mgA, about 900 mg total
weight. In one embodiment, the dimensions of the tablet are
0.33''.times.0.67''. In an even further embodiment, the tablet may
be a modified oval shape containing about 600 mgA, about 1070 mg
total weight. In one embodiment, the dimensions of the
aforementioned tablet are 0.41''.times.0.75''. A reference to
tablet shapes can be found in FIG. 25, page 51 of the Tableting
Specification Manual, fourth edition, published by the American
Pharmaceutical Association, Washington, D.C., 1995; incorporated
herein by reference in its entirety.
[0123] In one embodiment, the direct compression tablet may
comprise an amount of azithromycin equivalent to about 250 mgA. In
a further embodiment the direct compression tablet may comprise an
amount of azithromycin equivalent to about 500 mgA. In an even
further embodiment the direct compression tablet may comprise an
amount of azithromycin equivalent to about 600 mgA.
[0124] The tablets prepared from the pharmaceutical formulation of
the present invention exhibit acceptable physical characteristics
including good friability and hardness. The resistance of a tablet
to chipping, abrasion or breakage under conditions of storage and
transportation depends on its hardness and friability.
[0125] Friability is a standard test known to one skilled in the
art. Friability is measured under standardized conditions by
weighing out a certain number of tablets (generally 20 tablets or
less), placing them in a rotating Plexiglas drum in which they are
lifted during replicate revolutions by a radial lever, and then
dropped approximately 8 inches. After replicate revolutions
(typically 100 revolutions at 25 rpm), the tablets are reweighed
and the percentage of formulation abraded or chipped is calculated.
The friability of the tablets, of the present invention, is
preferably in the range of about 0% to 3%, and values about 1%, or
less, are considered acceptable for most drug and food tablet
contexts. Friability which approaches 0% is particularly
preferred.
[0126] If desired, the tablet may be coated. The reasons for
coating a tablet may include masking the taste of the drug, making
tablets easier to swallow, protection against chipping during
packaging, a barrier for moisture or light to improve product
stability, and enhance product appearance or recognition.
[0127] The coating process may include the use of a coating
solution or suspension, usually aqueous that has acceptable
viscosity for spraying and properties for it to adhere to the
surface of the tablet when applied. During the coating process, the
coating solution or suspension is atomized into fine droplets that
come into contact with the tablet. As the droplets dry, a film is
formed on the tablet which is the coating. There are several types
of coating equipment used to coat tablets. One type is the pan
coater in which tablets are rotated in a pan and coating solution
is applied to the tablets as tablets tumble in the pan. Another
coating process involves suspending the tablets in a column of air
while the coating solution is sprayed onto the tablet (fluid bed
process). One example of this is the Wurster column coating
process. The tablet may be coated by any known process and the
manner of application is not limited to any particular
equipment.
[0128] The tablet coating(s) may be a white or colored Opadry.RTM.
(Colorcon, West Point Pa.) suspension or a clear Opadry.RTM.
solution. Alternatively a typical coating formulation would consist
of a film forming polymer(s) such as hydroxypropyl methylcellulose
(HPMC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP)
with additional ingredients such as plasticizers, opacifiers,
colorants, and antioxidants. Sugar coating could also be used.
[0129] The dry blends, of the present invention, are suitable for
use in the preparation of a free flowing pharmaceutical
formulation. The formulation may be useful, for example, as a
preblend and for use in dosage forms such as capsules, sachets and
powders for suspension.
[0130] Alternatively, pharmaceutical formulations comprising
greater than about 80% by weight of azithromycin, and having the
good flow properties described, may be used to prepare other dosage
forms, such as capsules. In addition, it might be advantageous to
store bulk azithromycin and excipients separately prior to a direct
compression tableting operation.
[0131] Azithromycin formulations as defined in this aspect of the
invention may contain bulk drug by itself or bulk drug with one or
more excipients such as binders, diluents, disintegrants,
lubricants, fillers, carriers, and the like, as set forth
above.
[0132] The formulation may also be used in other applications,
including but not limited to filling a capsule dosage form or any
other process that requires good flow in the pharmaceutical
formulation.
[0133] The pharmaceutical compositions of the present invention may
be used for the treatment of bacterial or protozoal infections. The
term "treatment", as used herein, unless otherwise indicated, means
the treatment or prevention of a bacterial or protozoal infection,
including curing, reducing the symptoms of or slowing the progress
of said infection.
[0134] As used herein, unless otherwise indicated, the term
"bacterial infection(s)" or "protozoal infection(s)" includes
bacterial infections and protozoal infections that occur in
mammals, fish and birds as well as disorders related to bacterial
infections and protozoal infections that may be treated or
prevented by administering antibiotics such as the compound of the
present invention. Such bacterial infections and protozoal
infections and disorders related to such infections include, but
are not limited to, the following: pneumonia, otitis media,
sinusitis, bronchitis, tonsillitis, and mastoiditis related to
infection by Streptococcus pneumoniae, Haemophilus influenzae,
Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus
spp.; pharynigitis, rheumatic fever, and glomerulonephritis related
to infection by Streptococcus pyogenes, Groups C and G
streptococci, Clostridium diptheriae, or Actinobacillus
haemolyticum; respiratory tract infections related to infection by
Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus
pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae;
uncomplicated skin and soft tissue infections, abscesses and
osteomyelitis, and puerperal fever related to. infection by
Staphylococcus aureus, coagulase-positive staphylococci (i.e., S.
epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes,
Streptococcus agalactiae, Streptococcal Groups C-F (minute-colony
streptococci), viridans streptococci, Corynebacterium minutissimum,
Clostridium spp., or Bartonella henselae; uncomplicated acute
urinary tract infections related to infection by Staphylococcus
saprophyticus or Enterococcus spp.; urethritis and cervicitis; and
sexually transmitted diseases related to infection by Chlamydia
trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma
urealyticum, or Neisseria gonorroeae; toxin diseases related to
infection by S. aureus (food poisoning and Toxic shock syndrome),
or Groups A, B, and C streptococci; ulcers related to infection by
Helicobacter pylori; systemic febrile syndromes related to
infection by Borrelia recurrentis; Lyme disease related to
infection by Borrelia burgdorferi; conjunctivitis, keratitis, and
dacrocystitis related to infection by Chlamydia trachomatis,
Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.
influenzae, or Listeria spp.; disseminated Mycobacterium avium
complex (MAC) disease related to infection by Mycobacterium avium,
or Mycobacterium intracellulare; gastroenteritis related to
infection by Campylobacter jejuni; intestinal protozoa related to
infection by Cryptosporidium spp.; odontogenic infection related to
infection by viridans streptococci; persistent cough related to
infection by Bordetella pertussis; gas gangrene related to
infection by Clostridium perfringens or Bacteroides spp.; and
atherosclerosis related to infection by Helicobacter pylori or
Chlamydia pneumoniae. Bacterial infections and protozoal infections
and disorders related to such infections that may be treated or
prevented in animals include, but are not limited to, the
following: bovine respiratory disease related to infection by P.
haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow
enteric disease related to infection by E. coli or protozoa (i.e.,
coccidia, cryptosporidia, etc.); dairy cow mastitis related to
infection by Staph. aureus, Strep. uberis, Strep. agalactiae,
Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or
Enterococcus spp.; swine respiratory disease related to infection
by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric
disease related to infection by E. coli, Lawsonia intracellularis,
Salmonella, or Serpulina hyodyisinteriae; cow footrot related to
infection by Fusobacterium spp.; cow metritis related to infection
by E. coli; cow hairy warts related to infection by Fusobacterium
necrophorum or Bacteroides nodosus; cow pink-eye related to
infection by Moraxella bovis; cow premature abortion related to
infection by protozoa (i.e. neosporium); urinary tract infection in
dogs and cats related to infection by E. coli; skin and soft tissue
infections in dogs and cats related to infection by Staph.
epidermidis, Staph. intermedius, coagulase neg. Staph. or P.
multocida; and dental or mouth infections in dogs and cats related
to infection by Alcaligenes spp., Bacteroides spp., Clostridium
spp., Enterobacter spp., Eubacterium, Peptostreptococcus,
Porphyromonas, or Prevotella. Other conditions that may be treated
by the compounds and preparations of the present invention include
malaria and atherosclerosis. Other bacterial infections and
protozoal infections and disorders related to such infections that
may be treated or prevented in accord with the method and
compositions of the present invention are referred to in J. P.
Sanford et al., "The Sanford Guide To Antimicrobial Therapy," 26th
Edition, (Antimicrobial Therapy, Inc., 1996).
[0135] The term "effective amount" means the amount of azithromycin
which, when administered in--the present invention prevents the
onset of, alleviates the symptoms of, stops the progression of, or
eliminates a bacterial or protozoal infection in a mammal.
[0136] The term "mammal" is an individual animal that is a member
of the taxonomic class Mammalia. The class Mammalia includes, for
example, humans, monkeys, chimpanzees, gorillas, cattle, swine,
horses, sheep, dogs, cats, mice and rats.
[0137] In the present invention, the preferred mammal is a
human.
[0138] Typically, azithromycin, is administered in dosage amounts
ranging from about 0.2 mg per kg body weight per day (mg/kg/day) to
about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4
doses per day), although variations will necessarily occur
depending upon the species, weight and condition of the subject
being treated and the particular route of administration chosen.
The preferred dosage amount is from about 2 mg/kg/day to about 50
mg/kg/day.
[0139] The azithromycin may be administered orally, or by other
known means for administering azithromycin.
[0140] Although the foregoing invention has been described in some
detail for purposes of illustration, it will be readily apparent to
one skilled in the art that changes and modifications may be made
without departing from the scope of the invention described
herein.
EXEMPLIFICATION
[0141] The present invention will be further illustrated by means
of the following examples. It is to be understood, however, that
the invention is not meant to be limited to the details described
therein.
[0142] In the following examples, particle size distribution was
determined using a Malvern Mastersizer S (Malvern Instruments,
Worcestershire, UK) with a MS-1-Small Volume Sample Dispersion
Unit. This unit allowed for particle size analysis through a wet
sample dispersion step and subsequent particle size measurements
using laser diffraction. To determine the particle size, 60 to 75
milliliters of purified water were added to the small volume sample
dispersion unit and allowed to stir for about 15 seconds, followed
by a 5000 sweep background count. Immediately thereafter,
azithromycin bulk was added to this liquid until an obscuration
value of 15-25% was achieved, and measurement of the particle size
was accomplished using 5000 sweeps as exhibited by FIG. 1.
[0143] Carr's Compressibility Index of the azithromycin bulk was
measured by taking an initial density of a 15 gram sample in a 100
ml graduated cylinder. The sample was tapped 2000 times on a VanKel
Tap Density Tester (Model 50-1200, Edison, N.J.) and the tapped
density of the 15 gram sample in the 100 ml graduated cylinder was
taken. The procedure is described in Int. J. Pharm. Tech. &
Prod. Mfr., 6(3) 10-16, 1985.
[0144] Internal angle of friction of the bulk drug was measured by
the method described in "Some Measurements of Friction in Simple
Powder Beds", Hiestand, E. N. and Wilcox, C. J. (J. Pharm. Sci.
57(1968) 1421).
[0145] The shear cell consisted of a layer of powder between two
parallel flat surfaces. The lower surface was fixed and formed the
base, while the upper surface (sled) was attached to an actuator
which provided a force in a linear direction parallel to the plane
of the surfaces. Another force was applied on top of the sled using
weights of known mass. For each sample, the test was performed
several times using a different weight on the sled for each test.
The force, or resulting shear stress, required to pull the sled
across the powder layer increased as the weight on the sled, or
resulting normal stress was increased. When the powder bed yielded
during shear, it is said to have failed. This condition represented
incipient flow and occurred when the amount of force needed to move
the sled stopped increasing. The data at several normal stress
levels were plotted as the shear vs. normal stress at failure. This
plot is known as the yield locus, while the angle between the yield
locus and the abscissa is known as the Angle of Internal
Friction.
[0146] The following excipients'trade names are referenced in the
examples: [0147] Lactose (316 Fast Flo.RTM.) was obtained from
Foremost Farms, Baraboo, Wis. [0148] Microcrystalline cellulose
(Avicel.RTM. PH-200) was obtained from FMC Biopolymer, [0149]
Philadelphia, Pa. [0150] Croscarmellose sodium (Ac-Di-Sol.RTM.) was
obtained from FMC Biopolymer, [0151] Philadelphia, Pa. [0152]
Magnesium stearate was obtained from Mallinckrodt, Inc., St. Louis,
Mo. [0153] Colloidal silicon dioxide was obtained from Cabot
Corporation, Tuscola, Ill. [0154] Talc was obtained from Whitaker,
Clark & Daniels Inc., South Plainfield, N.J.
[0155] Further, in the following examples, the following drug lots
were evaluated:
[0156] Lot 1: Form N, unmilled
[0157] Lot 2: Form M, unmilled
[0158] Lot 3: Form A, unmilled
[0159] Lot 4: Form G, unmilled
[0160] Lot 5: Form A, milled on Fitzmill with .027'' screen,
hammers, low speed
[0161] Lot 6: Form A, milled on Fitzmill no screen, hammers, high
speed
[0162] Lot 7: Form A, milled on Fitzmill, .027'' screen, knives,
medium speed
[0163] Lot 8: Form A, milled on Fitzmill, .020'' screen, knives,
high speed
[0164] Lot 9: Form M, milled on Fitzmill, .033'' rasping screen,
bar rotor, low speed
[0165] Lot 10: Form F, unmilled
[0166] Lot 11: Form J, unmilled
EXAMPLE 1
Indices of Tableting Performance
[0167] Indices of tableting performance, for several azithromycin
forms, were assessed to identify any mechanical deficiencies or
attributes that may affect the ability to develop a direct
compression tablet formulation of azithromycin. This assessment was
performed in accordance with the procedures described in "Indices
of Tableting Performance" H. E. N. Hiestand and D. P. Smith, Powder
Technology 38 [1984] pp. 145-159.
[0168] More specifically, the Brittle Fracture Index, BFI, was
calculated from the ratio of a material's regular tensile strength
to its compromised tensile strength. Strain Index, SI, was
determined from the dynamic indentation hardness test. Worst Case
Bonding Index was determined by assessing the extent of particle
bonding remaining after decompression assuming a very short
compression dwell time and a plastic mechanism of particle
separation during decompression.
[0169] Bulk azithromycin lots 1, 2, 4, 7, 10 and 11 are different
crystalline forms, respectively, forms N, M, G, A, F and J. Lots 1,
2 and 4 were milled with a Fitzmill (Model J T, The Fitzpatrick
Co., Elmhurst, Ill.) using a 0.027'' screen and knives at high
speed in an attempt to match the smaller particle size of Lot 7.
Lots 10 and 11 were evaluated as is due to their relatively small
particle sizes.
[0170] The results of these assessments are provided, below, in
Table 1. TABLE-US-00001 TABLE 1 Indices of Tableting Performance
Brittle Worst Case Strain Tensile Fracture Bonding Index Index
Strength Lot # Index (BFI) (BL.sub.w) .times. 10.sup.2 (SI) Mpa #1
Form N 0.05 0.7 0.0044 0.75 #2 Form M 0.10 1.0 0.0048 0.79 #4 Form
G ND 0.8 0.0043 1.03 #7 Form A 0.10 0.9 0.0044 0.99 #10 Form F 0.37
0.9 0.0041 1.62 #11 Form J 0.11 0.7 0.0043 0.69 ND = not
determined
[0171] As shown above, the tableting indices were similar for Lots
1, 2, 4, 7 and 11 (Forms N, M, G, A and J). The data suggests that
the primary deficiencies of these materials, in forming tablets by
direct compression, are their low to moderate tensile strengths.
This may be manifested as low tablet hardness values. Further, the
brittle fracture indices indicate that bonds formed during
compression will more likely survive decompression when the tablet
is ejected from the die. Differences between these lots were not
significant. Thus, these lots would likely have a similar
probability of forming a robust direct compression tablet
formulation.
[0172] Lot 10 (form F), however, appeared to have significantly
different mechanical properties. It has a higher tensile strength
value indicative of forming stronger bonds. The flow properties of
Lot 10, however, were similar to the other lots having a similar
particle size distribution.
[0173] In general, a direct compression tablet may be feasible with
high drug loading (.about.60%) if low brittleness, and good bonding
excipients were used.
EXAMPLE 2
Particle Size Effect
[0174] The impact of azithromycin particle size on a direct
compression tablet was evaluated as follows. Using various lots of
azithromycin, direct compression tablets were prepared from a dry
blend of 59.3 wt % azithromycin, 26.9 wt % microcrystalline
cellulose as the binder, 8.9 wt % lactose as the diluent, 2.0 wt %
croscarmellose sodium as the disintegrant, and 2.9 wt % magnesium
stearate as the lubricant.
[0175] The ingredients were weighed (except for the magnesium
stearate), combined and blended in a low shear blender for 30
minutes. The blend was passed through a U.S. standard No.20 or
No.25 mesh screen to delump the blend. The screened blend was
returned to the blender and blended for an additional 30 minutes.
Prior to the addition of the magnesium stearate, the initial and
tapped densities of the blend were determined from which a Carr's
Compressibility Index for flow was calculated for the blend.
Magnesium stearate was then added to the blend, after which it was
blended for an additional five minutes.
[0176] The dry blends were compacted on a single station tablet
press Manesty F-press (Manesty, Liverpool, United Kingdom) with
0.262''.times.0.531'' modified capsule shaped tooling. The target
tablet weight was 450 milligrams. The tablets were tested for
hardness (kP scale), using a Schleuniger hardness tablet tester
(Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland), and for
friability (100 rotations/4 minutes) using a Vanderkamp Friabulator
Tablet Tester (Vankel, Cary, N.C., US).
[0177] The test results are provided in Table 2. TABLE-US-00002
TABLE 2 Angle of Dry Blend Avg. Run Internal Carr's Average Tablet
Tablet Tablet and Friction Index Weight Hardness Friability Lot #
(.degree.) (%) mg (% CV) (kP) (%) 1 ND 19 451.5 6.6 0.6 (0.67%, n =
10) (n = 10) (n = 5) 2 ND 25 445.1 6.7 ND (0.32%, n = 3) (n = 3) 3
31.0 25 455.3 6.2 1.1 (0.21%, n = 5) (n = 5) (n = 5) 4 30.5 30
442.4 10.1 0.52 (0.50%, n = 10) (n = 10) (n = 10) 5 31.6 30 455 8.6
0.32 (0.36%, n = 10) (n = 10) (n = 5) 6 32.6 30 452.5 4.1 1.8
(0.90%, n = 10) (n = 10) (n = 10) 7 34.5 34 450.8 12.5 3.67 (2.06%,
n = 5) (n = 5) (n = 5) 8 ND 37 No tablets N/A N/A 9 ND 46 No
tablets N/A N/A 10 ND 34 No tablets N/A N/A ND = Not Determined
[0178] Evaluation of the dry blends showed that the unmilled bulk
drug (Runs 1-4) resulted in acceptable flowing blends having a
Carr's Compressibility Index from 19 to 30 on the tablet press, and
tablets with acceptable weight control, hardness and friability.
The less aggressively milled bulk drug lots (Runs 5-6) also
resulted in acceptable flowing blends on the tablet press.
[0179] As shown in Table 2, more aggressively milled bulk drug lots
(Runs 8 and 9) and unmilled bulk drug having a small particle size
distribution (Run 10) produced poorer flowing blends (Carr's Index
of 34 to 46) such that tablets could not be compacted on the
Manesty F-press.
[0180] A compaction simulator was then used to compress blends
containing azithromycin from Lots 7, 8, 9 and 10. The compaction
simulator was designed as a single station tablet press in which
the compression dwell time can be adjusted to simulate different
types of tablet presses. In addition, the compaction simulator was
equipped with a mechanical agitator to assist in filling the tablet
die with dry blends to obtain a consistent tablet weight.
[0181] As shown in Runs 11, 12, 13A, 13B, 14A and 14B of Table 2A,
poor flowing blends that resulted in unacceptable tablets on the
Manesty F-press became acceptable tablets when compressed on the
compaction simulator. TABLE-US-00003 TABLE 2A Carr's Average Index
of Tablet Average dry Applied Upper Weight Tablet Tablet Drug blend
Compression Mg Hardness Feriability Run Lot (%) Force (kN) (% CV)
(kP) (%) 11 7 34 5.1 457.2 9.3 0.32 (2.53%, (n = 5) (n = 5) n = 5)
12 8 37 4.0 439.8 6.4 0.73 (1.08%, (n = 5) (n = 5) n = 5) 13A 9 46
4.6 428.7 10.6 0.35 (1.15%, (n = 10) (n = 10) n = 10) 13B 9 46 5.5
426.9 11.9 0.32 (1.44%, (n = 10) (n = 10) n = 10) 14A 10 34 4.2
444.9 10.4 0.38 (0.90%, (n = 5) (n = 10) n = 5) 14B 10 34 5.7 456.2
14.1 0.41 (0.62%, (n = 5) (n = 10) n = 5)
EXAMPLE 3
Drug Loading Effects
[0182] The effects of drug loading on the tableting properties of
azithromycin direct compression tablets were evaluated as follows.
Azithromycin tablets were evaluated with low, medium and high drug
loadings. The same manufacturing and testing procedures as set
forth in Example 2 were used.
[0183] Pharmaceutical formulations having the following drug
loadings were used (percentages are given as % weight):
TABLE-US-00004 Drug Loading .about.60% .about.45% .about.30%
Azithromycin 59.3% 44.5% 29.7% Microcrystalline 26.9% 38.0% 49.2%
Cellulose Lactose 8.9% 12.6% 16.2% Croscarmellose 2.0% 2.0% 2.0%
Sodium Magnesium 2.9% 2.9% 2.9%. Stearate
[0184] Runs 1, 2, 3, 4, 5 and 6, in Table 3, were conducted on a
Manesty F-press. The same bulk drug, Lot 8 was used for Runs 1-3,
Lot 10 for Runs 4-5, and Lot 11 for Run 6. Runs 7, 8, 9, 10, 11,
and 12 in Table 3A were conducted on the compaction simulator using
Lot 8, Lot 10, and Lot 11.
[0185] Initial evaluation using .about.60% drug loading of the
milled bulk drug Lot 8 and unmilled Lot 10 resulted in poor flowing
blends (Carr's Index of 37 and 34 respectively) and poor tablets on
the Manesty F-press as shown in Table 2 (Runs 3 and 5). However,
low drug loading (.about.30%) did improve the flow of the blend and
properties as shown in Table 3. TABLE-US-00005 TABLE 3 Average Drug
Average Tablet Carr's Index Load Tablet Weight Hardness Tablet
Friability Run Drug Lot (%) (%) mg (% CV) (kP) (%) 1 8 33 30 449.7
7.5 (max) 0.25 (0.56%, n = 10) (n = 5) (n = 5) 2 8 39 45 457.7 3.7
(max) 2.02 (3.38%, n = 8) (n = 4) (n = 4) 3 8 37 60 No tablets No
tablets No tablets 4A 10 28 30 441.70 11.5 0.27 (0.95%, n = 10) (n
= 10) 4B 10 28 30 446.9 20.2 0.31 (0.89%, n = 10) (n = 10) 5 10 34
60 No tablets No tablets No tablets 6A 11 33 30 450.2 10.6 0.20%
(0.36%, n = 5) (n = 2) (n = 3) 6B 11 33 30 449.0 16.4 0.44% (0.47%,
n = 5) (n = 2) (n = 5)
[0186] TABLE-US-00006 TABLE 3A Average Average Run/Lot Carr's
Applied Upper Tablet Tablet Tablet % Drug Index Compression Weight
Hardness Friability Loading (%) Force (kN) mg (% CV) (kP) (%) 7/8
33 7.2 459.6 12.9 0.21 30% (0.62%, (n = 10) n = 20) 8/8 39 5.8
455.2 10.5 0.13 45% (0.15%, (n = 5) (n = 5) n = 15) 9/8 37 4 439.8
6.4 0.73 60% (1.08%, (n = 5) (n = 5) n = 5) 10/10 34 4.2 444.9 10.4
0.38 60% (0.90%, (n = 5) (n = 10) n = 5) 11/11 33 6.8 452.0 18.3 ND
30% (n = 1) (n = 1) 12/11 33 4.4 451.0 12.3 0.35 30% (0.44%, (n =
5) (n = 5) n = 5) ND = Not Determined
[0187] As shown, above, in Table 3A, tablets made on the compaction
simulator 5 were significantly improved in hardness and friability
at medium drug load when compared to high drug load when using Lot
8. At low drug loading with Lot 8 or Lot 11, tablets with hardness
greater than 12 kP were achieved using the compaction simulator.
Tablets could also be made with Lot 8 or Lot 10 at the high drug
loading using the compaction simulator. Flow is not a critical
parameter for the compaction simulator since it uses a mechanical
agitator to force the blend into the die.
EXAMPLE 4
Effect of Lubricant
[0188] The effect of lubricant levels on the tableting properties
of the azithromycin direct compression tablet were evaluated as
follows. Direct compression tablet formulations, containing high an
low levels of magnesium stearate, as a lubricant, were prepared.
The high level lubricant formulation contained 59.3 wt %
azithromycin, 26.9 wt % microcrystalline cellulose, 8.9 wt %
lactose, 2.0 wt % croscarmellose sodium, and 2.9 wt % magnesium
stearate. The low level lubricant formulation contained 59.3 wt %
azithromycin, 28.3 wt % microcrystalline cellulose, 9.4 wt %
lactose, 2.0 wt % croscarmellose sodium, and 1.0 wt % magnesium
stearate.
[0189] Azithromycin lot 8 was used for the two lubricant level
formulations. The same manufacturing and testing procedures, from
Example 2, were used herein.
[0190] Evaluation of this bulk drug lot with lubricant at about 3%
resulted in a poor flowing blend (Carr's Compressibility Index of
37). Tablets could not be made on the Manesty F-press as shown in
Table 4. With the lubricant level at 1%, the blend was also poor
flowing (Carr's Compressibility Index of 47) and only unacceptable
tablets were made on the F-press with excessive build up of the
material on the punches. The tablets were very soft with
unacceptable low tablet weight (target tablet weight is 450 mg) and
poor weight control (% CV=5.1%). TABLE-US-00007 TABLE 4 Average
Carr's Index Average Tablet Tablet (Dry Blend) Lubricant Tablet
Weight Hardness Friability Run (%) (%) mg (% CV) (kP) (%) 1 37 3 No
tablet No tablet No tablet 2 47 1 418.3 3.3 2.5 (5.1%, n = 10) (n =
5)
[0191] As shown in Runs 3 and 4 in Table 4A, poor flowing blends
that resulted in unacceptable tablets on the Manesty F-press became
acceptable tablets when compressed on the compaction simulator.
Flow is not a critical parameter for the compaction simulator since
it uses a mechanical agitator to force the blend into the die.
Better tablet friability was achieved with the 1% lubricant level
blend compressed on the compaction simulator (Run 4).
TABLE-US-00008 TABLE 4A Carr's Average Index Tablet Average (Dry
Applied Upper Weight Tablet Blend) Compression mg Hardness Tablet
Friability Run (%) Lubricant (%) Force (kN) (% CV) (kP) (%) 3 37 3
4.0 439.8 6.4 0.73 (1.07%, (n = 5) (n = 5) n = 5) 4 47 1 4.2 462.8
5.8 0.15 (0.69%, (n = 10) n = 20)
EXAMPLE 5
Effect of Glidant
[0192] The effect of glidant on tableting properties of the
azithromycin direct compression tablet were evaluated as follows.
Typically, glidants are added into pharmaceutical formulations to
improve flow. As shown in this example, addition of glidants into
the formulation can improve flow.
[0193] Azithromycin direct compression tablets were prepared with
glidants to evaluate the effects on the direct compression tablet.
The same bulk drug, lot number 6, was used for all glidant
formulations. The same manufacturing and tablet testing procedures
from Example 2 were used in this example. Runs 1, 2, 3 and 4 were
conducted on the Manesty F-press.
[0194] The following pharmaceutical formulations were prepared:
TABLE-US-00009 Run # 1 2 3 4 Glidant Formulation wt % Azithromycin
59.3 59.3 59.3 59.3 Microcrystalline cellulose 26.8 26.8 26.7 26.9
Lactose 8.9 8.9 8.8 8.9 Croscarmellose Sodium 2.0 2.0 2.0 2.0
Colloidal Silicon Dioxide 0.1 -- 0.3 -- Talc -- 0.1 -- -- Magnesium
Stearate 2.9 2.9 2.9 2.9
[0195] TABLE-US-00010 TABLE 5 Carr's Index (Dry Tablet Blend)
Tablet weight hardness Tablet Run (%) Glidant mg (% CV) (kP)
Friability % 1 25 0.10% 455.5 4.6 2.29 silicon (0.4%, n = 5) (n =
5) (n = 7) dioxide 2 27 0.10% talc 449.5 3.6 2.68 (1.2%, n = 5) (n
= 5) (n = 7) 3 28 0.25% 445.2 4.7 Tablets silicon (1.06%, n = 10)
(n = 10) capped dioxide 4 30 No glidant 452.5 4.1 1.8 (0.9%, n =
10) (n = 10) (n = 10)
[0196] Initial evaluation of the bulk drug lot 6 without glidant,
as shown in Table 5, resulted in acceptable blend flow (Carr's
Compressibility Index of 30) on the Manesty F-press. The addition
of 0.1% silicon dioxide (Run 1) improved the flow as measured by
Carr's Compressibility Index and the weight uniformity as shown by
the lower weight % CV.
EXAMPLE 6
Effect of Sizing
[0197] The effect of sieving the bulk drug to selectively remove
fines from the bulk azithromycin lot follows. Lot 8 was screened
through a #200 mesh screen using a vibrating sieve analyzer
(Endecott's Octagon 200 test sieve shaker, Endecott, London,
England) for 20 minutes at an amplitude setting of 8. The drug
retained on the #200 mesh screen was sieved again using the same
screening process. The drug retained on the #200 mesh screen
(screened twice) was used in the following direct compression
formulation. The same manufacturing and testing procedures from
Example 2 were used in this example. The direct compression tablets
had the following composition, by weight: TABLE-US-00011
Azithromycin 59.3% Microcrystalline Cellulose 26.9% Lactose 8.9%
Croscarmellose Sodium 2.0% Magnesium Stearate 2.9%
[0198] A better flowing blend (Carr's Compressibility Index of 29)
was produced from the sieved bulk drug lot. When unsieved Lot 8 was
used, the blend was poor flowing (Carr's Compressibility Index of
37) and tablets could not be made (Run 1) on the Manesty F-press as
shown in Table 6. Using the sieved Lot 8 (Runs 2a and 2b),
acceptably hard tablets were produced. Runs 2a and 2b were
performed with different upper punch compression settings. Run 2b
had a higher setting resulting in greater compression. The target
tablet weight of 450 mg was achieved with good to excellent weight
control. TABLE-US-00012 TABLE 6 Carr's Index Average Average Tablet
(Dry Blend) Bulk Drug Lot Tablet Weight Hardness Run (%)
Pretreatment mg (% CV) (kP) 1 37 None, unsieved No tablet No tablet
2a 29 Screened twice 448.4 5.6 #200 mesh (1.48%, n = 5) (n = 5) 2b
29 Screened twice 449.2 8.3 #200 mesh (0.06%, n = 5) (n = 5)
* * * * *