U.S. patent application number 13/516942 was filed with the patent office on 2013-03-07 for composition comprising an amorphous non-crystalline glass form of azithromycin.
This patent application is currently assigned to North-West University. The applicant listed for this patent is Marique Aucamp, Wilna Liebenberg, Roelf Willem Odendaal. Invention is credited to Marique Aucamp, Wilna Liebenberg, Roelf Willem Odendaal.
Application Number | 20130059805 13/516942 |
Document ID | / |
Family ID | 43709135 |
Filed Date | 2013-03-07 |
United States Patent
Application |
20130059805 |
Kind Code |
A1 |
Odendaal; Roelf Willem ; et
al. |
March 7, 2013 |
COMPOSITION COMPRISING AN AMORPHOUS NON-CRYSTALLINE GLASS FORM OF
AZITHROMYCIN
Abstract
The invention relates to an amorphous non-crystalline glass form
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10-
,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-x-
ylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl
2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribo-hexopyranoside or
azithromycin having an infra-red pattern displaying characteristic
relatively broad peaks at approximately 3500 and 1727 cm.sup.-1 and
characteristic peaks at approximately 2970 and 2938 cm.sup.-1. The
invention further relates to a preparation method of increasing the
solubility of azithromycin including the steps of selecting
anhydrous, monohydrated or dihydrated azithromycin; elevating the
temperature of the azithromycin to above the melting point thereof;
and reducing the temperature of the melt sufficiently to allow it
to set into an amorphous non-crystalline glass form (Form-II) of
azithromycin having relatively increased solubility without
decreasing the structural stability thereof.
Inventors: |
Odendaal; Roelf Willem;
(Potchefstroom, ZA) ; Liebenberg; Wilna;
(Potchefstroom, ZA) ; Aucamp; Marique;
(Potchefstroom, ZA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Odendaal; Roelf Willem
Liebenberg; Wilna
Aucamp; Marique |
Potchefstroom
Potchefstroom
Potchefstroom |
|
ZA
ZA
ZA |
|
|
Assignee: |
North-West University
Potchefstroom
ZA
|
Family ID: |
43709135 |
Appl. No.: |
13/516942 |
Filed: |
December 15, 2010 |
PCT Filed: |
December 15, 2010 |
PCT NO: |
PCT/IB2010/055842 |
371 Date: |
November 5, 2012 |
Current U.S.
Class: |
514/29 ;
536/7.4 |
Current CPC
Class: |
C07H 1/00 20130101; A61P
31/04 20180101; C07H 17/08 20130101; A61P 37/04 20180101 |
Class at
Publication: |
514/29 ;
536/7.4 |
International
Class: |
C07H 17/08 20060101
C07H017/08; A61P 31/04 20060101 A61P031/04; A61K 31/7052 20060101
A61K031/7052 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2009 |
ZA |
2009/09098 |
Claims
1. A composition comprising an amorphous non-crystalline glass form
(Form-II) of azithromycin.
2. A composition according to claim 1 wherein the amorphous
noncrystalline glass form (Form-II) of azithromycin displays an
infra-red pattern having a characteristic relatively broad peak at
approximately 3500 and 1727 cm.sup.''1 and characteristic peaks
2970 and 2938 cm.sup.''1.
3. A composition according to claim 1 wherein the amorphous
non-crystalline glass form (Form-II) of azithromycin displays an
infra-red pattern substantially as depicted in FIG. 2.
4. A composition according to claim 1 displaying a differential
scanning calorimetry thermogram substantially as depicted in FIG.
12 and exhibiting a glass transition between 00 and 115 degrees
Celsius.
5. A composition according to claim 1 having at least 50% increased
solubility over anhydrous, monohydrated or dihydrated azithromycin
in water.
6. A composition according to claim 5 having at least 150%
increased solubility over anhydrous, monohydrated or dihydrated
azithromycin in water.
7. A composition according to claim 1 having at least 5% increased
solubility over anhydrous, monohydrated or dihydrated azithromycin
in 0.1 N HCl.
8. A composition according to claim 7 having at least 10% increased
solubility over anhydrous, monohydrated or dihydrated azithromycin
in 0.1 N HCl.
9. A composition according to claim 1 having at least 10% increased
solubility over anhydrous, monohydrated or dihydrated azithromycin
in a phosphate medium.
10. A composition according to claim 9 having at least 20%
increased solubility over anhydrous, monohydrated or dihydrated
azithromycin in a phosphate medium.
11. A method of increasing the solubility of azithromycin including
the steps of providing azithromycin selected from the group
consisting of anhydrous, monohydrated or dihydrated azithromycin;
elevating the temperature of the azithromycin to above the melting
point thereof; and reducing the temperature of the melt
sufficiently to allow it to set into an amorphous non-crystalline
glass form (Form-II) of azithromycin having relatively increased
solubility without decreasing the structural stability thereof.
12. A method according to claim 11 wherein the step of elevating
the temperature of the azithromycin to above its melting point
includes the further step of elevating the temperature thereof to
between 100 and 140 degrees Celsius, preferably 130 degrees
Celsius.
13. A method according to claim 11 wherein the temperature of the
selected azithromycin is elevated to above its melting point in the
absence of a solvent.
14. A medicament prepared from anhydrous, monohydrated or
dihydrated azithromycin in accordance with the method of claim
11.
15. A medicament prepared from amorphous non-crystalline glass form
(Form-II) of azithromycin in accordance with the method of claim 11
together with at least one inert pharmaceutically acceptable
carrier or diluents in a dosage form selected from the group
consisting of tablets; capsules; powders; solutions; syrups;
suspensions; bolus injection; continuous infusion; powder for
reconstitution; ointments; creams; gels; lotions; sprays enemas,
douche, pessary, transdermal patches, dermal patches and
lozenges.
16. Use of a pharmaceutically effective amount of an amorphous
noncrystalline glass form (Form-II) of azithromycin according to
claim 1 and prepared in accordance with the method of claim 11 in a
method of treating a patient suffering from a bacterial
infection.
17. Use of a pharmaceutically effective amount of an amorphous
noncrystalline glass form according to claim 1 and prepared in
accordance with the method of claim 11 in a method of preparing a
medicament for use in treating a patient suffering from a bacterial
infection.
18. A method of treating a patient suffering from bacterial
infections including the step of administering to such a patient a
pharmaceutically effective amount of an amorphous non-crystalline
glass form (Form-II) of azithromycin prepared in accordance with
the method of claim 11.
19. A composition comprising an amorphous non-crystalline glass
form (Form-II) of azithromycin substantially as herein described
and exemplified with reference to the accompanying figures.
20. A method of increasing the solubility of azithromycin
substantially as herein described and exemplified, with reference
to the accompanying figures.
Description
INTRODUCTION AND BACKGROUND TO THE INVENTION
[0001] This invention relates to a macrolide composition. More
particularly this invention relates to a novel amorphous form, of
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10-
,12,14-heptamethyl-15-oxo-11-{[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-x-
ylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl
2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribo-hexopyranoside or
azithromycin. This invention further relates to a preparation
method of a medicament. More particularly this invention relates to
a method of increasing the solubility of azithromycin.
[0002] Azithromycin is an azalide and a member of the macrolide
family of antibiotics. This 15-membered-ring, macrolide antibiotic,
is very similar in composition, chemical structure (semi-synthetic)
and mechanism of action to erythromycin. Polymorphs of azithromycin
commonly present as anhydrous (MM=749.00 g/mol), monohydrate
(MM=767.02 g/mol) or dihydrate (MM=785.02 g/mol) azithromycin. It
should however be noted that azithromycin is acid-stable in 0.1 N
HCl and that the dihydrate is currently the most stable polymorphic
form.
[0003] The chemical formula for azithromycin dihydrate is
C.sub.38H.sub.72N.sub.2O.sub.12.2H.sub.2O and the chemical
structure of anhydrous azithromycin differs from erythromycin
through methyl-substitution of a nitrogen atom in the lactone
ring.
[0004] The preparation of some amorphous forms of azithromycin has
previously been described in U.S. Pat. Nos. 6,245,903 and
6,451,990.
[0005] U.S. Pat. No. 6,245,903 describes an anhydrous form of
azithromycin and further provides a method to purify an amorphous
anhydrous azithromycin form using a chromatographic procedure or by
using a solvent evaporation method.
[0006] U.S. Pat. No. 6,451,990 describes a non-crystalline form of
azithromycin which includes the preparation method of forming a
solution of azithromycin and an aliphatic alcohol or cyclic ethers
and lyophilising said solution.
[0007] All non-crystalline forms of azithromycin referred to above
are manufactured using solvents and/or lyophilisation. Although the
aforesaid methods are well-known in the pharmaceutical industry for
the preparation of different forms of a drug there are several
disadvantages with these known methods. Some of the disadvantages
are that the methods are time-consuming and require reagents for
manufacturing. Yet a further disadvantage associated with these
methods is that the solvents in the structure of the
non-crystalline azithromycin can influence the physico-chemical
properties of azithromycin.
[0008] Azithromycin has an anti-bacterial spectrum parallel to
erythromycin's spectrum. It is however more effective against
Haemophilus influenzae and other gram-negative bacteria, including
Staphylococcus aureus; Streptococcus agalactiae; Streptococcus
pneumoniae; Streptococcus pyogenes; Haemophilus ducreyi; Moraxella
catarrhalis; Neisseria gonorrhoeae; Chlamydia pneumoniae; Chlamydia
trachomatis; Mycoplasma pneumoniae; Helicobacter pylori; Salmonella
typhi; and Mycobacterium avium intracellulare.
[0009] A disadvantage associated with known commercially available
azithromycin dihydrate (raw material) is that it is poorly soluble
in water.
[0010] A further disadvantage associated with azithromycin is that
its poor water-solubility influences other pharmacokinetic
properties resulting in the poor bioavailability (only 38% of an
orally administered dose reaches systemic circulation) of the
active drug.
[0011] Yet another disadvantage of azithromycin is that said poor
bioavailability necessitates the administration of relatively large
quantities of azithromycin in order to achieve the desired
therapeutic effect.
[0012] A disadvantage associated with the use of relatively large
quantities of azithromycin is that there is a potential increase in
the side-effects associated with this active ingredient, in turn
leading to poor patient compliance and potentially resulting in
bacterial drug-resistance.
[0013] An even further disadvantage associated with the use of
relative large quantities of azithromycin is that there is an
increase in the production and manufacturing cost of the product,
thereby increasing the cost of treatment.
OBJECTS OF THE INVENTION
[0014] An object of the present invention is to provide a stable
novel form of azithromycin. Another object of the invention is to
provide a method for increasing the solubility of azithromycin. Yet
another object of the invention is to provide a medicament prepared
in accordance with such a method with which the aforesaid
disadvantages may be overcome or at least minimised.
SUMMARY OF THE INVENTION
[0015] According to a first aspect of the invention there is
provided a composition comprising a stable amorphous
non-crystalline glass form (Form-II) of azithromycin.
[0016] The amorphous non-crystalline glass form (Form-II) of
azithromycin may display an infra-red pattern having a relatively
broad peak at approximately 3500 and 1727 cm.sup.-1 and at least
one characteristic peak at approximately 2970 and 2938 cm.sup.-1.
The infra-red pattern may be substantially depicted as in FIG.
2.
[0017] The amorphous non-crystalline glass form (Form-II) of
azithromycin may display a differential scanning calorimetry
thermogram substantially as depicted in FIG. 12 and exhibits a
glass transition between 100 and 115 degrees Celsius.
[0018] The amorphous non-crystalline glass form (Form-II) of
azithromycin may have at least 50%, preferably at least 150%,
increased solubility relative to anhydrous, monohydrated or
dihydrated azithromycin in water.
[0019] The amorphous non-crystalline glass form (Form-II) of
azithromycin may have at least 5%, preferably at least 10%,
increased solubility relative to anhydrous, monohydrated or
dihydrated azithromycin in 0.1 N hydrochloric acid (pH 1).
[0020] The amorphous non-crystalline glass form (Form-II) of
azithromycin may have at least 10%, preferably at least 20%,
increased solubility relative to anhydrous, monohydrated or
dihydrated azithromycin in phosphate buffer (pH 6.8).
[0021] According to a second aspect of the invention there is
provided a method of increasing the solubility of azithromycin
including the steps of: [0022] providing azithromycin selected from
the group consisting of anhydrous, monohydrated or dihydrated
azithromycin; [0023] elevating the temperature of the azithromycin
to above the melting point thereof; and [0024] reducing the
temperature of the melt sufficiently to allow it to set into an
amorphous non-crystalline glass form (Form-II) of azithromycin
having relatively increased solubility without decreasing the
structural stability thereof.
[0025] The step of elevating the temperature of the azithromycin to
above its melting point includes the step of elevating the
temperature thereof to between 100 and 140 degrees Celsius,
preferably 130 degrees Celsius, in the absence of a solvent.
[0026] The temperature of the selected azithromycin is elevated to
above its melting point in the absence of a solvent.
[0027] According to a third aspect of the invention there is
provided a medicament prepared from anhydrous, monohydrated or
dihydrated azithromycin in accordance with the method of the second
aspect of the invention.
[0028] According to a fourth aspect of the invention there is
provided use of a pharmaceutically effective amount of an amorphous
non-crystalline glass form (Form-II) of azithromycin in accordance
with the first aspect of the invention and prepared in accordance
with the method of the second aspect of the invention in a method
of treating a patient suffering from bacterial infections.
[0029] According to a fifth aspect of the invention there is
provided use of a pharmaceutically effective amount of an amorphous
non-crystalline glass form in accordance with the first aspect of
the invention and prepared in accordance with the method of the
second aspect of the invention in a method of preparing a
medicament for use in treating a patient suffering from bacterial
infections.
[0030] According to a sixth aspect of the invention there is
provided a method of treating a patient suffering from bacterial
infections including the step of administering to such a patient a
pharmaceutically effective amount of an amorphous non-crystalline
glass form (Form-II) of azithromycin in accordance with the first
aspect of the invention and prepared in accordance with the method
of the second aspect of the invention.
[0031] According to yet another aspect of the invention there is
provided a medicament prepared from amorphous non-crystalline glass
form (Form-II) of azithromycin in accordance with the method of the
second aspect of the invention, together with at least one inert
pharmaceutically acceptable carrier or diluents in the dosage form
selected from the group consisting of tablets; capsules; powders;
solutions; syrups; suspensions; bolus injection; continuous
infusion; powder for reconstitution; enemas; douche; pessary;
transdermal patch; dermal patch; ointments; creams; gels; lotions;
sprays and lozenges.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The invention will now be described further, by way of
example only, with reference to the accompanying drawings
wherein:
[0033] FIG. 1: is an infra-red (IR) pattern of prior art
azithromycin dihydrate (Vertical axis: transmittance (percentage);
Horizontal axis: wavenumbers (cm.sup.-1)); (The infra-red pattern
was obtained on a Shimadzu IRPrestige-21 (Japan), using a Pike
Multi-Reflectance ATR accessory, with Shimadzu IRsolution version
1.40 software. Pattern was recorded over a range of 400-4000
cm.sup.-1. KBr was used as background. The sample was dispersed in
a matrix of powdered potassium bromide and, through diffuse
reflectance infra-red Fourier transform spectroscopy (DRIFTS), the
IR-spectrum was measured in a reflectance cell.);
[0034] FIG. 2: is an IR pattern of amorphous non-crystalline glass
form (Form-II) of azithromycin according to the invention (Vertical
axis: transmittance (percentage); Horizontal axis: wavenumbers
(cm.sup.-1));
[0035] FIG. 3: is a characteristic XRPD (x-ray powder diffraction
pattern) of prior art azithromycin dihydrate raw material (Vertical
axis: intensity (Lin (counts)); Horizontal axis: 2 Theta
(degrees)); (Obtained on a PANalytical Xpert-Pro,
Goniometer=PW3050/60 (Theta/Theta); Minimum step size 2Theta:
0.001; Measurement Temperature [.degree. C.]: 25.00, Anode
Material: Cu, K-Alpha1 [.ANG.]: 1.54060, K-Alpha2 [.ANG.]: 1.54443,
K-Beta [.ANG.]: 1.39225, K-A2/K-A1 Ratio: 0.50000, Generator
Settings: 45 mA, 40 kV, Diffractometer Type: 0000000011018023,
Goniometer Radius [mm]: 240.00, Dist. Focus-Diverg. Slit [mm]:
91.00, Incident Beam Monochromator: No, Spinning: Yes);
[0036] FIG. 4: is a characteristic XRPD (x-ray powder diffraction
pattern) of amorphous non-crystalline glass form (Form-II) of
azithromycin (Vertical axis: intensity (Lin (counts)); Horizontal
axis: 2 Theta (degrees));
[0037] FIG. 5: is a characteristic XRPD (x-ray powder diffraction
pattern) of amorphous non-crystalline glass form (Form-II) of
azithromycin taken over a period of time wherein 0 is at time of
preparation, 1 is week 1, 2 is week 2, 3 is week 3 and 4 is week 4
(Vertical axis: intensity (Lin (counts)); Horizontal axis: 2 Theta
(degrees));
[0038] FIG. 6: is a solubility profile comparing the solubility of
prior art azithromycin dihydrate raw material and amorphous
non-crystalline glass form (Form-II) of azithromycin in water
(Vertical axis: concentration (mg/mL); Horizontal axis:
azithromycin form);
[0039] FIG. 7: is a solubility profile comparing the solubility of
prior art azithromycin dihydrate raw material and amorphous
non-crystalline glass form (Form-II) of azithromycin in 0.1 N HCl
(Vertical axis: concentration (mg/mL); Horizontal axis:
azithromycin form);
[0040] FIG. 8: is a solubility profile comparing the solubility of
prior art azithromycin dihydrate raw material and amorphous
non-crystalline glass form (Form-II) of azithromycin in Phosphate
buffer (Vertical axis: concentration (mg/mL); Horizontal axis:
azithromycin form);
[0041] FIG. 9: is a solubility profile comparing the solubility of
prior art azithromycin dihydrate raw material in different mediums
(Vertical axis: concentration (mg/mL); Horizontal axis:
medium);
[0042] FIG. 10: is a solubility profile comparing the solubility of
amorphous non-crystalline glass form (Form-II) of azithromycin in
different mediums (Vertical axis: concentration (mg/mL); Horizontal
axis: medium);
[0043] FIG. 11: is a DSC (differential scanning calorimetry) trace
of prior art azithromycin dihydrate raw material taken over a
period of time wherein 1 is week 0, 2 is week 2 and 3 is week 4
(Vertical axis: Heat flow (mW); Horizontal axis: temperature
(degrees Celsius)); (DSC trace obtained on a Shimadzu DSC-60A
(Japan) with TA60 version 2.11 software. Approximately 2 to 4 mg of
each sample was weighed and heated in open aluminium crucibles.
Samples were heated at 2.degree. C./min in an inert nitrogen
atmosphere.)
[0044] FIG. 12: is a DSC (differential scanning calorimetry) trace
of amorphous non-crystalline glass form (Form-II) of azithromycin,
taken over a period of time, according to one embodiment of the
invention wherein 0 is at time of preparation, 1 is week 1, 2 is
week 2, 3 is week 3 and 4 is week 4 (Vertical axis: Heat flow (mW);
Horizontal axis: temperature (degrees Celsius));
[0045] FIG. 13: is a thermal microscopy image (at 25 degrees
Celsius) of amorphous non-crystalline glass form (Form-II) of
azithromycin taken in the fourth week after preparation according
to one embodiment of the invention; and
[0046] FIG. 14: is a thermogravimetric analysis (TGA) trace overlay
of amorphous non-crystalline glass form (Form-II) of azithromycin
during stability study (Vertical axis: Weight (mg); Horizontal
axis: temperature (degrees Celsius)); (Obtained on a Shimadzu
DTG-60 (Japan) with TA60 version 2.11 software. Samples were heated
from 25 degrees Celsius to 150 degrees Celsius at 2.degree. C./min,
in open aluminium crucibles. Nitrogen gas was used as inert
atmosphere.).
DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION
[0047] According to a preferred embodiment of the invention there
is provided a method for increasing the solubility of azithromycin,
by providing a stable amorphous non-crystalline glass form
(Form-II) of azithromycin.
[0048] The method includes the steps of selecting azithromycin from
the group consisting of anhydrous, monohydrated or dihydrated
azithromycin; elevating the temperature of the azithromycin to
above the melting point thereof; and reducing the temperature of
the melt sufficiently to allow it to set into an amorphous
non-crystalline glass form (Form-II) of azithromycin having
relatively increased solubility.
Further Details of Respective Steps in the Method According to the
Invention:
[0049] The first step of the method, according to a preferred
embodiment of the invention is to select azithromycin raw material
from known commercially available anhydrous, monohydrate or
dihydrated form.
[0050] The following step of the method is to place the
azithromycin raw material in a suitable container, in the absence
of any solvents, and heat it to approximately 130 degrees Celsius
in a dry heat oven and afterwards cooling the melt to room
temperature (25 degrees Celsius).
[0051] Alternatively, the azithromycin raw material can be placed
in a suitable container and heated in any suitable environment to
approximately 130 degrees Celsius. The melt is then cooled to room
temperature (25 degrees Celsius).
Further Analysis and Findings
[0052] It has surprisingly been found that the amorphous
non-crystalline glass form (Form-II) of azithromycin is
structurally stable and significantly more soluble in water,
phosphate buffer and 0.1 N hydrochloric acid compared to
conventional anhydrous, monohydrate or dihydrated azithromycin
prepared according to prior art methods.
[0053] In further analysis of the amorphous non-crystalline glass
form (Form-II) of azithromycin, each of five replicate test tubes
were filled with an excess of amorphous non-crystalline glass form
(Form-II) of azithromycin and 10 ml of solubility medium. The
process was performed with each of the following mediums: 0.1 N
hydrochloric acid (pH 1), acetate buffer (pH 4.5), phosphate buffer
(pH 6.8) and distilled water. This method was also used for testing
the prior art azithromycin dihydrate.
[0054] The test tubes were then fixed to a rotating axis (54 rpm)
and submerged in a water bath at 37 degrees Celsius.+-.2 degrees
Celsius for twenty-four hours. The contents of the test tubes were
filtered through a 0.45 .mu.m filter and the respective filtrates
were subsequently diluted.
[0055] The concentrations of the filtrates were determined by HPLC
(high performance liquid chromatography) assay. The HPLC assay was
performed utilising a mobile phase (600:400) consisting of 8.7 g/L
potassium dihydrogen phosphate buffer (pH 4.5) and acetonitrile. A
Luna C18 250 mm.times.4.6 mm column was used with a flow rate of
0.5 mL/min and a wavelength of 210 nm. Validation of this method
provided a linear regression r.sup.2 of 0.9999.
[0056] Referring to FIGS. 6 to 10, it was determined that the
solubility of azithromycin raw material (dihydrate) is
17.966.+-.0.113 mg/mL in acetate buffer (pH 4.5), 8.442.+-.0.069
mg/mL in phosphate buffer (pH 6.8), 40.814.+-.0.368 mg/mL in 0.1N
HCl and 0.148.+-.0.028 mg/mL in distilled water. The phosphate
buffer consists of potassium dihydrogen phosphate, sodium hydroxide
and water and the acetate buffer consists of sodium acetate
trihydrate, glacial acetic acid and water. It was further
determined that the solubility of amorphous non-crystalline glass
form (Form-II) of azithromycin is 18.045.+-.0.485 mg/mL in acetate
buffer (pH 4.5), 10.968.+-.0.182 mg/mL in phosphate buffer (pH
6.8), 45.703.+-.0.917 mg/mL in 0.1 N HCl and 1.357.+-.0.233 mg/mL
in distilled water. In fact, in comparison with the raw material,
amorphous non-crystalline glass form (Form-II) of azithromycin has
a 9.16 fold (816%) improvement in solubility in water (FIG. 6), a
1.3 fold (30%) improvement in pH 6.8 phosphate buffer and a 1.12
fold (12%) improvement in 0.1 N HCl (FIG. 7) as medium. It was
found that the amorphous non-crystalline glass form (Form-II) of
azithromycin is at least 50%, more particularly at least 150% more
soluble than anhydrous, monohydrated or dihydrated azithromycin in
water. It was further found that the amorphous non-crystalline
glass form (Form-II) of azithromycin is at least 5% more,
particularly at least 10% more soluble than dihydrated azithromycin
in a 0.1 N HCl medium. It was yet further found that the amorphous
non-crystalline glass form (Form-II) of azithromycin is at least
10% more, particularly at least 20% more soluble than dihydrated
azithromycin in a phosphate buffer medium.
[0057] FIG. 3 shows a characteristic XRPD pattern of the raw
material azithromycin and confirms that the azithromycin is in a
crystalline form. This is in contrast to the amorphous
non-crystalline glass form (Form-II) of azithromycin (FIG. 4) which
exhibits the characteristic amorphous halo generally obtained with
amorphous forms.
[0058] Referring to FIGS. 1 and 2, the infra-red (IR) pattern
wavenumbers associated with peaks for both the raw material (FIG.
1) and the amorphous non-crystalline glass form (Form-II) of
azithromycin (FIG. 2) can be summarised as follow:
TABLE-US-00001 Azithromycin dihydrate Azithromycin glass 3567 and
3496 cm.sup.-1 (Sharp peaks) 3500 cm.sup.-1 (Relatively broad peak)
3251 cm.sup.-1 (Relatively broad peak) No peak 2971 cm.sup.-1 2970
and 2938 cm.sup.-1 1720 cm.sup.-1 (Sharp peak) 1727 cm.sup.-1
(Relatively broad peak)
[0059] The most distinguishing difference between the IR patterns
of the raw material (FIG. 1) in comparison with the IR pattern
obtained for the amorphous non-crystalline glass form (Form-II) of
azithromycin (FIG. 2) lies between wavenumbers 3580 to 1727
cm.sup.-1.
[0060] The IR pattern of azithromycin dihydrate (FIG. 1) displays
peaks of interest at wavenumber 3600 to 3000 cm.sup.-1. These peaks
represent the hydrate (two water molecules) found in the structure
of azithromycin dihydrate. In contrast, FIG. 2 displays only one
broad peak at wavenumber 3500 cm.sup.-1 and no peak at 3251
cm.sup.-1, which indicates a lack of hydrated molecules in the
amorphous non-crystalline glass form (Form-II) of azithromycin.
[0061] The IR-pattern of the raw material (FIG. 1) displays five
separate, clearly distinguishable peaks at 3567, 3496, 3251, 2971
and 1720 cm.sup.-1. This is in contrast to the amorphous
non-crystalline glass form (Form-II) of azithromycin which display
peaks at 3500 (broad peak), 2970, 2938 and 1727 (broad peak)
cm.sup.-1.
[0062] The applicant established that amorphous non-crystalline
glass form (Form-II) of azithromycin is structurally stable (at
40.degree. C. and 75% relative humidity) over a period of time and
remained amorphous as shown in the XRPD pattern (FIG. 5). In FIG. 5
the amorphous non-crystalline glass form (Form-II) of azithromycin
displayed the characteristic amorphous halo generally obtained with
amorphous forms over the 4 week testing period. In FIG. 13 it was
further evident from the micrograph of the amorphous
non-crystalline glass form (Form-II) of azithromycin that Form-II
did not transform to a crystalline solid form of azithromycin but
remained non-crystalline.
[0063] Referring to FIG. 11, the DSC (differential scanning
calorimetry) trace of prior art azithromycin dihydrate illustrates
the two desolvation peaks of the dihydrate between 80 degrees
Celsius and 100 degrees Celsius and further illustrates a melting
point at 119 degrees Celsius to 121 degrees Celsius. In contrast to
FIG. 11, FIG. 12 shows the thermogram of amorphous non-crystalline
glass form (Form-II) of azithromycin and depicts the absence of the
two desolvation peaks between 80 degrees Celsius and 100 degrees
Celsius and further displays a glass transition between 100 degrees
Celsius and 115 degrees Celsius.
[0064] The stability tests indicate that the amorphous
non-crystalline glass form (Form-II) of azithromycin remained
structurally stable as an amorphous non-crystalline form.
[0065] The thermogravimetric analysis (TGA) trace of FIG. 14
illustrates the weight loss of amorphous non-crystalline glass form
(Form-II) of azithromycin over a period of time. The TGA, together
with the Karl Fischer titration, results (averaging 3 to 4%)
indicate the presence of water in the amorphous azithromycin. It is
submitted that the presence of water did however not influence the
solubility or structural stability of amorphous azithromycin in any
way.
[0066] Amorphous non-crystalline glass form (Form-II) of
azithromycin is formulated for administration in any convenient way
and the invention includes within its scope pharmaceutical
compositions comprising amorphous non-crystalline glass form
(Form-II) of azithromycin adapted for use in human or veterinary
medicine.
[0067] The pharmaceutical compositions are presented for use in a
conventional manner with the aid of a pharmaceutically acceptable
carrier or excipient and may also contain, if required, other
active ingredients. The amorphous non-crystalline glass form
(Form-II) of azithromycin is typically formulated for oral, buccal,
topical or parenteral administration.
[0068] Oral administration is the preferred dosage form,
particularly in the form of tablets and capsules. The
pharmaceutical composition for oral administration conveniently
takes the form of tablets, capsules, powders, solutions, syrups or
suspensions prepared by conventional means with acceptable
excipients. Buccal administration compositions take the form of
tablets or lozenges formulated in conventional manner.
[0069] The amorphous non-crystalline glass form (Form-II) of
azithromycin is further formulated for parenteral administration by
bolus injection or continuous infusion. Formulations for injection
are presented in unit dosage forms in ampoules, or in multi-dose
containers, with an added preservative. The compositions further
take such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and contain formulatory agents such as
suspending, stabilising and/or dispersing agents. Alternatively,
the active ingredient is in powder form for reconstitution with a
suitable vehicle.
[0070] The amorphous non-crystalline glass form (Form-II) of
azithromycin is yet further formulated in topical applications,
comprising ointments, creams, gels, lotions, powders; transdermal
patches, dermal patches or sprays prepared in a conventional
manner.
[0071] The particulate unsolvated anhydrous form of nevirapine
(Form-I) is yet further formulated in rectal and vaginal
compositions such as suppositories or retention enemas containing
conventional suppository bases such as cocoa butter or other
glycerides.
[0072] For oral administration a convenient daily dosage regime of
amorphous non-crystalline glass form (Form-II) of azithromycin is a
total of 200 mg to 500 mg per day for three days, dependent upon
the age and condition of the patient.
[0073] The amorphous non-crystalline glass form (Form-II) of
azithromycin prepared in accordance with the method of the present
invention is formulated into a medicament and used in a method of
treating a patient suffering from a bacterial infection by
administering to such a patient a pharmaceutically effective amount
thereof of a total of 200 mg to 500 mg per day for three days,
dependent upon the age and condition of the patient.
[0074] It will be appreciated that the disadvantages associated
with prior art forms of azithromycin, namely anhydrous, monohydrate
of dihydrate forms, could be alleviated with the method according
to the invention. In particular, the bioavailability of
azithromycin could be increased as a result of the increased
solubility of amorphous non-crystalline glass form (Form-II) of
azithromycin. Moreover, reduced quantities of amorphous
non-crystalline glass form (Form-II) of azithromycin would be
required in use in treating patients suffering from bacterial
infections, resulting not only in reduced risk to side-effects but
to a reduced cost in treatment. Yet further, the advantages
associated with the preparation of Form-II is done in the absence
of any solvent, this being more cost-effective and less time
consuming than known prior art methods.
[0075] Applicant thus foresees that amorphous non-crystalline glass
form (Form-II) of azithromycin would not only present a relatively
cheaper alternative to conventional production and manufacturing
methods, but would also present a product that is superior in
solubility to conventional anhydrous, monohydrate or dihydrate
forms of azithromycin.
[0076] It will be appreciated further that variations in detail are
possible with a method for preparing a medicament and a medicament
prepared with such a method, according to the invention without
departing from the scope of this disclosure.
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