Title of Invention

CRYSTALLINE AZITHROMYCIN SESQUIHYDRATE

Abstract A crystalline from of azithromycin selected from the group consisting of forms D,e, substantially pure f, substantially pure G,H,J,M substantially in the absence of azithromycin dihydrate, N,O,P,Q and R.
Full Text FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
COMPLETE SPECIFICATION [See Section 10; rule 13]
"CRYSTALLINE AZITHROMYCIN SESQUIHYDRATE"
PFIZER PRODUCTS INC., a corporation organized under the laws of the State of Connecticut, United States of America, of Eastern Point Road, Groton, Connecticut 06340, United States of America,

The following specification particularly describes the nature of the invention and the manner in which it is to be performed:



Background of the Invention
This invention relates to crystal form of Azithromycin for the treatment of bacterial infections.
Background of the Invention This invention relates to crystal forms of azithromycin. Azithromycin is sold commercially and is an effective antibiotic in the treatment of a broad range of bacterial infections. The crystal forms of this invention are likewise useful as antibiotic agents in mammals, including man, as well as in fish and birds.
Azithromycin has the following structural formula:


Azithromycin is described and claimed in United States Patents 4,517,359 and 4.474,768. It is also known as 9-deoxo-9a-aza-9a-methyl-9a-homoerythomycin A.
Other patents or patent applications which directly or indirectly cover azithromycin
include: EP 298,650 which claims azithromycin dihydrate; U.S. Patent 4,963,531 which claims
a method of treating a strain of Toxoplasma gondii species; U.S. Patent 5,633,006 which
claims a chewable tablet or liquid suspension pharmaceutical composition having reduced
bitterness; U.S. Patent 5.686,567 which claims an intermediate useful in the preparation of
azithromycin; U.S. Patent 5.605.889 which daims an oral dosage form that reduces the "food
eflecT associated with the administration of azithromycin; U.S. Patent 6.068,859 which daims
a controlled dosage form containing azithromycin; U.S. Patent 5,498,699 which daims a
composition containing azithromycin in combination with bivalent or bivalent metals; EP
925.789 which daims a method of treating eye infections; Chinese patent application CN
1123279A which relates to water soluble salts of azithromycin; Chinese patent application CN
104694 5C which relates to azithromycin sodium dihydrogenphosphate double salts; Chinese
patent application CN 1114960A which relates to azithromycin crystals. Chinese patent
application CN 1161971A which relates to azithromycin crystals; Chinese patent application
CN 1205338A which relates to a method of preparing water soluble sarts of azithromycin;
International Publication WO 00/32203 which relates to an ethanolate of azithromycin; and

European patent application EP 984,020 which relates to an azithromycin monohydrate isopropanol clathrate.
Summary of the Invention The present invention relates to crystal forms of azithromycin. As used herein, the term "crystal form(s)" or "form(s)", unless otherwise noted, means one or more crystal forms of azithromycin.
In particular, the present invention relates to a crystal form of azithromycin wherein said crystal form is selected from forms C, D, E, F, G, H, J, M, N, 0, P, Q and R wherein said forms are as defined herein. Forms F, G, H, J, M, N, O, and P belong to family I azithromycin and belong to a monoclinic P21 space group with cell dimensions of a = 16.3±0.3 A, b ~ 16.2±0.3 A. c *= 18.4+0.3 A and beta = 109 ± 2°. Forms C. D. E and R belong to family II azithromycin and belong to an orthorhombic P2, 2t2, space group with cell dimensions of a = 8.9±0.4 A. b - 12.3±0.5 A and c «= 45.8±0.5 A Form Q is distinct from families I and II.
Form F azithromycin is of the formula CMH72N2O12*H2O"0.5C2H5OH 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 and having powder X-ray diffraction 26 peaks as defined in Table 9. The 13C ssNMR (solid state Nuclear Magnetic Resonance) spectrum of form F has two chemical shift peaks at approximately 179±1 ppm. those being 179.5±0.2 ppm and 178.6±0.2"ppm, a set of five peaks between 6.4 to 11.0 ppm, and ethanol peaks at 58.0±0.5 ppm and 17.2±0.5 ppm. The solvent peaks can be broad and relatively weak in intensity.
The invention also relates to substantially pure form F azithromycin, form F azithromycin substantially free of form G azithromycin and form F azithromycin substantially free df azithromycin dihydrate.
The invention further relates to methods of preparing form F azithromycin by treating azithromycin with ethanol to complete dissolution at 40-70°C and cooling with reduction of ethanol or addition of water to effect crystallization. Also included are methods of making substantially pure form F azithromycin, form F azithromycin substantially free of form G azithromycin and form F azithromycin substantially free of azithromycin dihydrate.
Form G azithromycin is of the formula CJ,HT;N2O12"1.5H,0 in the single crystal structure, being azitrtromycin sesquftydrate. Form G is further characterized as containing 2.5-6% water and The invention also relates to substantially pure form G azimrornydn, and form G azithromycin substantially free of azithromycin dihydrate.

The invention further relates to methods of preparing substantially pure form G azithromycin, and form G azithromycin substantially free of azithromycin dihydrate by treating azithromycin with a mixture of methanol and water or acetone and water to complete dissolution at 40-60°C and cooling to effect crystallization.
Form H azithromycin is of the formula C38H72N2012"H2OC3HB02 being azithromycin monohydrate hemi-1,2 propanediol solvate.
Form J azithromycin is of the formula C3eH72O12*H2O*0.5C3H7OH in the single crystal structure, being azithromycin monohydrate heml-n-propanol solvate. Form J is further characterized as containing 2-5% water and 1-5% 1-propanol by weight in powder samples and having powder X-ray diffraction 2G peaks as defined in Table 9. The 13C ssNMR spectrum of form J has two chemical shift peaks at approximately 179±1 ppm, those being 179.6±0.2 ppm and 178.4+0.2 ppm, a set of five peaks between 6.6 to 11.7 ppm and an n-propanol peak at 25.2±0.4 ppm. The solvent peak can be broad and relatively weak in intensity.
The invention further relates to methods of preparing form J by treating azithromycin with n-propanot to complete dissolution at 25-55°C and cooling with addition of water to effect crystallization.
Form M azithromycin is of the formula C38H72N2O12"HrOO.5CaH/OH, 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 and having powder X-ray diffraction 28 peaks as defined in Table 9. The 13C ssNMR spectrum of form M has one chemical shift peak at approximately 17911 ppm, being 179.6*0.2 ppm, a peak at 41.9±0.2 ppm and a set of six peaks between 6.9 to 16.4 ppm and an isopropanol peak at 26.0±0.4 ppm. The solvent peak can be broad and relatively weak in intensity.
The invention also relates to substantially pure form M azithromycin, form M azithromycin substantially free of form G azithromycin and form M azithromycin substantially free of azithromycin dihydrate.
The invention further relate* to methods of preparing substantially pure form M azithromycin, form M azithromycin substantia^ free of form G azithromycin and form M azithromycki substantially free of azithromycin dihydrate by treating azithromycin with isopropanol to complete dissolution at 40-60°C and reduction of isopropanol followed by cooing or cooling followed by addition of water to effect crystallization,
Form N azithromycin is • mixture of isomorphs of FamSy 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 efhanof, isopropanof. n-propanof. propylene glycol, acetone. acetonltrte. butanol. pentanoi, etc. The weight percent of water can range from 1-5% and the total weight percent of organic solvents can be 2-5% with each solvent content of 0.5 to 4%.


The samples of form N display all characteristic peaks of members of Family I in various proportions. Form N may be characterized as "mixed crystals" or "crystalline solid solutions" of Family I isomorphs.
Form N displays chemical shifts as a combination of isomorphs in Family I. The peaks may vary in chemical shift ppm within ± 0.2 ppm and in relative intensities and width due to the mixing of variable proportion of isomorphs contained in the form N crystalline solid solution.
Form P azithromycin is of the formula CMH72N2O12"H2f>0.5C5H12O being azithromycin monohydrate bemi-n-pentanol solvate,
Form Q azithromycin is of the formula CMH72N2Ol2"H2f>0.5C4H8O being azithromycin monohydratehemMetrahydrofuran solvate.
Form R azithromycin is of the formula CMH72N2012»H2C5H120 being azithromycin monohydrate mono-methyl tert-butyl ether solvate.
Form D azithromycin is of the formula C3aH72N2012"H2OCeH12 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 and having representative powder X-ray diffraction 26 peaks as defined in Table 9. the ."C-5sNMR spectrum, ofform D_displays.has_o/ie chemical shift peak at approximately 179±1ppm. being 178.1±0.2ppm and peaks at I03.9±0.2ppm, 95.1±0.2ppm. B4.2±0.2ppm, and a set of 3 peaks between 8.4 to 11 ppm.
The invention further relates to methods of preparing form D by slurrying azithromycin dihydrate with cydohexane.
Form E azithromycin is of the formula C38H72N20|2«H20*C4H»0 being azithromycin monohydrate mono-tetrahydrofuran solvate.
The invention further relates to azithromycin in an amorphous state and a method of preparing amorphous azithromycin that comprises the removal of water and/or solvents from the azithromycin crystal lattice. The X-ray diffraction powder pattern for amorphous azithromycin displays no sharp 26 peaks but has two broad rounded peaks. The first peak occurs between 4* and 13*. The second peak occurs between 13" and 25*.
The invention also relates lo pharmaceutical compositions for the treatment of a bacterial infection or a protozoa infection In a mammal, fish, or bird which comprises a therapeutically effective amount of the crystalline compounds referred to above, or amorphous azithromycin, and a pharmaceuticaBy acceptable carrier.
The invention abo relates to a method of treating a bacterial infection or a protozoa Wecbon in a mammal, fish, or bird which comprises administering to said mammal, fish or brd a therapeutically effective amount of the crystalline compounds referred to above, or amorphous azithromycin.

The present invention also relates to methods of preparing crystal forms of azithromycin which comprise the slurrying of azithromycin in an appropriate solvent or the dissolution of azithromycin in a heated organic solvent or organic solvent/water solution and precipitating the crystalline azithromycin by cooling the solution with reduction of solvent volume or by dissolving azithromycin in a solvent or solvent mixture and precipitating crystalline azithromycin by the addition of water to the solution. Azithromycin in amorphous state is prepared by healing crystalline azithromycin in a vacuum.
The term "treatment", as used herein, unless otherwise indicated, means the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention, including curing, reducing the symptoms of or slowing the progress of said infection. The terms "treat" and "treating* are defined in accord the foregoing term "treatment".
The term "substantially free" when referring to a designated crystalline form of azithromycin means that there is less than 20% (by weight) of the designated crystalline form(s) present, more preferably, there is less than 10% (by weight) of the designated form(s) present, more preferably, there is less than 5% (by weight) of the designated form(s) present, and most preferably, there is less than 1% (by weight) of the designated crystalline fomn(s) present. For instance, form F azithromycin substantially free of azithromycin dihydrate means form F with 20% (by weight) or less of azithromycin dihydrate. more preferably, 10% (by weight) or less of azithromycin dihydrate, most preferably, 1% (by weight) of azithromycin dihydrate.
The term "substantially pure" when referring to a designated crystalline form of azithromycin means that the designated crystalline form contains less than 20% (by weight) of residual components such as alternate polymorphic or isomorphic crystalline form(s) of azithromycin. It is preferred that a substantially pure form of azithromycin contain less than 10% (by weight) of alternate polymorphic or Isomorphic crystalline forms of azithromycin, more preferred is less than 5% (by weight) of alternate polymorphic or isomorphic crystalline forms of azithromycin, and most preferably less than 1% (by weight) of alternate polymorphic or isomorphic crystalline forms of azithromycin.
The term "substantially in the absence of azithromycin dihydrate* when referring to bulk oystaline azithromycin or a composition containing crystalline azithromycin means the crystalline azithromycin contains less than about 5% (by weight) azithromydn diiydrate. more preferably less than about 3% (by weight) azithromydn dfrydrate. and mod preferably less than 1% (by weight) azithromycin dftydrate.
As used herein, unless otherwise indicated, the term "bacterial Hection(aJ" or "protozoa infection" indudes bacterial Infections and protozoa infections and diseases caused by such infections that occur in mammals, fish and birds as well as disorders related to

bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compound of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include, but are not limited to, the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to i 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 saprophytics or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi. Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; 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 dacryocystitis 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 intracellulars; gastroenteritis related to infection by Campylobacter Jejuni: htestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by BordeteBa pertussis; gas gangrene related to infection by Clostridium perfringens or Baderoktes spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Also induded are atherosclerosis and malaria. Bacterial infections and protozoa infections and disorders related to such kifections 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. muHodda, Mycoplasma bovis, or BordeteBa spp.; cow enteric disease related to infection by £ cof or protozoa (I.e.. coocidia. Cryptosporidia, etc.); dairy cow mastitis related to infection by Staph, aureus. Strep, uberis, Strap, agalactiae, Strep, dysgalactiae. Kiebshia spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection


by A. pleura, 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. coir, 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 bacterial .infections and protozoa infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et a!., "The Sanford Guide To Antimicrobial Therapy," 26th Edition, (Antimicrobial Therapy. Inc., 1996).
The present invention also includes isotopically-labeled compounds wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, SH, ,3C, ,4C, tsN, ,80, and ,70. Such radiolabelled and stable-isotopically labelled compounds are useful as research or diagnostic tools.
Brief Description of the Drawings Figure 1 is a calculated powder X-ray diffraction pattern of azithromycin form A. The scale of the abscissa is degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 2 k an experimental powder X-ray rjiffraction pattern of azithromycin form A. The scale of the abscissa is in degrees 2-theta (2 0). The ordinate is the intensity in counts.
Figure 3 is an overlay of Figures 1 and 2 with the calculated diffraction patterns of azithromycin form A (Figure 1) on the bottom and the experimental diffraction pattern of aathromycn form A (Figure 2) on the top. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate b the intensity n counts.
Figure 4ka calculated powder X-ray diffraction pattern of azithromycin form C. The tcato of the abscissa b in degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 5 b a calculated powder X-ray diffraction pattern of azithromycin form D. The icato of the abscissa b in degrees 2-theta (2 0). The ordinate is the intensity in counts.
Figure 6 b an experimental powder X-ray diffraction pattern of azithromycin form D. The scale of the abscissa b ki degrees 2-theta (2 0). The ordinate b the intensity In counts.

Figure 7 is an overlay of Figures 5 and 6 with the calculated diffraction pattern of azithromycin form D (Figure 5) on the bottom and the experimental diffraction pattern of azithromycin form D (Figure 6) on the top. The scale of the abscissa is in degrees 2-theta (2 G). The ordinate is the intensity in counts.
Figure 8 is a calculated powder X-ray diffraction pattern of azithromycin form E. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 9 is a calculated powder X-ray diffraction pattern of azithromycin form F. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 10 is an experimental powder X-ray diffraction pattern of azithromycin form F. The scale of the abscissa is in degrees 2-theta (2 0). The ordinate is the intensity in counts.
Figure 11 is an overlay of Figures 9 and 10 with the calculated diffraction pattern of azithromycin form F (Figure 9) on the bottom and the experimental diffraction pattern of azithromycin form F (Figure 10) on the top. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 12 is a calculated powder X-ray diffraction pattern of azithromycin form G. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity is counts.
Figure 13 is an experimental powder X-ray diffraction pattern of azithromycin form G. The scale of the abscissa is in degrees 2-theta (2 0). The ordinate is the intensity in counts.
Figure 14 is an overlay of Figures 12 and 13 with the calculated diffraction pattern of azithromycin form G (Figure 12) on the bottom and the experimental diffraction pattern of azithromycin form G (Figure 13) on the top. The scale of the abscissa is In degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 15 is a calculated powder X-ray diffraction pattern of azithromycin form J. The scale of the abscissa is in degrees 2-theta (2 0). The ordinate ks the intensity in counts.
Figure 16 is an experimental powder X-ray diffraction pattern of azithromycin form J. The scale of the abscissa is in degrees 2-theta (2 0). The ordinate is the intensity in counts.
Figure 17 is an overlay of Figures 15 and 16 with the calculated diffraction pattern of azithromycin form J (Figure 15) on the bottom and the expenmental diffraction pattern of azithromycin form J (Figure 16) on the top. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate it the WensJty h counts.
Figure 18 h an experimental powder X-ray diffraction pattern of azithromycin form M. The scale of the absdssa b in degrees 2-theta (2 6). The ordinate is the Intensity in counts.
Figure 19 to an experimental powder X-ray diffraction pattern of azithromycin form N. The scate of trteabs is in degrees 2-theta (2 6). The ordinate is the intensty in counts,

Figure 20 is an experimental powder X-ray diffraction pattern of amorphous azithromycin. The scale of the abscissa is in degrees 2-theta (2 8). The ordinate is the intensity in counts.
Figure 21 is a 13C solid state NMR spectrum of azithromycin form A. Figure 22 is a 13C solid state NMR spectrum of azithromycin form D. Figure 23 is a 13C solid state NMR spectrum of azithromycin form F. Figure 24 is a 13C solid state NMR spectrum of azithromycin form G. Figure 25 is a 13C solid state NMR spectrum of azithromycin form J. Figure 26 is a "c solid state NMR spectrum of azithromycin form M. Figure 27 is a 13C solid state NMR spectrum of azithromycin form N. Figure 28 is a 13C solid state NMR spectrum of amorphous azithromycin. Figure 29 is a 13C solid state NMR spectrum of a pharmaceutical tablet containing form G azithromycin.
Figure 30 is an experimental powder X-ray diffraction pattern of azithromycin form Q. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity in counts.
Figure 31 is an experimental powder X-ray diffraction pattern of azithromycin form R. The scale of the abscissa is in degrees 2-theta (2 6). The ordinate is the intensity in counts. Figure 32 is a 13C solid state NMR spectrum of azithromycin form H. Figure 33 is a 13C solid state NMR spectrum of azithromycin form R. >
Detailed Description of the Invention
Azithromycin has been found to exist in different crystalline forms. A dihydrate, form A, and a non-stroichiometric hydrate, form B, are disclosed in European Patent EP 298 650 and U.S. Patent 4.512,359. respectively. Sixteen other forms have been discovered, namely forms C. D. E, F. G. H. I. J. K. L. M. N. O. P. Q and R. These forms are either hydrates or hydrale"sorvates of azithromycin free base. Forms L and K are the metastabie lower hydrate forms of A. detected at high temperature. Crystal structures of forms A, C. D, E. F. G, H. J and O have been solved. The structural data of these crystal forms are given below:
Table 1: CrystaOographic data of azithromycin form A.


Unit cell dimensions a = 14.735 (5) A
b-16.844 (7) A
c = 17.81 (1)A
a=90°
3-90°
y*90°
2 (per formula) 4
Density (g/cm3) 1.18
R 0.060
Table 2: Crystallographic data of azithromycin form C.
FormC

Empirical formula Formula weight Crystal size (mm) Space group Unit cell dimensions
Z (per formula) Density (o/cm3) R

C3,H72N2012-H2O
767.15
0.16x0.16x0.19
P2,2,2| ortborhombic
a - 8.809 (3) A
b«= 12.4750 (8) A
c-45.59 (3) A
a-90°
0=90°
T-90°
4
1.01
0.106

Table 3: Crystallographic data of azithromycin form D.
FormD

Empirical formula Fonnuh wvifbf Crystallize (nun) Space group Unit ccO dimensions

CMH73NjOu«H;OC«Hu
851.15
0.52 x0J2x 0.16
P2j2(2, ortborbombic
a-8.8710 (10) A

2 (per formula) Density (g/cm3) R

b- 12-506 (2) A
c- 45.697 (7) A
α=90°
β=90°
Y=90°
4
1.12
0.0663


Table 4: Crystallographic data of azithromycin form E.
FormE
Empirical formula CMHnN20,2-H2O-C4H,0
Formula weight 839.2
Crystal size (mm) 0.17x0.19x0.20
Space group P2|2,2| orthorliombic
Unit cell dimensions a - 8.869 (3) A
b-12.086 (3) A
c-46.00(1) A
a-90*
0=90*
y-90*
Z (per formula) 4
Density (g/cm*) 1.13
R 0.087
Table 5: Crystallographic data of azithromycin form F.
FormF

Empirical formula Qyrtal tax (mm) Formula wrigbl
SfWCCfTOUp
Unit cell dimeosii

CMlitaNjOu*ll/H).SCjll«0
0.14*0.20x0.24
790J
P2, moooclinic
■ -16L28I(2)A
b-16.»3 e- 18.490 (3) A

α-90°
β= 109.33(1)°
y =90°
Z (per formula) 4
Density (g/cm3) 1.13
R 0.0688
Table 6: Crystallographic data of azithromycin form G.
FormG

Formula Formula weight Crystal size (mm) Space group Unit cell dimensions
2 (per formula) Density (g/cm ) R

C„H72N,0,2"1.5H20
776.0
0.04 x 0.20 x 0.24
P2| monoclinic
a = 16.4069(8) A
b= 162922(8) A
c-18.3830 (9) A
"a*OT
p-110.212(2)°
Y = 90°
4
1.12
0.0785

Table 7: Crystallographic data of azithromycin form H.

Empirical formula Cryiul size (mm) FonnuU weigh! Space group Unit cell diaxasiom

Form iH
C»HnNAH IjO-O-SC,! I.Q,
0.14x020x024
805.0
P2( moooclmic
I-I6.I77(I)A
b-16.241 (2) A
c- 18.614 (I) A
a-90*
P-108J4(1)-

Z (per formula) Density (g/cm3) R

y = 90° 4
1.15 0.0687

Table 8: Crystallographic data of azithromycin form J.
Form J

Formula Formula weight Crystal size (mm) Space group Unit cell dimensions
2 (per formula) Density (g/cm5) R

CjjHnNjOu"HzO •O.SCJH.O
796.0
0.40x0.36x0.20
P2| monoclinic
a =16.191(6) A
b= 16.237(10) A
c= 18.595(14) A
a=90°
8= 108.92(4)°
y = 90°
4
1.14
0.0789

Table 8A: Crystallographic data of azithromycin form O.
ForniO

Formula Formula weight Crystal toe (nun) Space group Unii cell dimension!
Z (per formula)

Cj.1 InNjOu-O^HaO «0.5C.H,oO
795.04
0.40x036x0 JO
P21 monoclinic
a-16.3602(11) A
b-16.2042(11) A
c-I83459(|2) A
a-90*
P- 109.66(10)"
4

Density (g/cm8) 1.14
R 0.0421
Among these sixteen crystal forms, two isomorphic families are identified. Family I
includes forms F, G, H, J, M, N, 0, and P. Family II includes forms C, D, E and R. Form Q is
distinct from families / and U. The forms within a family are isomorphs that crystallize in the
same space group with slight variation of cell parameters and comprise chemically related
structures but different elemental composition. In this case, the variation in chemical
composition among the isomorphs arises from incorporation of different water/solvent
molecules. Consequently, the isomorphs display similar but non-identical X-ray diffraction
patterns and- solid-state NMR-spectra- (ssNMR). Other-techniques such as near infrared
spectroscopy (NIR), differential scanning calorimetry (DSC), gas chromatography (GC),
thermalgravimetric analysis (TGA), or thenmalgravimetric analysis/infrared spectroscopy
analysis (TG-IR), Karl Fischer water analysis (KF) and molecular modeling/visualization
provide data for affirmative identification of isomorphs. Dehydration/desolvation
temperatures were determined by DSC with a heating rate of 5*C/min
Form C: This crystal form was identified from a single crystal structure (Table 2) - a monohydrate of azithromycin. It has the space group of P2,2,2i and similar cell parameters as that of forms D and E; therefore, it belongs to Family II isomorphs. Its calculated powder pattern is similar to that of forms D and E.
Form D: Form D was crystallized from cyclohexane. The single crystal structure of form D shows a stoichiometry of a monohydrale/monocyclohexane solvate of azithromycin (Table 3). Cyclohexane molecules were found to be disordered in the crystal lattice. From single crystal data, the calculated water and cyclohexane content of form D is 2.1 and 9.9%. respectively. Both the powder pattern and the calculated powder pattern of form D are similar to those of forms C and E. The powder samples of form D showed a desotvation/dehydration endotherm with an onset temperature of about 87°C and a broad endotherm between 200* 280"C (decomposition) in DSC analysis at 5°CAnin from 30-300*C.
Form D to prepared by slurrying azithromycin in cyclohexane for 2-4 days. The solid fcym D azithromycin is colected by filtration and dried.
Form E: Form E was obtained as » single crystal coOected in a THF/water medium. It it a monohydrate and mono-THF sorvale by single crystal analysis (Table 4). By Ms sngie crystal structure, the calculated PXRO pattern is similar to that of form C and form D making It • fam#y II isomorph.
Form E it prepared by dissolving azithromycin in THF (telrahydrofuran). Diffusing water vapor lo saturated azithromycin THF solution over time yields crystals of Form E.

I

Form F: The single crystal of form F crystallized in a monoclinic space group. P2,, with the asymmetric unit containing two azithromycin, two waters, and one ethanol, as a monohydrate/hemi-ethanolate (Table 5). It is isomorphic to forms all family I azithromycin crystalline forms. The calculated PXRD pattern of this form is similar to those of other family I isomorphs. The theoretical water and ethanol contents are 2.3 and 2.9%, respectively. The powder samples show a dehydration/desolvation endotherm at an onset temperature between 110-125CC. Form F is prepared by dissolving azithromycin in ethanol (1-3 volumes by weight) at a temperature of about 50-70°C. Upon complete dissolution, the solution is cooled to subambient temperature to cause precipitation. The volume of ethanol can be reduced by vacuum distillation with stirring for 1-2 hours to increase the yield. Alternatively, water (optionally chilled to 0-20°C) about 0.1-2 volume can be added with collection of solids within 30 minute after water addition. Cooling the ethanol solution of azithromycin prior to the addition of water to below below 20"C, preferably below 15*C. more preferably below 10, and most preferably 5"C results in substantially pure azithromycin form F. The solid form F azithromycin is collected by filtration and dried.
Form G: The single crystal structure of form G consists of two azithromycin molecules and three water molecules per asymmetric unit (Table 6). 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, which is well below stoichiometric quantities of solvate. This form dehydrates with an onset temperature of about 110 -120°C.
Form G may be prepared by adding azithromycin to a premixed organic solvent/water mixture (1/1 by volume), where the organic solvent can be methanol, acetone, acetonitrile, ethanol or isopropanol. The mixture is stirred and heated to an elevated temperature, e.g. 45-55*C for 4-6 hours to cause dissolution. Precipitation occurs during cooling to ambient temperature. The solid form G azithromycin is collected by filtration and dried.
Form H: This crystal form is a monohydratememi-propytene glycol solvate of azithromycin free base (Table 7). It was isolated from a formulation solution containing propylene grycoi. The crystal structure of form H is isomorphic to crystal forms of Famty I.
Azithromycin form H is prepared by dissolving azithromycin dfrydrate in 6 volumes of propylene glycol. To the resulting propylene glycol solution of azithromycin, 2 volumes of water is added and precipitation occum. The slurry b stirred for 24 hours and the solids are fttered and air-dried at ambient temperature to afford crystalline Form H.
Form J: Form J is a rronoftydreteifternr n-propanot solvate (Table 8). The calculated solvent content is about 3.8% n-propanol and about 2.3% water. The experimental data shows from about 2.5 to about 4.0% n-propanol and from about 2.5 to about 3% water intent for powder samples. Its PXRD pattern is very simlar to those of its isomorphs F, G.

H, M and N. Like F and G, the powder samples have a dehydration/desolvation endotherm at 115- 125°C.
Form J is prepared by dissolving azithromycin in 4 volumes of n-propanol at a temperature of about 25-55cC Water, about 6-7 volumes, is added at room temperature and the slurry is continuously stirred for 0.5-2 hours. The solid form J azithromycin is collected by filtration and dried.
Form K: The PXRD pattern of form K was found in a mixture of azithromycin form A and microcrystalline wax after annealing at 95°C for 3 hours. It is a lower hydrate of form A and is a metastable high temperature form.
Form L: This form has only been observed upon heating the dihydrate; form A. In variable temperature powder X-ray diffraction (VT-PXRD) experiments, a new powder X-ray diffraction pattern appears when form A is heated to about 90°C. The new form, designated form L, is a lower hydrate of form A because form A loses about 2.5 weight % at 90 °C by TGA, thus corresponding to a conversion to a monohydrate. When cooled to ambient temperature, form L rapidly reverts to form A.
Form M: Isolated from an isopropanol/water slurry, form M incorporates both water and isopropano/. lis PXRD pattern and ss-NMR spectrum are very similar to those of Family I isomorphs,.indicatingihal_itJ5elangsJo_Farriily.I.. By analogy.to the known crystal structures of Family I isomorphs, the single crystal structure of form M would be a monohydrate/hemi-isopropranolate. The dehydration/desolvation temperature of form M is about 115-125°C.
Form M may be prepared by dissolving azithromycin in 2-3 volumes of isopropanol (IPA) at 40-50°C. The solution is cooled to below 15°C. preferably below 10°C, more preferably about 5°C and 2-4 volumes of cold water about 5°C are added to effect precipitation. Seeds of form M crystals may be added at the onset of crystallization. The slurry is stirred less than about 5 hours, preferably less than about 3 hours, more preferably less than about 1 hour and most preferably about 30 minutes or less and the solids are collected by filtration. The solids may be reslumed In isopropanol. This procedure provides form M substantially in the absence of azithromycin dihydrate.
Form N: Isolated from water/ethanot/isopropanoi slurry of form A, form N crystals may contain variable amounts of the crystallization solvents and water. Its water content varies from about 3.4 to about 5.3 weight percent Analysis by GC Headspace reveals a variable servant content of ethano! and isopropanol. The total solvent content of form N sample* b usuafty lower than about 5% depending on the conditions of preparation and dryrtg. The PXRD pattern of form N is similar to that of forms F, G, H, J and M of the Famly I bomorphs. The derrydration/desotvation endotherm(s) of the samples of form N may be broader and may vary between 110-130°C.

Form N azithromycin may be prepared by recrystallizing azithromycin from a mixture of azithromycin crystal latice-incorporating organic solvents and water, such as ethanol, isopropanol, n-propanol, acetone, acetonitirile etc. The solvent mixture is heated to 45-60°C and azithromycin is added to the heated solvent mixture, up to a total of about 4 volumes. ") Upon dissolution, 1-3 volumes of water are added with continuous agitation at 45-60°C. Form N azithromycin precipitates as a white solid. The slurry is allowed to cool to ambient i temperature with stirring. Solid form N azithromycin is isolated by filtration and dried.
Form O: This crystal form is a hemihydrale hemi-n-butanol solvate of azithromycin free base by single crystal structural data (Table 8A). It was isolated from n-butanol solution of azithromycin with diffusion of antisolvent. The crystal structure of form O is isomorphic to
crystal forms of Family I
Azithromycin is completely dissolved in n-butanol. Addition of an antisolvent, such as hexane, water, IPE or other non-solvent, by diffusion results in precipitation of Form O.
Form P: This is a proposed crystal form, being a hemihydrale hemi-n-pentanol solvate of azithromycin free base. It can be isolated from an n-pentanol solution of azithromycin with diffusion of an antisolvent. The crystal structure of form P is isomorphic to crystal forms of Family I.
Form P of azithromycin may be prepared as following: Azithromycin is completely dissolved in n-pentanol; addition of an antisolvent, such as hexane, water, isopropyl ether (IPE) or other non-solvent, by diffusion results in precipitation of Form P.
Form Q: The crystal form of Q exhibits a unique powder X-ray diffraction pattern. It contains about 4% water and about 4.5% THF, being a hydrate hemi THF solvate. The main dehydration/desolvation temperature is from about 80 to about 110°C.
Azithromycin dihydrale is dissolved in 6 volumes of THF and 2 volumes of water are added. The solution is allowed to evaporate to dryness at ambient conditions to afford orystaline Form Q.
Form R: This crystalline form is prepared by adding amorphous azithromycin to 2.5 volumes of tert-butyl methyl ether (MTBE). The resulting thick while suspension is stirred 3 days at ambient conditions. Solids are collected by vacuum filtration and air dried. The resuffog buk azithromycin form R has a theoretical water content of 2.1 weight % and a tfieoretical methyl tort-butyl ether content of 10.3 weight %.
Due to the simlarity in the* structures, bomorphs have propensty to form a mixture of the forms within a famly, sometimes termed as "mixed crystals" or "crystalline solid solution". Form N is such a solid crystalline solution and was found to be a mixture of Famly I jsomorphs by solvent composition and solid-state NMR data.

I

Both Family I and Family II isomorphs are hydrates and/or solvates of azithromycin. The solvent molecules in the cavities have tendency to exchange between solvent and water under specific conditions. Therefore, the solvent/water content of the isomorphs may vary to a certain extent.
The crystal forms of isomorphic Family I are more stable than form A when subjected to heating. Forms F, G, H, J, M and N showed higher onset dehydration temperatures at 110-125 °C than that of form A with an onset dehydration temperature at about 90 to about 110°C and simultaneous solid-state conversion to form L at about 90°C.
Amorphous azithromycin: All crystal forms of azithromycin contain water or solvent(s) or both water and solvent(s). When water and solvent(s) are removed from the crystalline solids, azithromycin becomes amorphous. Amorphous solids have advantages of high initial dissolution rates.
The starting material for the synthesis of the various crystal forms in the examples below was azithromycin dihydrate unless otherwise noted. Other forms of azithromycin such as amorphous azithromycin or other non-dihydrate crystalline forms of azithromycin may be used.
Examples
Example 1: Preparation of Form D
Form D was prepared by slurrying azithromycin dihydrate in cyclohexane for 2-4 days at an elevated temperature, e.g. 25-50°C. The crystalline solids of form O were collected by filtration and dried.
Example 2: Preparation of Form F
2A" Azithromycin dihydrate was slowly added to one volume of warm ethanol, about 70°C. and stirred to complete dissolution at 65 to 70°C. Seeds of Form F 1- 2% wt may be introduced to facilitate the crystallization. The solution was allowed to cool gradually to 2 -5°C and one volume of chilled water was added The crystalline solids were collected shortly (preferably less than 30 minutes) after addition of water by vacuum filtration.
2B: Azithromycin dftydrate b slowly added to one volume of warm ethanol, about 70*C. and stirred to complete dissolution at 65 to 70°C. Seeds of Form F 1- 2% wt may be produced to facilitate the crystallization. The solution is allowed to cool graduaffy to 2 - 5*C and ethanol volume may be reduced by vacuum d"atHatjon. After stirring up to 2 hours the cry»trtne solids are collected by vacuum Rtration. The isolation of the crystals yields substantia^ pure form F azithromycin, form F azithromycin substantiaty free of form G azithromycin and form F azJtriromycin substantially free of azithromycin dihydrate.

Example 3: Preparation of Form G
A reaction vessel was charged with form A azithromycin. In a separate vessel, 1.5
volumes methanol and 1.5 volumes water were mixed. The solvent mixture was added to the
reaction vessel containing the form A azithromycin. The slurry was stirred with heating to
50°C for approximately 5 hours. Heating was discontinued and the slurry was allowed to cool
with stirring to ambient temperature. The form G azithromycin was collected by filtration and
allowed to air dry for approximately 30 minutes. The collected form G azithromycin was
further dried in a vacuum oven at 45°C. This procedure yields substantially pure form G
azithromycin, and form G azithromycin substantially free of azithromycin dihydrate.
Example 4: Preparation of Form J
Form J was prepared by dissolving azithromycin in 4-volumes ofn-propanol at a temperature of about 25°C. Water (6.7 volumes) was added and the slurry is continuously stirred for 1 hour, followed by cooling to about 0°C. The solid form J azithromycin was collected by filtration and dried.
Example 5: Preparation of Form M Substantially in the Absence of Azithromycin Dihydrate
5A; Azithromycin dihydrate is completely dissolved in 2 volumes of warm isopropanol 40 - 50°C. Seeds of Form M may be optionally introduced to facilitate the crystallization. The solution is then cooled to 0-5°C and 4 volumes of chilled water as antisolvent are added and the solids are collected by vacuum nitration. The solids are reslurried in 1 volume of isopropanol for 3-5 hours at 40-45 °C and then cooled to 0-5°C. The crystalline solids are collected shortly (about 15 minutes) after addition of water by vacuum nitration. The solids are reslurried in 0.5 to 1 volume of isopropanol at 25-40°C and cooled to about 5°C followed by filtration to collect solids of form M.
5B: Azithromycin dihydrate (1940 grams) was completely dissolved in 2 volumes of warm isopropanol (45°C). The resulting dear solution was filtered through an inline 0.2 um filter into a dean flask. The temperature was maintained at 45°C and the solution was seeded with form M crystals. 7.6 L of chiled water was added over B minutes. The solution was cooled to 5*C and a thick slurry was noted. The solids were isolated by vacuum filtration and transferred to a dean flask. The crystalline azithromycin was slurried in 1 volume of isopropanol alcohol with warming to 35*C. The slurry was then cooled to 5*C for 30 minutes and the solid crystaline material was Altered off.
These procedures yield substantiaty pure form M azithromycin, form U azithromycin substantiaty free of form G azithromycin and form M azitriromycin substantiaty free of ezithf omyoin cWiydrate
Example 6: Preparation of Form N

Two volumes of ethanol and 2 volumes of isopropanol were added to a reaction vessel and heated to 50°C. Azithromycin form A was added with stirring to the heated ethanol/isopropanol mixture to yield a clear solution. The reaction vessel was charged with 2 volumes distilled water (ambient temperature). Stirring was continued at 50°C and solid form N azithromycin precipitated after approximately 1 hr. Heating was discontinued 5 hours after the addition of the water. The slurry was allowed to cool to ambient temperature. Precipitated form N azithromycin was collected by filtration and dried for 4 hours in vacuum oven at 45°C.
Example 7: Preparation of amorphous azithromycin
Crystalline form A azithromycin was heated to 110-120°C in an oven for overnight under vacuum. The amorphous solids were collected and stored with desiccant as needed. Example 8: Preparation of Form H
Azithromycin dihydrate or other crystal forms was dissolved in 6 volumes of propylene glycol. To the resulting propylene glycol solution of azithromycin, 2 volumes of water were added and precipitation occurred. The slurry was stirred for 24 hours and the solids were filtered and air-dried at ambient temperature to afford crystalline Form H. Example 9: Preparation of Form Q
The crystalline powder was prepared by dissolving 500 mg azithromycin Form A in 2 ml THF. To the clear, colorless solution at room temperature was added 1 ml water. When the solution became cloudy an additional 1ml THF was added to dissolve the azithromycin completely, and the solution was stirred at ambient temperature. Solvent was allowed to evaporate over 7 days, after which the dry solids were collected and characterized.
Example 10: Powder X-ray diffraction analysis
Powder patterns were collected using a Bruker D5000 diffractometer (Madison, Wisconsin) equipped with copper radiation, fixed slits (1.0. 1.0. 0.6mm). and a Kevex solid state detector. Data was collected from 3.0 to 40.0 degrees in 2 theta using a step size of 0.04 degrees and a step time of 1.0 seconds. The results are summarized in Table 9.
The experimental PXRD diffraction pattern of azithromycin form A is given in figure 2.
The experimental PXRD diffraction pattern of azithromycin form D is given in figure 6.
The experimental PXRD diffraction partem of azithromycin form F "» given in figure
10.
The experimental PXRD diffraction pattern of azithromycin form G is given in figure
13.
The experimental PXRD diffraction pattern of azitrtrornydn form J it given In figure
16.
The experimental PXRD diffraction partem of azithromycin form M Is given in figure
18.

The experimental PXRD diffraction pattern of azithromycin form N is given in figure 19.
The experimental PXRD diffraction partem of amorphous azithromycin is given in figure 20.
The experimental PXRD diffraction pattern of azithromycin form Q is given in figure 30.
The experimental PXRD diffraction pattern of azithromycin form R is given in figure 31.
The experimental variability from sample to sample is about ± 0.2° in 2 theta, and the same variations were observed between the calculated powder from single crystal structure and experimental data. Detailed analysis showed that the isomorphs in Family I can be discerned by PXRD with sets of characteristic peaks given in Table 9.
Table 9. Azithromycin Powder X-ray Diffraction Peaks in 2-theta ±0,2°

A |D |F |G J M IN Q
12 M 5.7 5.0 5.0 5.0 6J S.7
7.9 7.3 61 5.8 5.7 5.6 7.3 6.1
93 7.7 7.4 6J %2 6J 7.8 6J
9.9 10.1 7.6 7.4 7.3 7.3 9.8 M
11.2 10.6 8.9 7.9 7.8 7.8 11.2 9.5
12.0 11.5 9.6 9.8 8.2 8.2 11.9 10.6
12.7 12.3 10.3 10.2 9.7 9.8 12.5 IU
13.0 12.8 11.2 10.6 10.3 10.2 14.0 11.5
14.0 13.6 11.5 11.2 11.2 If.2 14.3 12.4
15.6 14.5 11.9 11.$ 11.4 11.9 jit 12.7
16.0 |i54 12J 12.0 11.9 122 15-i 13.4
16.4 154 125 12.5 12.3 12-5 1&.7 13.6
16.6 16.9 a$ 13J 12-5 14.0 16.1 14.1
17.5 1BJ U3 H.0 11$ 14$ iii 14.4
18.2 10.0 UT 14.4 14.2 15J 17.1 i4J»
16.7 19-0 1ft H* UJ 110 17.4 115"
19.1 : to* 13*3 Il4.» iu fCf 1*4 iU
19* i H4 J 15.7 jlSJ I1&.7 17.1 19.0 iU
205 l 1.6 J JJ i 5.7 UJB 17J 10.4 19.0 "
20.9 2 2.0 1 «J 1 6.3 ro.0 16.4 20.6 19.5
21.2 2 3.0 1 LI 1 6J J f7.0 J18.5 |204 19.6

21.6 23.3 17.2 17.2 17.2 19.1 21.0 20.2
21.8 17.7 17.4 17.S 19.6 21.6 20.5
24.0 1B.0 17.B 18.1 20.0 22.5 21.1
18.5 18.1 16.5 20.4 23.5 21.6
19.0 18.6 19.0 20.9 21.9
I I19"6 19.0 19.7 21.7 22.2
I J20.0 19.6 20.0 22.5 23.6
20.5 20.0 20.4 23.2 25.1
21.0 20.5 20.9 23.6
21.7 21.1 21.7
22,0 21.8 22.4
22.4 22.5 22.6
22.6 23.5 23.3 •
>3.1 23.5
!3.5
i K ) f ( i . 1 M N Q
The peaks underlined are the characteristic peaks among forms A, D, Family I and 6. The peaks in italic and underlined are the sets of peaks that are characteristic within Family I isomorphs.
Family I isomorphs have the following common characteristics: the diffraction peaks at 6.2, 11-2. 21.0±0.1 and 22.5 ±0.1 degree in 2-theta. Each isomorph displays representative sets of diffraction peaks given in the following, and each set has characteristic spacing between the peaks.
The diffraction peak positions reported are accurate to within ± 02 degree of 2-theta.
A representative PXRD pattern of form A is shown in figure 2. Form A displays peaks at 9.3,13.0 and 18.7 degrees of 2-theta.
A representative PXRD pattern of form D b shown in figure 6. Form O displays peaks at 3.9.10.1,10.6 and 21.4 degrees of 2-4heta.
A representative PXRD pattern of Form F Is shown In figure 10. Form F displays the characteristic peaks of Famiy I and three sets of peaks, being sat 1 at 2-theta of 11.2 and 11.5; sat 2 at 2-theta of 13.9. 14 J, 14.7 and 14A; sat 3 at 2-theta of 162,16.6. 17.1. 17.2
and 17.7.
A representative PXRD pattern of Form G is shown in figure 13. Form O displays the characteristic peaks of FamBy I and three sets of peaks, being set 1 at 2-theta of 112 and


11.6 2; set at 2-theta of 14.0, 14.4, 14.6 and 14.9; set 3 at 2-theta of 16.3, 16.6, 172, 17.4 and 17.8.
A representative PXRD pattern of Form J is shown in figure 16. Form J displays the characteristic peaks of Family I and three sets of peaks, being set 1 at 2-theta of 11.2 and 11.4; set 2 at 2-theta of 13.9, 14.2 and 14.6; set 3 at 2-theta of 16.0, 16.6, 17.0, 17.2 and 17.5.
A representative PXRD pattern of Form M is shown in figure 18. Form M displays the characteristic peaks of Family I and three sets of peaks, being set 1 at 2-theta of 11.2; set 2 at 2-theta of 14.0 and 14.6; set 3 at 2-theta of 15.9,16.6.17.1 and 17.5.
A representative PXRD pattern of Form N is shown in figure 10. Form N displays the characteristic peaks of Family..!..The sets of peaks of-form N are similar to those of forms F, G. J and M, being set 1 at 2-theta of 11.2 to 11.6; set 2 at 2-theta of 13.9 to 15.0; and set 3 at 2-theta of 15.9 to 17.9, with the peaks may vary slightly in position, intensity and width due to mixing of variable proportion of isomorphs in Family I.
A representative PXRD pattern of form Q is shown in figure 30. Form Q displays peaks at 2-theta of 6.8,8.4 and 20.2 degree.
A representative PXRD pattern of form R is shown in figure 31.
Example 11: Single crystal X-ray analysis >
Data were collected at room temperature using Bruker X-ray diffractometers equipped with copper radiation and graphite monochrome tors. Structures were solved using direct methods. The SHELXTL computer library provided by Bruker AXS, Inc facilitated all necessary crystallographic computations and molecular displays (SHELXTL™ Reference Manual. Version 5.1. Bruker AXS. Madison. Wisconsin. USA (1997)).
Example 12: Calculation of PXRD pattern from single crystal data
To compare the results between a single crystal and a powder sample, a calculated powder pattern can be obtained from single crystal results. The XFOG and XPOW computer prograrm provided as part of the SHELXTL computer library were used to perform Into calculation. Comparing the calculated powder pattern with the experimental powder partem confirms whether a powder sample corresponds to an assigned sngle crystal structure (Table 9A). This procedure was performed on the crystal forms of azithromycin A, D. F. G. and J.
The calculated PXRD diffraction pattern of azithromycin form A is given In figure 1.
Th# calculated PXRD diffraction partem of azithromycin form D is given in flour* 5.
The calculated PXRD diffraction pattern of azithromycin form F Is given In figure 9.
The calculated PXRD diffraction pattern of azithromycin form G to given in figure 12.
The calculated PXRD diffraction pattern of azithromycin form J b gtven In figure 15.

The results are displayed in the overlaid powder X-ray diffraction patterns for forms A, D, F, G, and J in figures 3, 7, 11, 14 and 17, respectively. The lower pattern corresponds to the calculated powder pattern (from single crystal results) and the upper pattern corresponds to a representative experimental powder pattern. A match between the two patterns indicated the agreement between powder sample and the corresponding single crystal structure.
Table 9A: Cacluated and Experimental PXRD Peaks of Isomorphs of Family I

f- calculated V experimenta CJ calculated G experimental J calculated j experimental W expeiimeniai
5.2 5.0
5.7 5.8 5.8 " 5.7 5.6
K3" 6.2 6.2 6.2 6.3 6.2 6.2
■/>r 7.4 7.5 7.4 7.4 7J 75
fJB 7.8 7.9 7.9 7.9 75 75
e:e 8.9 8.9 9.3 8.3 8.2 8.2
" 9.9 9.8 9.9 9.9 9.6 9.7 95 "
10.3 10.3 10.2 10.4 10.3 10.2
■ 10.9 10.9 10.6
" 11.3 11J2 11.3 11.2 11.2 112 112
11.5 11.4 11.6 11.6 11.4 11.4 mssmg
1Z0 11.9 12.0 11.9 12.0 115 11.9
1Z3 12.2 1Z3 12.3 12JT 12.2
— 125 125 12.5 " 12.5 12J6 125 125"~
14.0 14.0 13.4 13.3 14.0 13.8 14.0
14.3 14.3 14.1 14.0 14.2 14.2 mssmg
14.4 14.4
._ 14.7 14.7 -14.7 14.6 14.7 14.6 14.6
14.9 14.8 14.9 14.9 14.8
15.4 15J 15.4 15.3 15 J 1SJ 15J
—" 15.8 15.7 15.7 .... 1W " 155 157 15.9
16.2 16.2 16.3 16a 16.0 16.0 missing
18.fi
165 "" 16.6 16.6"" 16.7 165 16.6
" 1/.1 17.2 17.1 17.1 "~ 17JD 17.1
17.3 17.3 17.3 17.2 17.4 17.2 mssmg
1/5 17.4 175 17.4 17.fi
175 175
■ 177 17.7 " 17.9 175" 17.9
—18.0 18.TJ 18.1 18.1 18.2 w.r 154
18.6 lei 18.7 18.7 16-5 181 185
19.1 " 19.0 19.1 " 19.0 19.1 iSXT 19.1
— 19.7 - 19.6 19,6 "—19.6 195 19.7 195 "■"
20.0 20.0 " " 20.0 "20.0 20.1 200 20:0
205 204 " 206 205 20.5 20.4 20.4
21.1 21.0 " 21.2 ~ 21.0 205 20.9 20.9 ~
— 71.1 21.7 21.5 21 £ Tl.t 21.7
~~ Zil 225 215 21J 215
225 22.4 22J 222 ZZ5 72A 225
ZZ-7 223 225 225 22j " TIM
211 21T~ " 22.9 23-4 zu " 2X2
23.6 235 215 " 235 | 23.7 23.5 23.5
Example 13: Solid Stale NMR Anarysb
Solid Slate NMR analysis:
Al "C solid stale NMR spectra were collected on an 11.75 T spectrometer (Bruker Btospln, Inc., BUerica. MA), corresponding to 125 MHz iaC frequency. The spectra were collected using a cross-polarization magic angle spinning (CPMAS) probe operating at

ambient temperature and pressure. Depending on the quantity of sample analyzed, 7 mm BL or 4 mm BL Bruker probes were employed, accomodating 300 mg and 75 mg of sample with maximum speeds of 7 kHz and 15 kHz. respectively. Data were processed with an exponential line broadening function of 5.0 Hz. Proton decoupling of 65 kHz and 100 kHz were used with the 7mm and A mm probes, respectively. A sufficient number of acquisitions were averaged out to obtain adequate signal-to-noise ratios for all peaks. Typically, 600 scans were acquired with recycle delay of 3.0 s, corresponding approximately to a 30 minute total acquisition time. Magic angle was adjusted using KBr powder according to standard NMR vendor practices. The spectra were referenced relative to either the methyl resonace of hexamethylbenzen (HMB) at 17.3 ppm or the upfield resonance of adamantane (ADM) at 29.5 ppm. HMB referenced spectra show chemical shifts of all peaks shifted down field by 0.08 ppm with respect to same spectra referenced to ADM. The spectral window minimally included the spectra region from 190 to 0 ppm. The results are summarized in Table 10. Ss-NMR spectra for forms M, H and R were referenced to ADM, Ss-NMR spectra for forms A, D, G, F, J and N were referenced to HMB. Forms H and R were spun at a rate of 15 kHz.
Table 10.13C ss-NMR chemical shifts of Azithromycin (± 0.2 ppm)

\ D G F J M M hi R
178.1 178.1 179.5* 179.5 179.6 179.6 179.6 179.5 177.9




104.1 103.9 105.5 178.6 178.4 105.6 178.7 178.7 104.6




98.4 95.1 103.5 105.5 105.5 103.4 105.6 105.4 103.6





34.6 34.2 95.0 103.4 103.4 94.9 103.6 103.2 95.3
92.6 79.4 36.2 94.9 95.0 86.7 95.0 95.0 35.4
p9J 78.9 J3.1 96.4 36.4 32.9 36.5 36.4 34.0
(78.3 75.7 78.9 93.0 32.9 79.3 33.1 B2.7 79.4
75.6 74.6 785 79.1 795 78.1 79.0 795 79.0
74.7 74.0 77.6 78.1 78.1 77.0 77.9 78.3 75.6
73.9 72.9 76.4 77.9 76.8 76.7 76.5 78.0 74.5
73.5 71.9 75.7 76.5 765 74.7 74 8 76.4 73.9
70.6 71.0 74.7 74.7 74.7 745 745 74.7 73.9
38 0 59.4 74.3 74.1 74.1" 71.3 73.6 74.1 72.9
565 >7A ?3.5 73.5 72.0" 595 71.6 73.5 71.8
S3* >5.7 71.3 71.4 71.3 58.6 395 73.1 71.0
53.2 4.7 >9.1 S9.1 395 67.3 68.7 7li 59.1
52.2 95 >8.8 E >8.6 38.6 665 67.3 69.1 57.5


44.3 45.8 57.4 57.3 67.3" 55.5 562 68.4 55.6
42.6
- 43.1 B5.9 56.1 562" 53.8 55.7 57.3 54.5
M1.7 40.6 652 65.6 55.5" 63.3 53.7 56.9 49.4
39.1 37.1 64.0 53.6 53.7 50.0 58.7 56.1 45.7
35.4 36.4 63.3 58.0 50.0 47.1 50.1 55.5* 42.9
34.6 29.6 50.0 50.0 46.9 45.9 47.1 63.7* 41.6
26.9 29.3 46.9 47.0 45.9 44.7 46.0 49.9 40.4
26.3 28.0 W6.0 45.9 44.7 43.8 44.8 46.8 37.0
23.7 27.7 W4.5 44.7 43.7 41.9 43.8 45.9 36.2
23.3 22.1 43.7 43.7 41.6 41.1 41.5 44.5 29.4
21.7 E1.1 41.5 41.5 41.0 37.4 41.1 43.8* 29.0
19.5 18.6 40.8 41.1 37.1 36.2 37.3 41.7 28.2.
17.5 16.7 37.5 37.3 36.5" 33.6 36.5 40.9 27.4
15.9 16.1 36.5 36.4 35.4" B0.1 33.7 37.1 21.4
13.2 10.6 33.6 33.6 33.5 28.1 30.4 36.3 20.8
11.3 SU> 30.0 30.3 30.4 27.2 28.1 33.7 18.7
72. 6\6 27-9 28.0 28.0 260 27.2 33.3 16.5
27.3 27.1 27.1 23.2 2&0 30.5* 16.1
23.1 23.2 252 22.8 23.2 27.9 15.7
22.5 22.6 232 22.5 22.6 27.1 10.3
21.9 21.9 |22.5" 21.8 22.0 23.1 9J5
The chemical shifts labeled in bold and underlined are the peaks or sets of peaks representative of each form. The chemical shifts labeled in italic are the solvent peaks that may be broad and variable (± 0.4 ppm). The chemical shifts labeled with single asterisk may show splitting of
Table 10 (continued). 13C ss-NMR chemical shifts of Azithromycin (± 02 ppm)

A p G F J Vi N H R
20.9 20.8 21.9" 20.2 20.8 22.6 BJ)
20.2 20.4 20.7 18.9 19.0 22.3 16
18.B 18.9 18.9 V7.4 tt.S n.s
17.0 16.8 16.8 16.3 15.8 20.7
116.0 UZi 15.6" 15.5 12.2 20.3
122 15.7 12.1 12.1 9J3 18.8
10.4 12.2 11.5 10.3 34 17.1
9.9 — 10;-1 12.1 9.6 — 7.9 16.6









9.3 9JJ 10.0 9.3 6.6 15.8
7.6 ^3 9;3 7.7 15.4
6.5 7.9 8.1 7.1 12.0
3.6 3.8" 9.9
91.
7,9
7J)
-
The chemical shifts labeled in bold and underlined are the peaks or sets of peaks representative of each form. The chemical shifts labeled in italic are the solvent peaks that may be broad and variable (± 0.4ppm). The chemical shifts labeled with single asterisk may show splitting of The chemical shifts reported are accurate to within ± 02 ppm unless otherwise indicated.
A representative "*C s»NMR spectrum of form A to shown in figure 21. Form A displays 8 peak at 178.1 ppm, and peaks at 104.1.98.4,84.6.26.9,13.2,11J3 and 12 ppm.
A representative "C s*NMR spectrum of form D is shown in figure 22. Form D displays the highest chemical shift peak of 178.1 ppm and peaks at chemical shifts of 103.9. 95.1. 64.2. 106. 90and8 6ppm.
A representative 13C ssNMR spectrum of form F is shown in figure 23. Form F has two chemical shift peaks at approximately 179.1 ± 2 ppm, being 179.5 ppm and 178.6 ppm.

and a set of 5 peaks at 10.1, 9.8, 9.3, 7.9, and 6.6 ppm, and ethanol peaks at 58.0±0.5 ppm and 17.2±0.5 ppm. The solvent peaks can be broad and relatively weak in intensity.
A representative 13C ssNMR spectrum of form G is shown in figure 24. Form G has the highest chemical shift peak of 179.5 ppm, being a single peak with possible splitting of A representative 13C ssNMR spectrum of form J is shown in figure 25. Form J has two chemical shift peaks at approximately 179.1 ± 2 ppm, those being 179.6 ppm and 178.4 ppm, a set of 4 peaks at 10.0, 9.3. 8.1 and 6.8 ppm and n-propanol peaks at 11.5+0.5 ppm and 25.2±0.5 ppm. The solvent peak can be broad and relatively weak in intensity.
A representative 13C ssNMR spectrum of form M is shown in figure 26. Form M has one chemical shift peak at 179±1 ppm, being 179.6 ppm, peaks at 41.9, and 16.3 ppm, a set of 5 peaks at 10.3, 9.6, 9.3, 7.7 and 7.1 ppm and an isopropanol peak at 26.0± 0.5 ppm. The solvent peak can be broad and relatively weak in intensity.
A representative 13C ssNMR spectrum of form N is shown in figure 27. Form N displays chemical shifts as a combination of isomorphs in Family I. The peaks may vary in chemical shift and in relative intensities and width due to the mixing of variable proportion of isomorphs contained in the form N crystalline solid solution.
A representative 1SC ssNMR spectrum of amorphous form is shown in figure 28. The amorphous azithromycin displays broad chemical shifts. The characteristic chemical shifts have the peak positions at 179 and 11 ± 0.5ppm.
A summary of the observed ssNMR peaks for forms A, O, F, G, H, J, M, N and R azithromycin is given in Table 10.
Example 14: NMR Analysis of a Dosage Form
To demonstrate the ability of 13C ssNMR to identify the form of azithromycin contained in a pharmaceutical dosage form, coated azithromycin tablets containing form G azithromycin were prepared and analyzed by l3C ssNMR. Tablets were wet granulated and tabietted on an F-Press (Manesty, Liverpool, UK) using 0.262" x 0.531* tooling. Tablets were formulated and tabietted to contain 250 mg of form G azithromycin with a total tablet weight of 450 mg using the formula given below. The tablets were uniformly coated with pink Opadry lie ((ritxture of lactose rnonohydrate. hydroxypropytmethytcellutose. titanium dioxide, Drug & Cosmetic red # 30. and triaceUn) (Cotorcon, West Point, PA).

Material Percentage Batch(g)
Azithromycin form "G* 58.23 174.69
Pregellatinized com starch 6.00 18.00




[Anhydrous dicalcium phosphate 30.85 92.55
Sodium croscarmelose 2.00 6.00
Magnesium stearate with 10% sodium laurel sulfate 2.92 8.76
Total 100.00 300.00
A coated tablet was gently crushed and the powdered sample was packed with a packing tool in solid state rotor containing no 13C background. Analysis of the sample was performed under conditions outlined in Example 13.
A representative 13C ssNMR spectrum of the tablet containing form G azithromycin is given in Figure29. __
Example 15: Antimicrobial activity:
The activity of the crystal forms of the present invention against bacterial and protozoa pathogens is demonstrated by the compound"s ability to inhibit growth of defined
- - _
strains of human (Assay I) or animal (Assays II and III) pathogens.
Assay I
Assay I, described below, employs conventional methodology and interpretation
criteria and is designed to provide direction for chemical modifications that may lead to
compounds that circumvent defined mechanisms of macroiide resistance. In Assay I, a panel
of bacterial strains is assembled to include a variety of target pathogenic species, including
representatives of macroiide resistance mechanisms that have been characterized. Use of
this panel enables the chemical structure/activity relationship to be determined with respect to
potency, spectrum of activity, and structural elements or modifications that may be necessary
to obviate resistance mechanisms. Bacterial pathogens that comprise the screening panel
i are shown in the table below. In many cases, both the macrolide-susceptible parent strain
and the macrolide-resistant strain derived from it are available to provide a more accurate
assessment of the compound"s ability to circumvent the resistance mechanism. Strains that
contain the gene with the designation of ermA/ermB/ermC are resistant to macrolides,
mcosamides. and streptogramin B antibiotics due to modifications (methytation) of 235 rRNA
molecules by an Enm methytase. thereby generally prevent the binding of afl three structural
classes. Two types of macroiide efflux have been described; msrA encodes a component of
an efflux system In staphylococci that prevents the entry of macrolides and streptogramins
whle mtfAJE encodes a fransmembnane protein that appears to efflux only macrolides.
hactivstion of macroiide antibiotics can occur and can be mediated by either a
prtosphoryiation of the 7-ftydroxy! (mph) or by cleavage of the macrocydk: lactone (esterase).
The strains may be characterized using conventional polymerase chain reaction (PCR)
technology and/or by sequencing the resistance determinant The use of PCR technology In
-3o -

this application Is described in J. Sutdiffe et al., "Detection Of Erythromycin-Resistant Determinants By PCR", Antimicrobial Agents and Chemotherapy, 40(11), 2562*2566 (1996). The assay Is performed in microtiler trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition; Approved Standard. published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains. The crystalline compound is initially dissolved in dimethylsulfoxide (DMSO) as 40 mg/ml stock solution.
D:D
Strain Designation Macrolide Resistance Mechanism(s)
Staphylococcus aureus 1116 susceptible parent
Staphylococcus aureus 1117 ErmB
Staphylococcus aureus 0052 susceptible parent
Staphylococcus aureus 1120 ErmC
Staphylococcus aureus 1032 msrA, mph, esterase
Staphylococcus hemolyticus 1006 msrA, mph
Streptococcus pyogenes 0203 susceptible parent
Streptococcus pyogenes 1079 ErmB
Streptococcus pyogenes 1062 susceptible parent
Streptococcus pyogenes 1061 ErmB
Streptococcus pyogenes 1064 ErmB
Streptococcus agalactiae 1024 susceptible parent
Streptococcus agalactiae 1023 ErmB
Streptococcus pneumoniae 1016 Susceptible
Streptococcus pneumoniae 1046 ErmB
Streptococcus pneumoniae 1095 ErmB
Streptococcus pneumoniae 1175 MefE
Streptococcus pneumoniae 0085 Susceptible
"Haemophilus influenzae 0131 SuscepUbte
Moraxefta catarrrtaiis 0040 Susceptible
ItforaxeAa catarrhal 1055 erythromycin intermediate resistance
Escherichia coti 0266 Susceptible
Assay ■ is uttized to test for activity against Pasteunia mutodcta and Assay III Is utlized lo test for activity against Posteurvia hoemofytica.
Assay tl

This assay is based on the //quid dilution method In microliter formal A single colony of
P. muttodda (strain 59A067) is inoculated into 5 ml of brain heart infusion (BHI) broth. The test
compound is prepared by solubilizing 1 mg of the compound in 125 jil of dimethylsulfoxide
(DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The
concentrations of the test compound used range from 200 ng/ml to 0,098 pg/ml by two-fold
serial dilutions. The P. multocida inoculated BHI is diluted with uninoculated BHI broth to make
a 104 cell suspension per 200 pi. The BHI cell suspensions are mixed with respective serial
dilutions of the test compound, and incubated at 37°C for 18 hours. The minimum inhibitory
concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of
growth of P. multocida as determined by comparison with an uninoculated control.
Assay III This assay is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated into BHI broth and incubated overnight at 37°C with shaking (200 rpm). The next morning, 300 fd of the fully grown P. haemolytica preculture is inoculated Into 3 ml of fresh BHI broth and is incubated at 37 °C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of two-fold serial dilutions are prepared. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches 0.5 McFarland standard density, about 5 pi of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37"C. Initial concentrations of the test compound range from 100-200 \io)m\. The MIC is equal to the concentration of the test compound exhibiting 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control.
The in vivo activity of the crystal forms of the present invention can be determined by conventional animal protection studies wed known to those skilled in the art, usually carried out in mice.
Mice are allotted to cages (10 per cage) upon their arrival, and alowed to acclimate for
a rnhimum of 48 hours before being used. Animate are inoculated with 0.5 mt of a 3 x 10s
CRJ/rrt bacterial suspension (P. muttodda strain 59A006) tntraperHoneafly. Each experiment
has at least 3 non-medicaled control groups hckxfirig one infected with 0.1X challenge dose
and two Infected w*h IX challenge dose; a 10X challenge data group may also be used.
Generaly, at mice in a gfven study can be challenged within 30-00 minutes, espeaasy f a
repeating syringe (such as • Comwafl& syringe) is used to administer (he chaflenge. Thirty
mrutes after chasenglng has begun, the first compound treatment is given. It may be
necessary fore second person to begin compound dosing fat of the an#nate have not been
challenged at the end of 30 minutes. The routes of administration are subcutaneous or oral
doses. Subcutaneous doses are administered into the loose skin in the back of the neck

whereas oral doses are given by means of a feeding needle. In both cases, a volume of 0.2 ml is used per mouse. Compounds are administered 30 minutes, 4 hours, and 24 hours after challenge. A control compound of known efficacy administered by the same route is included in each test Animals are observed daily, and the number of survivors in each group is recorded. i The P. multocida model monitoring continues for 96 hours (four days) post challenge.
The PDso is a calculated dose at which the compound tested protects 50% of a group of mice from mortality due to the bacterial infection that would be lethal in the absence of drug treatment
The crystal forms of the present invention (hereinafter "the active compound(s)"), may be administered through oral, parenteral, topical, or rectal routes in the treatment or prevention of bacterial or protozoa infections. In general the active compound is most desirsbly
administered in dosages ranging from about Q.2 mg per kg, bc-dy 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. However, a dosage level that is in the range of about 2 mg/kg/day to about 50 mg/kg/day is most desirably employed. Variations may nevertheless occur depending upon the species of mammal, fish or bird being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compound may be administered atbfte-JX-Jn_cornbination with pharmaceuticaify acceptable carriers or diluents by the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the active compound may be administered in a wide variety of different dosage forms, I.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, serves, suppositories, jellies, gels, pastes, lotions, ointments, sachets, powders for oral suspension, aqueous suspensions, injectable solutions, efocirs, syrups, and the Ifce. Such carriers include solid diuentf a liters, sterito aqueous media and various non-toxic organic solvents, etc Moreover, oral pharmaceutical compositions can be suitably sweetened anoVor fiavored In general the active compound is present In such dosage forms at concentration levels ranging from about 1.0% to about 70% by weight
~~ For waf auniinistration, tablets containing various exdpients such as rnicrocrystaline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be

employed along with various disinlegranls such as starch (and preferably com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tab-letting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral admin/stration, solutions of the active compound in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oOy solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques will known to those skilled in the art.
Additionally, it is also possible to administer the active compound topically and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice.
For administration to animals other than humans, such as cattle or domestic animals, the active compounds may be administered in the feed of ihe animals or orally as a drench composition.
The active compound may also be administered in the form of liposome delivery systems, such as small unlamellar vesides, large unBamellar vesides and multilamellar vesides. Liposomes can be formed from a variety of phospholipids, such as cholesterol, slearytamne or phosphatidylcholines.

WE CLAIM;

1. Crystalline azithromycin sesquihydrate wherein, the said crystal form of azithromycin is selected from the group consisting of F, G, H, M substantially in the absence of azithromycin dihydrate, N and O, characterized as having a 13C solid state NMR spectrum comprising a plurality of peaks with chemical shifts of 179. 5ppm, being a single peak with splitting of between 10.4ppm, 9.9ppm; 9.3ppm; 7.6ppm; 6.5ppm.
2. Crystalline azithromycin sesquihydrate as claimed in claim 1 in substantially pure form.
3. A crystalline form of azithromycin as claimed in claim 2 wherein said azithromycin comprises 90% or more by weight azithromycin sesquihydrate.

Dated this 28th day of October, 2003.
(RANJNA MEHTA DUTT)
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANT(S)

Documents:

00999-mumnp-2003-cancelled pages(18-7-2007).pdf

00999-mumnp-2003-claims(granted)-(18-7-2007).doc

00999-mumnp-2003-claims(granted)-(18-7-2007).pdf

00999-mumnp-2003-correspondence(22-8-2007).pdf

00999-mumnp-2003-correspondence(ipo)-(5-1-2007).pdf

00999-mumnp-2003-form 19(28-10-2003).pdf

00999-mumnp-2003-form 1a(12-6-2007).pdf

00999-mumnp-2003-form 2(granted)-(18-07-2007).doc

00999-mumnp-2003-form 2(granted)-(18-7-2007).pdf

00999-mumnp-2003-form 3(28-10-2003).pdf

00999-mumnp-2003-form 3(5-3-2007).pdf

00999-mumnp-2003-form 3(5-7-2004).pdf

00999-mumnp-2003-form 5(28-10-2003).pdf

00999-mumnp-2003-form-pct-ipea-409(28-10-2003).pdf

00999-mumnp-2003-form-pct-isa-210(28-10-2003).pdf

00999-mumnp-2003-petition under rule 137(6-3-2007).pdf

00999-mumnp-2003-petition under rule 138(6-3-2007.pdf

00999-mumnp-2003-power of attorney(26-9-2000).pdf


Patent Number 209165
Indian Patent Application Number 999/MUMNP/2003
PG Journal Number 11/2008
Publication Date 14-Mar-2008
Grant Date 22-Aug-2007
Date of Filing 28-Oct-2003
Name of Patentee PFIZER PRODUCTS INC.
Applicant Address EASTERN POINT ROAD, GROTON, CONNECTICUT 06340
Inventors:
# Inventor's Name Inventor's Address
1 ZHENG JANE LI C/O PFIZER GLOBAL RESEARCH AND DEVELOPMENT, EASTERN POINT ROAD, GROTON, CONNECTICUT 06340 USA
2 ANDREW VICENT TRASK C/O PFIZER GLOBAL RESEARCH AND DEVELOPMENT, EASTERN POINT ROAD, GROTON, CONNECTICUT 06340
PCT International Classification Number C07H17/08
PCT International Application Number PCT/IB02/01570
PCT International Filing date 2002-05-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/292,565 2001-05-22 U.S.A.
2 60/297,741 2001-06-12 U.S.A.
3 60/343,041 2001-12-21 U.S.A.