FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"TRIHEMIHYDRATE, ANHYDRATE AND
HYDRATE FORMS OF CEFDINIR"
Abbott Laboratories, a company incorporated in USA having its Registered Office at
D-377/AP6A-1,100 Abbott Park Road, Abbott Park, IL 60064-6008, USA.
The following specification particularly describes the invention and the manner in
which it is to be performed

Brief Description of the FiGures
Figure 1 is the single crystal X-ray diffraction pattern of a trihemihydrate form of cefdinir.
Figure 2 is the powder X-ray diffraction pattern of a trihemihydrate form of cefdinir.
Figure 3 is the single crystal X-ray diffraction pattern of a lower hydrate form of cefdinir.
5 Figure 4 is the powder X-ray diffraction pattern of a lower hydrate form of cefdinir.
Figure 5 is the powder X-ray diffraction pattern of anhydrate cefdinir.
Figure 6 shows two powder X-ray diffraction patterns of two lower hydrate forms of cefdinir
Figure 7 is the DMSG analysis showing the Desorption Isotherm of Cefdinir hydrates.
10 Summary of the Invention
The present invention describes trihemihydrate, anhydrate, and other iso-structural
lower hydrate forms of Cefdinir.
In one embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
15 weight of water), with a characteristic peak in the powder X-ray diffraction pattern (PXRD
pattern, hereinafter) at a value of two theta of 5.4± 0.1°.
In another embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
20 10.7± 0.1°,
In another embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
14.2±0.10
25 In another embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
I5.2±0.10.
In another embodiment the present invention describes a novel trihemihydrate crystal
30 form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
21.4+0.1°.
3

In another embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
29.2±0.,1°.
5 In another embodiment the present invention describes a novel trihemihydrate crystal
form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately 14% by
weight of water), with a characteristic peak in the PXRD pattern at a value of two theta of
and 30.6+ 0.1°.
In yet another embodiment the present invention describes a novel trihemihydrate
10 crystal form of Cefdinir with 3.5 moles of water per molecule of Cefdinir (approximately
14% by weight of water), and characteristic peaks in the PXRD pattern at values of two theta
of 5.4+ 0.1°, 10.7+ 0.1°, 14.2± 0.1°, 15.2± 0.1°, 21.4+ 0.1°, 29.2+ 0.1°, and 30.6+ 0.1°.
hi another embodiment the present invention describes isostructural lower hydrate
crystal forms of Cefdinir with a content of water from 1.7% to 6.1% of water by weight. A
15 lower hydrate of the present invention has a characteristic peak in the PXRD pattern at a
value of two theta of 6.0+ 0.1°.
In another embodiment the present invention describes a lower hydrate with a
characteristic peak in the PXRD pattern at a value of two theta of 8.0+ 0.1°.
hi another embodiment the present invention describes a lower hydrate with a
20 characteristic peak in the PXRD pattern at a value of two theta of 11.9± 0.1°.
In another embodiment the present invention describes a lower hydrate with a
characteristic peak in the PXRD pattern at a value of two theta of 15.9+ 0.1°.
In another embodiment the present invention describes a lower hydrate which has a
characteristic peak in the PXRD pattern at a value of two theta of 16.4+ 0.1°.
25 hi another embodiment the present invention describes a lower hydrate with a
characteristic peak in the PXRD pattern at a value of two theta of 22.4+ 0.1°.
In another embodiment the present invention describes a lower hydrate with a
characteristic peak in the PXRD pattern at a value of two theta of 23.0+ 0.1°.
In another embodiment the present invention describes a lower hydrate with 1.7% to
30 6.1% of water by weight which has characteristic peaks in the PXRD pattern at values of two
theta of 6.0+ 0.1°, 8.0± 0.1°, 11.9±0.1°, 15.9± 0.1°, 16.4± 0.1°, 22.4±0.1°, and23.0±0.1°.
4

In yet another embodiment the present invention describes a novel anhydrate crystal
form of Cefdinir with a characteristic peak in the PXRD pattern at a value of two theta of
5.5+0.1°.
In another embodiment the present invention describes a novel anhydrate crystal form
5 of Cefdinir with a characteristic peak in the PXRD pattern at .a value of two theta of 10.9±
0.1°.
In yet another embodiment the present invention describes a novel anhydrate crystal
form of Cefdinir with a characteristic peak in the PXRD pattern at a value of two theta of
12.6+0.1°.
10 In yet anotlier embodiment the present invention describes a novel anhydrate crystal
form of Cefdinir with a characteristic peak in the PXRD pattern at a value of two theta of
14.7±0.1°.
In yet another embodiment' the present invention describes a novel anhydrate crystal
form of Cefdinir with a characteristic peak in the PXRD pattern at value of two theta of 16.6+
15 0.1°.
In another embodiment the present invention describes a novel anhydrate crystal form
of Cefdinir with a characteristic peak in the PXRD pattern at a value of two theta of 21.8±
0.1°.
In another embodiment the present invention describes a novel anhydrate crystal form
20 of Cefdinir with a characteristic peak in the PXRD pattern at value of two theta of 27.3+ 0.1°,
In yet another embodiment the present invention describes a novel anhydrate crystal
form of Cefdinir with characteristic peaks in the PXRD pattern at values of two theta of 5.5±
0.1°, 10.9± 0.1°, 12.6± 0.1°, 14.7+ 0.1°, 16,6+ 0.1°, 21.8± 0.1°, and 27,3± 0,1°.
Another embodiment of the present invention relates to a pharmaceutical composition
25 comprising the trihemihydrate form of Cefdinir of the present invention in combination with
a pharmaceutically acceptable carrier.
In yet another embodiment, the present invention relates to a pharmaceutical
composition comprising any of the lower hydrate forms of Cefdinir of the present invention
in combination with a pharmaceutically acceptable carrier.
30 In another embodiment, the present invention relates to a pharmaceutical composition
comprising the anhydrate form of Cefdinir of the present invention in combination with a
pharmaceutically acceptable carrier.

5

Other embodiments relate to a method for treating bacterial infections by
administering any of the pharmaceutical compositions of the present invention.
5 Detailed Description of the Invention
The present invention relates to a hydrate form of Cefdinir, such as trihemihydrate, an
anhydrate form of Cefdinir, and isostructural lower hydrate forms of Cefdinir,
In general, crystalline organic substances contain different amounts of solvent within
their crystalline lattice. As used herein hydrates are defined as crystalline forms of an organic
10 substance in which the solvent is water. Hydrates and the anhydrous crystalline forms are
characterized by their X-ray diffraction patterns as measured by PXRD and single crystal X-
ray Diffraction. Hydrates may solvate.or desolvate to form other hydrates. Figure 1 is the
single crystal X-ray Diffraction for the trihemihydrate form of Cefdinir. For four molecules
of Cefdinir (large structures) there are 14 molecules of water within the lattice (single dots),
15 representing a 3.5 moles of water per molecule of Cefdinir). It was unexpectedly found mat
Cefdinir also exists in several lower hydrate forms that despite significant variations in their
molar content of water maintain the same PXRD pattern. These low hydrate forms are also
called isostructural or isomorphic hydrates because they retain the three-dimensional order of
the original crystal, as defined by space group symmetry and the lattice parameters, but have
20 variable amounts of water in the lattice. Figure 3 is the single crystal X-ray Diffraction for
one of this isostructural lower hydrates, which shows that for four molecules of Cefdinir
(large structures) there are 5 molecules of water within the lattice (single dots), representing
0.8 moles of water per molecule of Cefdinir.
PXRD was performed on samples of Cefdinir using an XDS-2000 / X-ray
25 diffractometer equipped with a 2 kW normal focus X-ray tube and a Pel tier cooled
germanium solid-state detector (Scintag Inc., Sunnyvale, CA). The data was processed using
DMSNT software (version 1.37). The X-ray source was a copper filament operated at 45 kV
and 40 mA. The alignment of the goniometer was checked daily using a Corundum standard.
The sample was placed in a thin layer onto a zero background plate, and continuously
30 scanned at a rate of 2° two-theta per minute over a range of 2 to 40° two-theta.
Characteristic PXRD pattern peak positions are reported in terms of the angular
positions (two theta) with an allowable variability of ± 0.1°. This allowable variability is

6

specified by the U.S. Pharmacopeia, pages 1843-1884 (1995). The variability of ± 0.10 is
intended to be used when comparing two powder X-ray diffraction patterns. In practice, if a
diffraction pattern peak from one pattern is assigned a range of angular positions (two theta)
which is the measured peak position ±0.1° and if those ranges of peak positions overlap, then
5 the two peaks are considered to have the same angular position (two theta). For example, if a
diffraction pattern peak from one pattern is determined to have a peak position of 5.2°, for
comparison purposes the allowable variability allows the peak to be assigned a position in the
range of 5.1° - 5.3°. If a comparison peak from the other diffraction pattern is determined to
have a peak position of 5.3°., for comparison purposes the allowable variability allows the
10 peak to be assigned a position in the range of 5.2° - 5.4°. Because there is overlap between
the two ranges of peak positions (i.e., 5.1° - 5.3° and 5.2° - 5.4°) the two peaks being
compared are considered to have the same angular position (two theta).
Figures 2, 4 and 5 show the different PXRD patterns of the trihemihydrate, an
isostructural lower hydrate, and the anhydrate forms of Cefdinir, respectively. As shown in
15 Figure 2,. the trihernihydrate crystal form of Cefdinir, which contains 3.5 moles of water for
each molecule of Cefdinir (approximately 14% by weight of water) shows characteristic
peaks in the PXRD pattern at values of two theta of 5.4+ 0.1°, 10.7± 0.1°, 14.2± 0.1°, 15.2±
0.1°, 21.4+ 0.1°, 29.2+ 0.1°, and 30.6+ 0.1°. The upper line represent the predicted pattern
obtained from single crystal data and the lower line is the experimental pattern. Figure 4
20 shows the isostructural lower hydrate that has characteristic peaks in the PXRD pattern at
values of two theta of 6.0+ 0.1°, 8.0+ 0.1°, 11.9+ 0.1°, 15.9+ 0.1°, 16.4+ 0.1°, 22.4+ 0.1°,
and 23.0± 0.1°. The upper line represent the predicted pattern obtained from single crystal
data and the lower line is the experimental pattern, as for the trihemihydrate, the predicted
pattern matches well with the pattern obtained experimentally. As discussed above, these
25 isostructural lower hydrates have different contents of water, from 1.7% to 6.1% by weight,
but maintain similar powder X-ray diffraction patterns. Figure 6 shows the similarity
between the PXRD patterns obtained from two of the isostructural lower hydrates of the
present invention, one with around 6% of water and another with around 4% of water (1.5
and 0.8 moles of water per molecule of Cefdinir). A novel anhydrate crystal form of
30 Cefdinir, which contains zero percent of water, shows characteristic peaks in the powder X-

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ray diffraction pattern at values of two theta of 5.5± 0.1°, 10.9+0.1°, 12.6±0.1°, 14.7±0.10,
16.6+0.1°, 21.8+ 0.1°, and 27.3+ 0.1° (Figure 5).
Dynamic Moisture Sorption/Desorption Gravimetric analysis (DMSG hereinafter)
was performed for the isostructural lower hydrates. A vacuum moisture balance (MB 300G,
5 VTI Corporation) was used to study the moisture sorption and desoprtion. Samples were first
dried at 50 °C under vacuum to a constant weight. The relative humidity was increased to
90% in 10% increments. If the sample weight remained unchanged (i.e. changed by≤ 3
mg/15 min), the moisture content was recorded. The balance was calibrated before the
experiment and the accuracy of the relative humidity measurement was verified with
10 polyvinylpyrrolidone K90. Figure 7 shows the moisture desorption isotherm of the hydrates
of the present invention. Sharp steps, for example with relative humidity changes from 40%
to 50%, occur when the crystal undergoes phase change, i.e. a crystalline structure change.
Relatively, flat regions represent a unique phase, i.e. where the crystalline structure does not
change and is more physically stable. Increases in the relative humidity from 10% to almost
15 40%, results in a series of lower hydrate forms of Cefdinir. The novel lower hydrate forms,
which are the subject of the present invention,, varied but maintained the same crystalline
structure and PXRD patterns (see Figure 6). An increase in.the relative humidity from 40%
to 50% induced a crystalline structure change, and further increases of the relative humidity
from 50% to 90% induced the formation of a more stable phase of. the crystal corresponding
20 to a trihemihydrate form of Cefdinir containing approximately 14% by weight of water.
Table 1 summarizes the weight changes of the different hydrate forms of Cefdinir
relative to changes in relative humidity. The weight changes are expressed by percentage of
water content and by the calculated theoretical molar content of water.

8
TABLE 1

% Relative
Humidity % of water by
weight Calculated moles
of water Hydrate
80.07 14.33 3.67 Trihemihydrate
89.90 14.80 3.81 Trmemihydrate
79.94 14.73 3.79 Trihemihydrate
70.00. 14.68 3.77 Trihemihydrate
60.10 14.63 3.76 Trihemihydrate

50.08 14.53 3.73 Trihemihydrate
40.19 6.13 1.43 Lower hydrate
30.17 5.71 1.33 Lower hydrate
20.24 4.94 1.14 Lower hydrate
10.24 3.80 0.87 Lower hydrate
P

Pharmaceutical compositions
5 In accordance with methods of treatment and pharmaceutical compositions of the
invention, the compounds can be administered alone or in combination with other agents.
When using the compounds, the specific therapeutically effective dose level for any
particular patient will depend upon factors such as the disorder being treated and the severity
of the disorder; the activity of the particular compound used; the specific composition
10 employed; the age, body weight, general health, sex, and diet of the patient; the time of
administration,- the route of administration; the rate of excretion of the compound employed;
the duration of treatment; and drugs used in combination with or coincidently with the
compound used. The compounds can be administered orally, parenterally, intranasally,
rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants,
15 diluents, vehicles, or combinations thereof. The term "parenteral" includes infusion as well
as subcutaneous, intravenous, intramuscular, and intrasternal injection.
Parenterally administered aqueous or oleaginous suspensions of the compounds can
be formulated with dispersing, wetting, or suspending agents. The present invention
appreciates that the solid forms of the present invention; e.g.: the Trihemihydrate and the

20 isostructural lower hydrates can be formulated into suspension products. The injectable
preparation can also be an injectable solution or suspension in a diluent or solvent. Among
the acceptable diluents or solvents employed are water, saline, Ringer's solution, buffers,
monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as
monoglycerides or diglycerides.
25 The effect of parenterally administered compounds can be prolonged by slowing their
release rates. One way to slow the release rate of a particular compound is administering
injectable depot forms comprising suspensions of poorly soluble crystalline or otherwise
water-insoluble forms of the compound. The release rate of the compound is dependent on
its dissolution rate, which in turn, is dependent on its physical state. Another way to slow the release rate of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow the release rate of a particular compound is administering inj ectable depot forms comprising microcapsule

5 matrices of the compound trapped within liposomes, or biodegradable polymers such as
polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug
to polymer and the composition of the polymer, the rate of drug release can be controlled.
Transdermal patches can also provide controlled delivery of the compounds. The rate
of release can be slowed by using rate controlling membranes or by trapping the compound
10 within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase
absorption.
Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules, hi these solid dosage forms, the active compound can optionally comprise
excipients such as sucrose, lactose, starch, microcrystalline cellulose, mannitol, talc, silicon
15 dioxide, polyvinylpyrrolidorie, sodium starch glycolate, magnesium stearate, etc. Capsules,
tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with
enteric coatings or other release-controlling coatings. Powders and sprays can also contain
excipients such as talc, silicon dioxide, sucrose, lactose, starch, or mixtures thereof. Sprays
can additionally contain customary propellants such as chlorofluorohydrocarbons or
20 substitutes thereof.
Liquid dosage forms for oral administration include emulsions, microemulsions,
solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These
compositions can also comprise adjuvants such as wetting, emulsifying, suspending,
sweetening, flavoring, and perfuming agents. Liquid dosage forms may also be contained
25 within soft elastic capsules.
Topical dosage forms include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays, inhalants, and transdermal patches. The compound is mixed, if necessary
under sterile conditions, with a carrier and any needed preservatives or buffers. These dosage
forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins,
30 starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, talc and
zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be
prepared by mixing the compounds with a suitable non-irritating excipient such as cocoa

12

butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the
rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders,
and solutions are also contemplated as being within the scope of this invention.
Form I of Cefdinir
5 A pure Cefdinir can be obtained by acidifying the solution containing Cefdinir at
room temperature or under warming and thereby having the crystals separate out of the
solution.
Suitable examples of the solution containing Cefdinir may include, for example, an
aqueous solution of the alkali metal salt of Cefdinir. The solution containing Cefdinir is
10 acidified, if necessary, after said solution is subjected to a column chromatography on
activated charcoal, nonionic adsorption resin, alumina, acidic aluminium oxide. The
acidifying process can be carried out by adding an acid such as hydrochloric acid or the like
preferably in the temperature range from room temperature to 40° C., more preferably, from
15° to 40° C. The amount of the acid to be added preferably makes the pH value of the
15 solution from about 1 to about 4.
A pure Cefdinir can be also obtained by dissolving the Cefdinir in an alcohol
(preferably methanol), continuing to stir this solution slowly under warming (preferably
below 40° C.), preferably after the addition of water warmed at almost the same temperature
as that of said solution, then cooling this solution to room temperature and allowing it to
20 stand.
During the crystallization of Cefdinir, it is preferable to keep the amount slightly
beyond the saturation. Cefdinir obtained according to aforesaid process can be collected by
filtration and dried by means of the conventional methods.
7-[2-(2-Animothiazol-4-yl)-2-hydjoxyminoacetamido]-3--vmyl--3-cephem-4-
25 carboxylic acid (syn isomer) (29.55 g) can be added to water (300ml) and the mixture
adjusted to pH 6.0 with saturated sodium bicarbonate aqueous solution. The resultant
solution can be subjected to a column chromatography on activated charcoal and eluted with
20% aqueous acetone. The fractions are combined and concentrated to a volume of 500 ml.
The resultant solution pH is adjusted to 1.8 at 35° C. with 4N hydrochloric acid. The
30 resultant precipitates are collected by filtration, washed with water and dried to give 7-[2-(2
aminotruazol-4-yl)-2-hydroxyiTunoacetamido]-3-vmyl-3-cephem-4-cafboxylic acid (syn
isomer).
11

Alternatively, to a solution of 7-[2-(2-aminothiazol-4-yl)-2-hydroxyminoacetamido]-
3-vinyl-3-cephem-4-carboxyIic acid (syn isomer) (0.5 g) in methanol (10 ml) can be added
dropwise warm water (35° C.; 1.5 ml) at 35° C. and the resultant solution stirred slowly for 3
minutes, then allowed to stand at room temperature. The resultant crystals are collected by
5 filtration, washed with water and then dried to give 7-[2(2-3-aminothiazol-4-yl)-2-
hydroxyminioacetamido]3-vinyl-3-cephem-4-carboxylic acid (syn isomer) as crystals.
The Trihemihydrate form of Cefdinir was prepared by suspending Cefdinir, (c.a. 0.8g)
in 1:1 ethanol:ethylacetate solution (a 5 mL beaker was used). To this suspension,
approximately 6 drops of concentrated H2S04 was added with intermittent sonication. The
10 solution first turned clear and then a thick yellowish gel was formed. To the gel a couple of
drops of water was added and the gel was transferred to the funnel and an attempt to wash the
gel resulted in the formation of a white suspension. The white suspension was transferred to
centrifuge tubes and centrifuged. The two phases were separated. The aqueous layer
discarded, more water was added, vortex mixed and centrifuged. This procedure was repeated
15 until the pH of the aqueous layer was about 3.5. The solid was then analyzed.
Another method to make the Trihemihydrate form is to suspend Cefdinir, c.a. 0.8 g in
1:1 ethanol : ethylacetate solution (a 5 mL beaker was used). To this suspension,
approximately 6 drops of concentrated H2S04 was added with intermittent sonication. The
solution first turned clear and then a thick yellowish gel was formed. To the gel a couple of
20 drops of water was added and the gel was transferred to centrifuge tubes as follows: To each
14mL tube, 9mL water was added, then sufficient gel was added to make 12mL and 2mL of
water added to give 14ml., Six such tubes were prepared. In each tube white suspension was
formed. The white suspension was centrifuged. The two phases were separated. The aqueous
layer discarded, more water was added, vortex mixed and centrifuged. This procedure was
25 repeated until the pH of the aqueous layer was about 3.5. The solid was then analyzed.
Lower hydrate forms of Cefdinir were generated by heating the Trihemihydrate at
75°C for 30 min, or by air drying during 3-24 hours, depending on the sample size.
The foregoing is merely illustrative of the invention and is not intended to limit the
invention to the disclosed embodiments. Variations and changes, which are obvious to one
30 skilled in the art, are intended to be within the scope and nature of the invention, which are
defined, in the appended claims.
12

We claim:
1. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 5,4+ 0.1°.
2. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 10,7+ 0. 1 °.
3. A Trihemihydrate crystal forth of Cefdinir with a characteristic peak in the powder X ray
diffraction pastern at value oftwo theta of 14.2+ 0. 1°.
4. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 15.2+ 0. 1°.
5. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 21.4+ 0. 1°.
6. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 29.2+ 0. 1 °.
7. A Trihemihydrate crystal form of Cefdinir with a characteristic peak in the powder X ray
diffraction pattern at value of two theta of 30. 6+ 0.1°.
8. A Trihemihydrate, crystal form of Cefdinir with characteristic peaks in the powder X ray
diffraction pattern at values of two theta of 5. 4+ 0. 1°, 10.7+ 0.1°, 14.2+ 0,1°, : 15.2+
0.1°, 21.4+0.1°, 29.2+0.1°, and 30. 6+0.1°.
9. The crystalline form as claimed in claim 8, which contains 3.5 moles of water per
molecule of Cefdinir.
10. The crystalline form as claimed in claim 8, which content of water is 14% by weight.
11. A pharmaceutical composition comprising the Trihemihydrate form of claims 8 or 9 in
combination with a pharmaceutically acceptable carrier.

Dated this 5lh day of October 2006

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