Note: Descriptions are shown in the official language in which they were submitted.
X-6456 -1-
IMPROVEMENTS IN OR RELATING TO
CEPHALOSPORIN DERIVATIVES
This invention rela-tes to novel cephalosporin
5 deriva-tives, more par-ticularly to a novel crystalline
hyd:rochloride sal-t of cephalexin monohydrate, and -to
:its prepara-tion from certain novel crystalllne alkanol
sol~a-tes.
Over the past decade, there has been much
interest in the development of con-trolled release
delivery systems involving the concep-t of an elementary
osmotic purnp, see, for instance, Theeuwes, F.,
"Elementary Osmotic Pump", J. Pharm. Sci., Vol. 64,
1975, pp 1987-1991, and U.S. Paten-t Specifications
Nos. 3,845,770, 3,977,404, 4,008,719, 4,014,334,
4,016,880, ~,034,758, 4,036,227, 4,036,22~, 4,096,238,
3,916,899, 4,111,203, 4,116,241, 4,160,020 4,200,098
and 4,210,139.
In order to function in such a delivery
system, the active agent must be sufficiently soluble
in water and/or body fluids to permit development of
sufficient differential osmotic pressure to effect re-
lease of the pharmaceutical from -the device. The agent
mus-t also be of sufficient s-tability that it retains
its pharmacologicaI potency throughout the entire re-
lease period.
Although cephalexin monohydra-te, i.e., 7-(D-
2--amino-2-phenylacetamido)-3-methyl-3-cephem-4-carbox-
yLic acid monohydrate, see U.S. Patent Specification
No. 3,655,656, has proven to be of immense value to man-
kincl in the tre~tment of bacterial infections, its
X-6456 -2-
pharmacokinetic profile is such that it is most effec-
tive when administered using a multiple dosage regime.
Thus, -this compound would appear to be an ideal candi-
date for incorporation in an osmotic controlled release
s~stem of -the type described above so tha-t the fre-
uency of dosing could be reduced.
Unfor-tunately, while cephalexin monohydrate is
~deally sui-ted for formulation into conventional dosage
orms such as capsules and table-ts, it does no-t lend
1~ itself to formulation as -the active ingredient i.n dosage
forms employing the osmotic pump technology, primarily
because of its relatively low water solubility and the
consequent low osmotic pressure of its solutions.
Attempts to solve this problem by forming
the crystalline sodium salt of the monohydrate failed
since, although the solubility of that material was
acceptable (552 mg/ml in water), it rapidly degraded
in solu-tion, being stable for less than two hours at
ambient temperature.
In addition, attempts using conventional pro-
cedures to prepare hydrochloride salts of cephalexin
monohydrate in crystalline form failed totally. (In
this context, i-t should not be forgot-ten -that amorphous
cephalosporin derivatives are generally uns-table and
t~at it is only the crystalline forms of cephalexin
which are oE suficient s-tability to be of value in
pha.rmaceutical formulations.) Only by virtue of a
chance observation as described below, and the develop-
ment o a novel synthesis involving an unusual lattice
txansEormation, did it finally become poss:ible -to syn-
X-6456 -3-
thesize the compound of the invention, i.e., crystal-
line cephalexin hydrochloride monohydrate.
According -to the present invention there is
provided crystalline cephalexin hydrochloride mono-
hydra-te.
This new crystalline salt is unusually soluble
i.n water, forming a sa-turated aqueous solution contain-
:inc~ 76~ mg per ml of distilled water at 37C. The pH of
th~t solution is about 0.5. This solu-tion exhibits an
LC) osmotic pressure of 143 atmospheres. This is -to be
contras-ted ~ith cephalexin monohydrate which has a
solubility of only 12.6 mg per ml oE distilled water and
which solution exhibits a pH of 3.2 and an osmotic
pressure of only 1.5 a-tmospheres.
Fur-ther, the high solubility of the hydro-
chloride monohydrate gives it the potential for pro-
viding high blood levels of cephalexin immediately upon
administration in conventional pharmaceutical formula-
-tions such as tablets and capsules.
The novel crystalline salt of the invention
has the following X-ray powder diffraction properties
when measured with a 114.6 mm Debye-Scherrer camera
using a nickel-filtered copper target tube of 1.5418~.
~L2~ 3
X-6~56 -4-
Relative
Spacing, d( A ): Intensities, I/I
14.03 ~.oo
7.08 .33
5.42 .33
4.63 .73
4.41 .27
4.31 .13
4.17 .47
3.99 .13
3.78 .40
3.70 .27
3.55 .53
3.38 .20
3.21 .07
3.12 .07
3.03 .07
2.85 .13
2.73 .03
2.65 .03
2.59 .03
2.53 .13
2.37 .20
2.29 .13
2.18 .03
2.14 .03
l.gg6 .13
1.959 .07
t~a~ fl'~
X-6456 -5-
As intimated previously, it was surprisingly
discovered -that the crystalline cephalexin hydrochloride
monohydrate could be derived from the corresponding
crystalline C1 4 alkanol hydrochloride solvates.
The Applicants had prepared the novel crys-
talline ethanol solvate of cephalexin hydrochloride and
were surprised by its instability. They discovered
that, under certain conditions of relative humidity, a
most unusual transformation was taking place. Thus,
under those conditions, water molecules were displacing
the ethanol molecules from the crystal lattice, thus
providing the monohydrate of the invention. Interest-
ingly, the X-ray powder diffraction pat-terns of the two
solvates, although similar, were not identical, so that
after the displacement has occurred there is a molecular
rearrangement of the lattice framework.
Further study showed that this same displace-
ment occurred to a greater or lesser extent with all
of the crystalline C1 4 alkanol solvates.
According to a second aspect of the inven-tion
there is provided a process for preparing crystalline
cephalexin hydrochlori.de monohydrate which comprises
hydrating a crystalline cephalexin hydrochloride C1 4
alkanol solvate.
The hydration is preferably accomplished by
exposing -the solvate to an atmosphere, typically air,
having a relative humidity of from about 10 to about 50%.
Temperatures of from about 10 to about 50C provide sat-
isfactory conversion rates. In yeneral, the higher the
temperature, the lower should be the relative humidity.
~3 ~f~
X-6456 ~6-
Hydration of the alkanol solvate is most
facile with the methanol and e-thanol solvates. Indeed,
hydration of the propanol and butanol solvates is much
more difficult to drive to completion~
The crystalline alkanol solvates of the inven-
tion can be prepared by adding an excess of hydrogen
chloride or hydrochloric acid to an alkanolic suspen-
sion of cephalexin monohydrate. When preparin~ the
C1 2 alkanol solvates, it is preferred to use anhydrous,
i.e., gaseous hydrogen chloride during the formation of
the alkanol solvate. On the other hand, the C3 4
alkanol solva-tes are preferably formed using aqueous
hydrochloric acid.
The cephalexin hydrochloride alkanol solva-te
typically crystallizes out of solution. The crystalli-
zation can be assisted by chilling, preferred crystal-
lization temperatures being from 15 to 25C, most
preferably from 20 to 22C, or by addition of ~n anti-
solvent such as a hydrocarbon solvent, for example
hexane. Seeding with crystals of -the hydxochloride
monohydrate or alkanolate may also assist the
crystallization process.
The crystalline cephalexin hydrochloride
alkanol solvates are new compositions of matter, and
are provided in one aspect of the invention.
While the crystalline cephalexin hydrochloride
alkanol solvate intermediates of the invention are rela-
tively stable under anhydrous conditions, if they are
exposed to an atmosphere having a relative humidity
~reater than about 10% the solvate becomes unstable and
~ f~
X-6456 -7-
converts to the monohydrate polymorph of the invention.
The rate of conversion varies depending upon the parti-
cle size of the solvate, the rela-tive humidity to which
it is exposed, and the ambient temperature. If the
solvate intermediate is subjected to an atmosphere hav-
ing a high relative humidity, the material does not form
the monohydrate crystalline structure provided by this
invenkion, but instead becomes an amorphous mass.
In a preferred embodiment, the ethanol hydro-
chloride solvate is exposed to air havin~ a relativehumidity of from about 20 to about 45%, at a temperature
of from about 20 to about 50C. Under such condi-tions
conversion to the hydrochloride monohydrate crystalline
form of this invention is substantially complete after
about one to about fifteen days.
The cephalexi~ hydrochloride monohydrate crys-
talline form of the invention is useful as an orally
active antibacterial agent, and is part.icularly well
suited for formulation in sustained release formulations
as described previously or in conventional dosage forms
such as tablets or capsules. Thus, the compound can be
admixed with conventional carriers and excipients such
as sucrose, polyvinylpyrrolidone, stearic acid, starch,
and the like and encapsul`ated or, if desired, the
formulation can be compressed into tablets. A pre-
ferred embodiment is a tablet adapted for human chemo-
therapy which provides for substantially immediate
release of the active ingredient into the biological
system.
X-6456 -8-
Such pharmaceutical formulations will contain
from about 10 to about 98% by weight of active ingredi-
ent, for example from about 200 to about 1200 mg of
active ingredient, and will be administered to a human
subject at the rate of one or more doses each day for
the con-trol and prevention of bacterial infections.
The compound can additionally be admixed with polymers
made from polymerizable materials such as methacrylate
esters, glycols, hydroxy acids such as lactic acid and
the like, and molded into tablets or the like.
~ hile the cephalexin hydrochloride monohydrate
crystalline form can be formulated for oral administra-
tion employing conventional encapsulation and tableting
technology, as described above, it is ideally suited to
formulation ~s a controlled release dosage form, espe-
cially employing osmotically actuated technology for
rate controlled drug delivery. For a compound to be
suitable for delivery via an osmotic pump, it must be
sufficiently soluble in water or similar fluid to be
solubilized over a period of time sufficiently long to
provide continuous delivery over a desired period at
pharmacologically effective rates, and sufficiently
stable when in solution to remain therapeutically effi-
cacious over the entire period of administration. The
compound of this invention uniguely satisfies these re-
quirements of solubility, osmotic pressure and stability.
The amount of cephalexin hydrochloride mono-
hydrate present in the osmotically-driven delivery
device is no-t critical but typically is an amount equal
to or greater than the amount r.ecessary -to osmotically
~ 3
X-6~56 -9-
operate the device for the desired period of drug re-
lease so that the desired therapeu-tic level of active
agent is achieved for the ~esired period of time.
Moreover, the cephalexin hydrochloride mono
hydrate crystalline structure of this invention can
easily be produced in a pharmaceutically acceptable
state of purity in that the level of C1 2 alkanol con-
taminant can be reduced below two, normally below one,
percent by weight. The novel monohydrate polymorph of
this invention therefore normally exists in a pharma-
ceutically-acceptable state of purity greater -than 98
percent, preferably and typically greater than 99 per-
cent by weight.
According to a further aspect of the inven-
tion, there is provided a pharmaceu-tical formula-tion
which comprises as the active ingredient crystalline
cephalexin hydrochloride monohydrate associated with
one or more pharmaceutically accep-table carriers or
excipients therefor.
The amount of cephalexin hydrochloride mono-
hydrate which is antibacterially effective is from about
1 to about 30 mg/kg of animal body weight. While cepha-
lexin hydrochloride monohydrate will display an activity
profile very similar to that of cephalexin monohydrate,
it is likely that higher blood levels and a more rapid
onset of action will be enjoyed with cephalexin hydro
chloride monohydrate than with the current commercial
cephalexin monohydrate, due to its unusually greater
solubility. Thus, the compound of the invention has
great potential as an immediate release tablet composi-
tion.
X-6~56 -10-
The invention will now be further illustrated
wi-th reference to the following non-limitative examples.
Example 1
Cephalexin hydrochloride e-thanol solvate
Cephalexin monohydrate (100 g) was suspended
in 300 ml of absolute ethanol. The suspension was
stirred at 25C while hydrogen chloride was bubbled
through the suspension until all particles were in
solution. The reaction mixture was stirred at 25C for
two hours, and then cooled to 0C and stirred for an
additional -two hours. The crystalline product was col-
lected by filtration and washed with 200 ml of l:l (v/v)
ethanol~ethyl acetate and then with 200 ml of ethyl
acetate. The product was identified as cephalexin
hydrochloride ethanol solvate. Yield 53 grams.
NMR: (D20): ~1.2 (t,-3H);
~ 2.02 (s, 1~);
~3.23 ~q, 2H);
~3.65 (ql 2H);
~5.0 (d, lH);
~ 5.3 (s, lH);
~5.61 (d, lH);
~7.59 (s, 5H).
X ray powder diffraction carried out with a
diffrac-tometer having a nickel-filtered copper target
tube of 1. 5405A.
~f~3'~
X-6456
Relative
Spacing, d(A) In-tensities, I/I
14.48 1.~0
10.04 .005
9.16 .01
8.58 .02
7.34 .095
6.10 .055
5.75 .05
5.~ .175
5.08 .01
4.62 .035
4.32 .035
4.02 .025
3.97 .025
3.78 .01
3.72 .035
3.68 .06
3.43 .01
3.36 .06
3.16 .035
3.04 .035
2.74 .01
2.54 .01
2.52 .025
2.45 .01
2.42 .015
X-6456 -12-
Example 2
Cephalexin hydrochloride monohydrate
To a stirred suspension of 45 kg of cephalexin
monohydrate in 168 liters of absolute ethanol were added
portion-wise over thirty minutes 5.7 kg of hydrogen
chloride. The reaction mixture was stirred at 25C for
thirty rninutes, and then was cooled to 10C and stirred
for an additional two hours. The crystalline pr.e-
cipitate tha-t had formed was collected by filtration and
washed with 24 liters of 1:1 (v/v) ethanol-hexane, and
finally with 22 liters of hexane. The fil-ter cake was
shown by NMR to be cephalexin hydrochloride ethanol
solvate (NMR consistent with that reported ln Example 1).
Elemental Analysis calculated for ethanol
solvate:
C H N O S HCl-CH CH OH
Theory: C, 50.29; H, 5.63i N, 9.77; S, 7.46; Cl, 8.25i
Found: C, 50.03; H, 5.45; N, 9.84; S, 7.35; Cl, 8.37.
The ethanol solvate filter cake from above was
exposed for two weeks to an atmosphere of air of about
35% relative humidity at a temperature of about 25-30~C
to provide 31.76 kg of cephalexin hydrochloride mono-
hydrate.NMR (D2O): ~2.06 (s, 3H)
~3.30 (q, 2H)
~5.0 (d, lH)
~5.32 (s, lH)
~5.68 (d, lH~
~7.61 (s, 5H).
~3i~
- 13 -
IR (KBr): 3290 cm~
3120
1760
1710
1680
1560
1490
Karl Fischer water analysisO 4.48% (n=4), consistent
with the presence of approximately one mole of water.
Residual ethanol determined to be 0.68~.
Elemental Analysis Calculated for cephalexin
hydrochloride monohydrate:
cl6~17N304S~HCl'H2
Theory: C, 47.82; H, 5.02; N, 10.46; S, 7.98; Cl, 8.82.
Found: C, 48.03, H, 4,82; N, 10.27; S, 7.87;
Cl, 8.90.
Differential thermal analysis demonstrated the
compound has a large broad endotherm at 109C which
appears to indicate a loss of volatile materials, and a
sharp exotherm at 202C which appears to indicate
decomposition of the compound. A thermal gravimetric
analysis showed a weight 1055 beginning at 63C which
resulted in a 5.7~ weight loss at 135C. At 150C
another weight loss began and continued through decom-
position. The co~pound demonstrat2d an X-ray powder
diffraction pattern consistent with that reported above
for cephalexin hydrochloride monohydrate.
~v~
X-6456 -14-
Example 3
The effect of humidity on the rate of change
of cephalexin hydrochloride ethanol solvate to cepha-
lexin hydrochloride monohydrate was studied by X-ray
diffraction of samples of the ethanol solvate after
storage at 25C in chambers of differen-t relative
humidities. The change from ethanol solvate to mono-
hydrate was followed by observing the disappearance of
an X-ray maximum having a d value of about 7.34A. The
resul-ts of -the s-tudy are presented in Table I.
Table I
Disappearance of 7.34A X-Ray
Maximum with Time at
Various Humidities at 25C.
Relative Humidity (%)
20Time 0 _20 32 _ 44
0 hours l9 units l9 units l9 units 19 units
24 18 lO 7 2
48 17 8 5
72 - 6 4
25144 - ~ 2 0
260 - 2
~88 - 1 0
Note: "-" means that no reading was taken.
A sample of the ethanol solvate held at 70%
rela-tive humidi-ty was totally dissolved within -twen-ty-
four hours.
X-6~56 -15-
Example 4
Stabili-ty of Cephalexin Hydrochloride
rnonohydrate.
A sample of cephalexin hydrochloride mono-
h~drc~te ~ro~n Example 2 was analyzed by high pressure
L:iquid chroma-tography and shown -to contain 84.6%
ccphalex:in. (This is equivalent to a puri-ty of about
~.2~ ~or -the cephalexin hydrochloride monohydra-te, -the
remainder being substan-tially all ethanol) Samples of
this ma-terial were s-tored at various temperatures for a
prolonged period of time. The samples were assayed
periodically by high pressure liquid chromatography
(HPLC) and by Karl Fischer (KF) titration. The results
of the study are given in the following Table II:
X - 6 4 5 6 - 1 6 -
a~
u~ ~ O r~ ~ u~
...... ~
O o~ O ~ O ~ ~ _
o ~ CO o ~ ~ ~ ,_ ~ o
U~
,~
OO ~ ~ ~00 ' ~
~ .. . . . . ~ ,.
D~ ~ u~d` ~ ~ ~ ~ :~. C
3 o
.- ~ o
U~ C U
o~ ~ ~ ~ ~ r~
n~ ~ 5 J L~
J .. . . . . _ 'A a.,
E~ ~ cr~ X O X c~
tJ 3
U~ --
~ 00 1-- ~ ,~ C
0 ~4 .. . . . .rl J
= :~
o ~ ~co ~ J ~- U
L~ ~ .. . . . . C
o~o~oooooo oo ~ ~
:~~J 5
a~ o O ~ ~
O ~cr~ o ~ o
o loooocr~ o~
5~ a~
O C ~ O
0~
'7 o ~u ~~DoO ~ 3 5
O ~I ' It~ ~O C ~ J
O ~
~J ~ ~ _
`I O ~ ~ :~
~1 ~1 O O ~ ~ J o
aJ ~ ~ ~ ~ ~ ~
.,~ ~ CO CO 0~00 0~ 00
~:
E~ ~ ~ ~ ~o o
,-- c1~ o a~ o ~ t
~J ~ ,~ `t . C :'~
O ~ J.5
~ 00o~) oo0 ) 00CO C:
:C ~ ~ O
ooo~~ O O r~
u~ D ~ O~a ~ o
4~ o u~~Ou~
o ul u~ 8 ~ L~
O~t ~'1 o~ 3 ~ ~ J
.~ ~1 .. . . . . ..
,-~ ~ ~t~ O o0 O1~ ~ q~ 5 5
.,.~ ~oo oo oO ~oO ~ ~ S O -1
.A C~, J J
~J a ~:1
V~ ~ ~
O ~O
~ "E3 o o o 3'~ 3 ~r~ Cl.
~Ul ~ C ~ ~ ~
~3~
X-6456 -17-
Example 5
Cephalexin hydrochloride me-thanol solvate
Anhydrous methanol (100 ml) was cooled to
5 5"C a~d tre~-ted with gaseous hydrogen chloride (8 g).
~ephalexin monohydra-te (35.2 g) was then added at room
ternperature. Solution of the cephalexin monohydrate
occurred Eollowed (within 15 minutes) by formation of
a thick slurry of -the ti-tle compound. Yield 18.0 g.
The X-ray diffraction pattern of this mate-
rial, carried out in the presence of mother liquor,
with a 114.6 mm Debye-Scherrer camera using a nickel-
filtered copper target tube of 1.5418~, in a sealed
glass capillary tube is given below.
Relative
Spacing, d(~)Intensities, I/I
13.97 1.00
7.10 .49
6.50 .01
6.0~ .01
5.65 .15
5.40 .40
4.69 .43
4.51 .03
4.38 .03
~.23 .50
X-6456 -18-
Relative
Spacing, d( A) Intensities, I/I
4.04 .03
3.78 .66
3.61 .44
3.48
3.41 .18
3.27 .04
3.07 .12
2.93 .06
2.86 .18
2.74 .03
2.61 13
2.56
2.42 .10 b
2.31 .13
2.22 .06
2.15 .04
2.05 .07
1.992 .01
1.946 .03
1.885 .06 b
1.790 .01
1.7'~8 .03
1.708 .01
~3~
--19--
Example 6
Cephalexin hydrochloride monohydrate
Hydrogen chloride gas (7.0 g) was dissolved
in me-thanol (lO0 ml) at room temperature. The methanol
was anhydrous (Karl Fischer analysis showed less than
0.12'~ by weight of water). Cephalexin monohydrate
(35.2 g) in solid forrn was then added to the reaction
m:iY.ture. Dissolution occurred. Crystallization oE
aephalexln hydrochloride me-thanol solvate occurred
approxima-tely fifteen minutes after seeding with cepha-
lexin hydrochloride monohydrate. Heat of crystallization
caused the temperature to rise from 22 to 30C.
After 3 hours at room temperature, the product was fil-
tèred off, and then washed with cold methanol. NMR
studies sho~7ed the initial formation of the methanol
solvate.
The methanol solvate prepared above was
exposed for three days to an air atmosphere having a
relative humidity of about 35% and at a temperature of
28C to provide 18.1 grams of crystalline cephalexin
hydrochloride monohydrate having an NMR and IR identical
with ihe product of Example 2.
Example 7
Cephalexin hydrochloride isopropanolate
Cephalexin dimethylformamide disolvate
(300 CJ) was slurried in isopropanol (2.215 L) and cooled
to :L3C. Concentrated hydrochloric acid (190 ml) was
~ 3~
X-6456 -20-
added rapidly, dropwise, to the reaction mixture at a
-ternperature between 13 and 17C. After addition was
comple-te, a yellow solution was formed. That solu-tion
~,7as warmed to 20C and slowly stirred. Cephalexin
5 hydrochloride isopropanol solva-te crystallized out in
the .form of a thick slurry which was stirred a-t room
ternperature for 2 hours, treated with hexane, 200 ml of
lsopropanol added and then stirred for a further 3 hours
at room temperature, cooled and then fil-tered. The
product was then washed with 1:1 (by volume) isopro-
panol/hexane (2 x 100 ml). Yield 254.1 g.
The X-ray diffraction pattern obtained for
-this material, measurement obtained with a Debye-
Scherrer camera using a nickel-filtered copper target
-tube of 1.5418A is given below:
Relative
d(A)Intensities, I/I
14.61 1.00
207.44 .17
6.15 .06
5.70 .27b
4.68 .30
254.40 .12
4.29 .12
4.10 .09
3.97 .06
3.83 .33
3.69 .12
3.53 .09
3.43 .18
3.25 .06
353.04 .09
~L23~
-21-
Relative
d(~; Intensities, I/I
2.96 .02
2.80 .08
2.69 03
2.56 09
2.50 .02
2.43 .02
2.35 .02
2.27 .0~
2.21 03
2.13 .02
2.0~ 03
Example 8
Cephalexin hydrochloride monohydrate
The isopropanolate product (35 g) of Example 7
was loaded into the fluid bed drier sold under the
trade mark l'Lab-Line" and allowed to humidify at tem-
peratures ranging between 24 and 27C~ After 18.5 hours
NMR studies of the final product showed that some 54
of the starting isopropanolate had been converted to
the crystalline hydrochloride monohydrate.
Example 9
Cephalexin hydrochloride n-propanol solvate
Cephalexin monohydrate (35.2 g3 was slurried
in anhydrous n-propanol (150 ml) cooled to approximately
10C and treated with gaseous hydrogen chloride (6.1 g).
The solution thus formed was seeded with the iso-
propanolate solvate formed in Example 7. Further n-
i.~ ;`
X-64~6 -22-
propanol (50 ml) was added and the reaction mixture
stirred at room temperature for a further 3 hours,
whereupon the desired _-propanol solvate crystallized
ou-t as a slurry. The slurry was then cooled for 2 hours
S and the title compound isolated, yield 39.1 g. NMR
showed the material to be -the _-propanola-te solvate.
'rhe X-rrly diffraction pattern of this material, measure~
tnent carried ou-t as with methanolate, for -the n-
propanolate is given below:
1~
d~A) I/I
14.92 1.00
7.58 .41
6.27 .06
5.g6 .13
5.57 .34
4.65 .5~
4.38 .41
2Q 4.23 .44
4.06 .41
3.78 .59
3.66 .06
3.50 .13
3.46 .22
3.41 .16
3.23 .06
~0 3.08 .11
2.g6 .03
2.81 .03
2.76 .05
2.67 .02
2.60 .06
2.53 .06
2.47 .03
2.37 .03
~0 2.33 .03
3~
X-6~56 -23-
d(A) I~I
2.25 .02
2.18 .11
2.03 .02
1.986 .03
l.gO4 .05
1.882 .03
1.820 .02
1.777 .02
1.735 .02
Example 10
Cephalexin hydrochloride monohydrate
The product of Example 9 was allowed to dry
in air at 30 to 35C under a relative humidity of abou-t
35%. After 15 days, NMR studies showed that approx-
ima-tely 73% of the _-propanolate solvate had transformed
to the monohydrate title cornpound.
Example 11
Tablet for Immediate Release Product
Ingredient Amoun-t
Cephalexin hydrochloride monohydrate 617.7 mg
oE Exampl.e 2 (850 mcg cephalexln/mg)
Povidone 12.6 mg
30 Carbox~nethylcellulose Sodium 26.0 mg
( C.ross t.inked )
Steari.c Acid 12.6 mg
Magnesium Stearate 6.3 mg
~3~3f~
X-6456 -24-
The cephalexin hydrochloride monohydrate was
granula-ted with povidone in dichloromethane. After
drying and sizing, the granules were blended to uni-
formity with the remaining ingredients and compressed.
Example 12
Table-t Formulation
Inyredien-t Amount
1~
Cephalexin hydrochloride monohydrate 617.7 my
(Example 2)
Povidone 12.6 mg
Emcosoy~ 26.0 mg
15 (excipient derived from defatted
soybeans; Edward Mendell Co., Inc.)
Stearic Acid 12.6 mg
Magnesium Stearate 6.3 mg
The above ingredients were blended as de-
scribed in Example 11 and compressed into tablets.
~L23~
X-6456 ~25-
Example 13
Ingredient Amount
5 ~ephalexin hydrochloride monohydra-te617.7 mg
(Example 2)
Povidone 12.6 mg
Starch 26.0 mg
Stearic Acid l2.6 mg
10 Maynesium Stearate 6.3 mg
The ingredients were blended by the method de-
scribed in Example 11. The resulting tablets were coated
with hydroxypropyl methyl cellulose for use as immediate
release antibacterial pharmaceutical form.
Example 14
Capsule formulation
Ingredien-t Amount
Cephalexin hydrochloride monohydrate 450 mg
Povidone 10 my
Magnesium S-tearate 5 mg
The ingredients were blended to uniformity
and placed into an elongated gelatin capsule.
