Note: Descriptions are shown in the official language in which they were submitted.
X~6456
IMPROVEMENTS IN OR RELATING TO
CEPHALOSPORIN DERIVATIVES
This invention relates to novel cephalosporin
derivatives, more particularly to a novel crystalline
hydrochloride salt of cephalexin MindWrite, and to
its preparation from certain novel crystalline alkanol
salivates.
Over the past decade, there has been much
interest in the development of controlled release
delivery systems involving the concept of an elementary
osmotic pump, see, for instance, Thus, F.,
"Elementary Osmotic Pump", J. Harm. Sat., Vol. 64,
1975, pup 1987-1991, and US. Patent Specifications
Nos. 3,845,770, 3,977,404, 4,008,719, 4,014,334,
4,016,880, 4,034,758, 4,036,227, 4,036,228, 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 no-
lease of the pharmaceutical from the device. The agent
must also be of sufficient stability that it retains
its pharmacological potency throughout the entire no-
lease period.
Although cephalexin MindWrite, i.e., ED
2-amino 2-phenylacetamido)-3-methyl-3~cephem-4-carbox-
yolk acid MindWrite, see US. Patent Specification
No. 3,655,656, has proven to be of immense value to man-
kind in the treatment of bacterial infections, its
I
.
,
X 6456 -2- 3
pharmacokinetic profile is such that it is most effect
live when administered using a multiple dosage regime.
Thus, this compound would appear to be an ideal candid
date for incorporation in an osmotic controlled release
system of 'eke type described above so that the ire-
quench of dosing could be reduced.
Unfortunately, while cephalexin MindWrite is
ideally suited for formulation into conventional dosage
forms such as capsules and tablets, it does not lend
itself to formulation as the active ingredient in dosage
forms employing the osmotic pump technology, primarily
because of its relatively low water volubility and the
consequent low osmotic pressure of its solutions.
Attempts to solve this problem by forming
the crystalline sodium salt of the MindWrite failed
since, although the volubility of that material was
acceptable (552 mg/ml in water), it rapidly degraded
in solution, being stable for less than two hours at
ambient temperature.
In addition, attempts using conventional pro-
seeders to prepare hydrochloride salts of cephalexin
MindWrite in crystalline form failed totally. (In
this context, it should not be forgotten that amorphous
cephalosporin derivatives are generally unstable and
that it is only the crystalline forms of cephalexin
which are of sufficient stability to be of value in
pharmaceutical formulations.) Only by virtue of a
chance observation as described below, and the develop-
mint of a novel synthesis involving an unusual lattice
transformation, did it finally become possible to sync
X-6456 I
thesis the compound of the invention, i.e., crystal-
line cephalexin hydrochloride MindWrite.
According to the present invention there is
provided crystalline cephalexin hydrochloride moo-
hydrate.
his new crystalline salt is unusually soluble
in water, forming a saturated aqueous solution contain-
in 766 my per ml of distilled water at 37C. The pi of
that solution is about 0.5. This solution exhibits an
osmotic pressure of 143 atmospheres. This is to be
contrasted with cephalexin MindWrite which has a
volubility of only 12.6 my per ml of distilled water and
which solution exhibits a pi of 3.2 and an osmotic
pressure of only 1.5 atmospheres.
Further, the high volubility of the hydra-
chloride MindWrite gives it the potential for pro
voiding high blood levels of cephalexin immediately upon
administration in conventional pharmaceutical formula-
lions 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~.
.
7~9
X-6456 -4-
Relative
Spacing, do Intensities, I/I
14.03 1.00
7.08 33
5.42 .33
4.63 .73
4.41 .27
4.31 .13
~.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
1.996 .13
1.959 .07
:
.
,, .
,
I
X-6455 -5-
As intimated previously, it was surprisingly
discovered that the crystalline cephalexin hydrochloride
MindWrite could be derived from the corresponding
crystalline C1 4 alkanol hydrochloride salivates.
The Applicants had prepared the novel cry-
Tulane ethanol salivate 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,
lo under those conditions, water molecules were displacing
the ethanol molecules from the crystal lattice, thus
providing the MindWrite of the invention. Interest-
tingly, the X-ray powder diffraction patterns of the two
salivates, 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-
mint occurred to a greater or lesser extent with all
of the crystalline C1 4 alkanol salivates.
According to a second aspect of the invention
there is provided a process for preparing crystalline
cephalexin hydrochloride MindWrite which comprises
hydrating a crystalline cephalexin hydrochloride C1 4
alkanol salivate.
The hydration is preferably accomplished by
exposing the salivate 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-
is factory conversion rates. In general, the higher the
temperature, the lower should be the relative humidity.
X-6456 - 6 79~
Hydration of the alkanol salivate is most
facile with the methanol and ethanol salivates. Indeed,
hydration of the propanol and buttonhole salivates is much
more difficult to drive to completion.
Crystalline cephalexin hydrochloride MindWrite,
and the aforementioned process for its production, are
also disclosed, and are claimed, in commonly assigned
Canadian Patent Application No. 468,655, Angel et at, filed
November 27, 1984, of which the present application is a
division].
The crystal alkanol salivates of another aspect of the invent
lion can be prepared by adding an excess of hydrogen
chloride or hydrochloric acid to an alkanolic suspend
soon of cephalexin MindWrite. When preparing the
C1 2 alkanol salivates, it is preferred to use an hydrous,
i.e., gaseous hydrogen chloride during the formation of
the alkanol salivate. On the other hand, the C3 4
alkanol salivates are preferably formed using aqueous
hydrochloric acid.
The cephalexin hydrochloride alkanol salivate
typically crystallizes out of solution. the crystal-
ration can be assisted by chilling, preferred crystal-
ligation temperatures being from 15 to 25C, most
I preferably from 20 to 22C, or by addition of an anti
solvent such as a hydrocarbon solvent, for example
hexane. Seeding with crystals of the hydrochloride
MindWrite or alkanolate may also assist the
crystallization process.
The crystalline cephalexin hydrochloride
alkanol salivates are new compositions of matter, and
are provided in one aspect of the invention.
While the crystalline cephalexin hydrochloride
alkanol salivate intermediates of the invention are rota
lively stable under an hydrous conditions, if they are
exposed to an atmosphere having a relative humidity
greater than about 10% the salivate becomes unstable and
X-6456 -7- ~3~7~9
converts to the MindWrite polymorph of the invention.
The rate of conversion varies depending upon the part-
ale size of the salivate, the relative humidity to Tush
it is exposed, and the ambient temperature. If the
salivate intermediate is subjected to an atmosphere have
in a high relative humidity, the material does not form
the MindWrite crystalline structure provided by this
invention, but instead becomes an amorphous mass.
In a preferred embodiment, the ethanol hydra-
chloride salivate is exposed to air having a relative humidity of from about 20 to about I at a temperature
of from about 20 to about 50C. Under such conditions
conversion to the hydrochloride MindWrite crystalline
form of this invention is substantially complete after
lo about one to about fifteen days.
The cephalexin hydrochloride MindWrite cry-
Tulane form of the invention is useful as an orally
active antibacterial agent, and is particularly 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, Starkey acid, starch,
and the like and encapsulated or, if desired, the
I formulation can be compressed into tablets. A pro-
furred embodiment is a tablet adapted for human comma-
therapy which provides for substantially immediate
release of the active ingredient into the biological
system.
.
, ~.~, ., ;-
X-6456 -8-
I 9
Such pharmaceutical formulations will contain
from about 10 to about 98% by weight of active ingredi-
en, for example from about ~00 to about 1200 my of
active ingredient, and will be administered to a human
subject at the rate of one or more doses each day for
the control 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 live, and molded into tablets or the like.
While the cephalexin hydrochloride MindWrite
crystalline form can be formulated for oral administer-
lion employing conventional encapsulation and tabulating
technology, as described above, it is ideally suited to
formulation as a controlled release dosage form, espy-
Shelley 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-
couches over the entire period of administration. The
compound of this invention uniquely satisfies these no-
quirements of volubility, osmotic pressure and stability.
The amount of cephalexin hydrochloride moo-
hydrate present in the osmotic~lly-driven delivery
device is not critical but typically is an amount equal
to or greater than the amount necessary to osmotically
,
X-64~6 -9-
operate the device for the desired period of drug no-
lease so that the desired therapeutic level of active
agent is achieved for the desired period of time.
Moreover, the cephalexin hydrochloride moo-
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-
tarninant can be reduced below two, normally below one,
percent by weight. The novel MindWrite polymorph of
this invention therefore normally exists in a forum-
ceutically-acceptable state of purity greater than I
percent, preferably and typically greater than 99 per-
cent by weight.
According to a further aspect of Ike invent
lion, there is provided a pharmaceutical formulation
which comprises as the active ingredient crystalline
cephalexin hydrochloride MindWrite associated with
one or more pharmaceutically-acceptable carriers or
excipients therefore
The amount of cephalexin hydrochloride moo-
hydrate which is antibacterially effective is from about
1 to about 30 mg/kg of animal body weight. While Sophie-
toxin hydrochloride MindWrite will display an activity
profile very similar to that of cephalexin MindWrite,
it is likely that higher blood levels and a more rapid
onset of action will be enjoyed with cephalexin hydra-
chloride MindWrite than with the current commercial
cephalexin MindWrite, due to its unusually greater
syllable. Thus, the compound of the invention has
great potential as an immediate release tablet compost-
lion.
Jo
X-6456 -10~ 7
The invention will now be further illustrated
with reference to the following non-limitative examples.
Example 1
Cephalexin hydrochloride ethanol salivate
Cephalexin MindWrite (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 got-
looted by filtration and washed with 200 ml of 1:1 (v/v)
lo ethanol-ethyl acetate and then with 200 ml of ethyl
acetate. The product was identified as cephalexin
hydrochloride ethanol salivate. Yield 53 grams.
NOR: (D20): ~1.2 (t, OH);
2.02 (s, lo);
~3.23 (q, OH);
~3.65 (q, OH);
~5.0 (d, lo);
5.3 (s, lo);
~5.61 (d, lo);
~7.59 (s, OH).
X-ray powder diffraction carried out with a
diffractometer having a nickel-filtered copper target
tube of 1. AYE.
~23~7~3~
X-6456
Relative
Spacing, do Intensities, I/I
14.48 1.00
10.04 .005
~.16 .01
8.58 .02
7.34 .095
6.10 .055
5.75 .05
lo 5.48 .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
I;
:
', : '
: .
- :
X-6456 -12- ~23~7~9
Example 2
Cephalexin hydrochloride MindWrite
To a stirred suspension of 45 kg of cephalexin
MindWrite 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 minutes, and then was cooled to 10C and stirred
for an additional two hours. The crystalline pro-
cipitate that 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 filter cake was
shown by NOR to be cephalexin hydrochloride ethanol
salivate (NOR consistent with that reported in Example 1).
Elemental Analysis calculated for ethanol
salivate:
Clowns Hal CH3CH2
Theory: C, 50.29; H, 5.63; N, 9.77; S, 7.46; Of, 8.25;
Found: C, 50.03; H, 5.45; N, 9.84; S, 7.35; Of, 8.37.
The ethanol salivate filter cake from above was
exposed for two weeks to an atmosphere of air of about
35% relative humidity at a temperature of about 25-30C
to provide 31.76 kg of cephalexin hydrochloride moo-
hydrate.NMR (D O): ~2.06 (s, OH)
2 ~3.30 I, OH)
~5.0 (d, lo)
~5.32 (s, lo)
~5.68 (d, lo)
~7.61 (s, OH).
Jo .
I,
I, . .
- 13 -
IT (KBr): 3290 cm 1
3120
1760
1710
1680
156
1490
Karl Fischer water analysis: 4.48% no consistent
with the presence of approximately one mole of water.
Residual ethanol determined to be 0.68%.
Elemental Analysis Calculated for cephaleY~in
hydrochloride MindWrite:
C16H17N304~-HCl'H2
Theory: C, 47.82; H, 5.02; N, 10.46; S, 7.98; Of, 8.82.
Found: C, 48.03, H, 4,82; N, 10.27; S, 7.87;
Of, 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 loss beginning at 63C which
resulted in a 5.7% weight loss at 135C. At 1~0C
another weight loss began and continued through deco-
position. The compound demonstrated an X-ray powder
- diffraction pattern consistent with that reported above
for cephalexin hydrochloride MindWrite.
;' .
r
~23~799
X-6456 -14-
Example 3
The effect of humidity on the rate of change
of cephalexin hydrochloride ethanol salivate to Sophie-
toxin hydrochloride MindWrite was studied my X-ray
diffraction of samples of the ethanol salivate after
storage at 25C in chambers of different relative
humidities. The change from ethanol salivate to moo-
hydrate was followed by observing the disappearance of
an X-ray maximum having a d value of about AYE. The
results of the study are presented in Table I.
Table I
Disappearance of AYE X-Ray
Maximum with Time at
Various Humidities at 25C.
Relative Humidity (%)
: 20 Time 0 20 32 44
0 hours 19 units units lo units 19 units
24 18 10 7 2
48 17 8 5
72 - 6 4
25144 - 4 2 0
260 - 2
888 - 1 0
Note: "-" means that no reading was taken.
A sample of the ethanol salivate held at 70%
; relative humidity was totally dissolved within twenty-
; four hours.
.
,.
.,
X-6456 -15- 3 7
Example 4
Stability of Cephalexin Hydrochloride
MindWrite.
S A sample of cephalexin hydrochloride moo-
hydrate from Example 2 was analyzed by high pressure
liquid chromatography and shown to contain 84.6%
cephalexin. (This is equivalent to a purity of about
99.2% for the cephalexin hydrochloride MindWrite, the
remainder being substantially all ethanol) Samples of
this material were stored at various temperatures for a
prolonged period of time. The samples were assayed
periodically by high pressure liquid chromatography
(HPLC) and by Karl Fischer OF titration. The results
of the study are given in the following Table II:
.. I,
I
X-6456 -16-
a I,
Jo Us Us o 1-- Us
O Go O I O CO 00 h
Rex I I I ox Ox -
I o ox
o I I, Jo ,- ox o
O Y . h J
h
+
o O I-- O
-- CC X X 0 X00 o
I 0
_ CJ~ I
SHEA J h
o
00 00 OWE 00 0
J 3
00 Jo O
o 0
Ox ...... r
If') I or) o us
E J
J + IDEA O - I-
O Jo rho
'I o r
I I owe ox
r_ ox Ox o
,_ ox o
I; O CJ~ O O Us J
Jo r-- 00 00 00 I 00 I h Jo ~,~
Lo Jo In
o o
r O I ED Ox E
O us O r
O Jo
Jo r_ O Al Jo
.:; o o o
" E Jo Al,
.,. 3: 00 00 00 00 00 ox I.
D X
I r I 0
a o an O us
r_- us Ox
o . c 3 I
I I JO co ox ox ox ox O r
I ox o o
on o o
O r7 LOU Jo Ox CAL, 0
O us o :) E
+ 0 E a MU
ox r` 3 s., .1
--owe o I J c C
I X 00 00C~1~ 00 r-l O Al
E
O O
Al E . o us o
0 0 0 E Al 3 or'
E 0 r- E E
0 ho I c
.
X-6456 -17- ~347~
Example 5
Cephalexin hydrochloride methanol salivate
An hydrous methanol (100 ml) was cooled to
5C and treated with gaseous hydrogen chloride (8 g).
Cephalexin MindWrite (35.2 g) was then added at room
temperature. Solution of the cephalexin MindWrite
occurred followed (within 15 minutes) by formation o
a thick slurry of the title compound. Yield 18.0 g.
The X-ray diffraction pattern of this mate-
fiat, 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, intensities, I/I
13.97 1.00
7~10 .49
6.50 .01
6.08 .01
5.65 .15
5.40 .40
4.69 .43
4.51 .03
4.38 .03
4.23 .50
,
I 39
X-6456 -18-
Rye l alive
Spacing, do Intensities, I/I
4.04 .03
3.78 .66
3.61 44
3.48 .29
3.41 .18
3.27 .04
3.07 .12
2.93 .06
2.86 .18
2.74 .03
2.61 .06
2.56 .13
2.42 lo 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
1.748 .03
1.708 .01
-19~ I
Example 6
Cephalexin hydrochloride MindWrite
Hydrogen chloride gas (7.0 g) was dissolved
in methanol (100 ml) at room temperature. The methanol
was an hydrous (Karl Fischer analysis showed less than
0.12% by weight of water). Cephalexin MindWrite
(35.2 g) in solid form was then added to the reaction
mixture. Dissolution occurred. Crystallization ox
cephalexin hydrochloride methanol salivate occurred
approximately fifteen minutes after seeding with Sophie-
toxin hydrochloride MindWrite. Heat of crystallization
caused the temperature to rise from 22 to 30C.
After 3 hours at room temperature, the product was lit-
toned off, and then washed with cold methanol. NOR
studies showed the initial formation of the methanol
salivate.
The methanol salivate prepared above was
exposed for three days to an air atmosphere having a
relative humidity of about 35% and at a temperature of
8C to provide 18.1 grams of crystalline cephalexin
hydrochloride MindWrite having an NOR and IT identical
with the product of Example 2.
example 7
Cephalexin hydrochloride isopropanolate
Cephalexin dimethylformamide disolvate
(300 g) was slurries in isopropanol (2.215 Lo and cooled
to 13C. Concentrated hydrochloric acid (190 ml) was
:
.
I 3
X-6456 -20-
added rapidly, drops, to the reaction mixture at a
temperature between 13 and 17C. After addition was
complete, a yellow solution was formed. That solution
was warmed to 20C and slowly stirred. Cephalexin
hydrochloride isopropanol salivate crystallized out in
the form of a thick slurry which was stirred at room
temperature for 2 hours, treated with hexane, 200 ml of
isopropanol added and then stirred for a further 3 hours
at room temperature, cooled and then filtered. 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 Deb-
Squarer camera using a nickel-filtered copper target
tube of AYE is given below:
Relative
intensities, I/I
14.61 1.00
20 7.44 .17
6.15 .06
5.70 .27b
4.68 .30
25 4.40 .12
4.29 .12
4.10 .09
3.97 .06
3.83 .33
3.69 .12
3.53 jog
3.43 .18
3.25 .06
35 3.04 .09
~:3~7~9
-21-
Relative
do Intensities, I/I
2.96 .02
2.80 .08
2.69 03
2.56 ~09
2.50 .02
2.43 .02
OWE .02
2.27 .08
2.21 .03
2.13 .02
2.05 ,03
Example 8
Cephalexin hydrochloride MindWrite
The isopropan,olate product 135 go of Example 7
was loaded into the fluid bed drier sold under the
trade mark "Lab-Line" and allowed to humidify at them-
portrays ranging between 24 and 27C. After 18.5 hours
NOR studies of the final product showed that some 54
of the starting isopropanolate had been converted to
the crystalline hydrochloride MindWrite.
Example 9
Cephalexin hydrochloride n-propanol salivate
Cephalexin MindWrite (35.2 g) was slurries
in an hydrous n-propanol (150 ml) cooled to approximately
10C and treated with gaseous hydrogen chloride (6.1 go.
The solution thus formed was seeded with the is-
propanolate salivate formed in Example 7. Further n-
i . , . , .
I
X-6456 -22-
propanol (50 ml) was added and the reaction mixture stirred at room temperature for a further 3 hours,
whereupon the desired n-propanol salivate crystallized
out as a slurry. The slurry was then cooled for 2 hours
and the title compound isolated, yield 39.1 g. NOR
showed the material to be the n-propanolate salivate.
The X-ray diffraction pattern of this material, measure-
mint carried out as with methanol ate, for the n-
propanolate is given below:
do I/I
14.~2 l.00
7.58 .41
6.27 .06
155.96 .13
5.57 .34
4.65 .59
4.38 .41
204.23 .44
4.06 .41
3.78 .59
` 3.66 .06
253.50 .13
3.46 .22
3.41 .16
3.23 .06
303.08 .11
2.96 .03
2.81 .03
2.76 OOZE
2.67 .02
352.60 .06
2.~3 .06
2.47 .03
2.37 .03
402.33 .03
,
-
I
X-6456 -23-
do I/I
2.25 .02
2.18 .11
2.03 .02
1.986 03
1.904 .05
1.882 .03
1.820 .02
1.777 .02
1.735 .02
Example 10
Cephalexin hydrochloride MindWrite
The product of Example 9 was allowed to dry
in air at 30 to 35C under a relative humidity of about
35%. After 15 days, NOR studies showed that approx-
irately 73% of the n-propanolate salivate had transformed
to the MindWrite title compound.
Example 11
Tablet for Immediate Release Product
US gradient Amount
Cephalexin hydrochloride MindWrite 617.7 my
of Example 2 (850 mug cephalexin/mg)
Povidone 12.6 my
30 Carboxymethylcellulose Sodium 26.0 my
cross Linked)
Starkey Acid 12.6 my
Magnesium Stewart 6.3 my
.
-
I
X-6456 -24-
The cephalexin hydrochloride MindWrite was
granulated with povidone in dichloromethane. After
drying and sizing, the granules were blended to unit
format with the remaining ingredients and compressed.
Example 12
Tablet Formulation
Ingredient Amount
Cephalexin hydrochloride MindWrite 617.7 my
(Example 2)
Povidone 12.6 my
Emcosoy~ 26.0 my
~excipient derived from defeated
15 soybeans; Edward Wendell Co., Inc.)
Starkey Acid 12.6 my
Magnesium Stewart 6.3 my
The above ingredients were blended as de-
scribed in Example 11 and compressed into tablets.
7~39
X-6456 I
Example 13
Ingredient Amount
5 Cephalexin hydrochloride MindWrite 617.7 my
(Example 2)
Povidone 12.6 my
Starch 26.0 my
Starkey Acid 12.6 my
10 Magnesium Stewart 6.3 my
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
20 Ingredient Amount
Cephalexin hydrochloride MindWrite 450 my
. Povidone 10 my
Magnesium Stewart 5 my
; 25
The ingredients were blended to uniformity
and placed into an elongated gelatin capsule.
, ;.
,.
,~.,~ . ,.
