CA1089447A - Sodium cefamandole crystalline forms - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A novel crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate is described herein. The novel mono-hydrate is prepared by either (a) exposing the crystalline methanol solvate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate to water at a relative humidity of between about 40 and 60 percent and at a temperature between about 20° and 30°C; or (b) exposing the crystalline anhydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate to water at a relative humidity of about 55 percent and at a temperature of about 25°C.
It is an intermediate for preparing the crystalline anhydrate form of sodium cefamandole, which is an antibiotic.

Description

SODIUM CEFAMANDOLE CRYSTALL:[NE FORMS
The cephalosporin antibiot:ic 7-(D-2-hydroxy-2-phenylacetamido)-3-(l-methyl-lH-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid represented by the structural formula ~o_c~c-~ T/~
OH ~ --CH s_o ~ ( I) OOH
CH

is described by Ryan in U.S. Patent No. 3,641,021. This antibiotic, referred to herein as cefamandole, is a potent broad spectrum parenteral antibiotic with excellent activity against infectious microorganisms of the gram-negative type.
Al.though cefamandole can be readily prepared, it has been difficult to obtain a pharmaceutically acceptable salt of cefamandole in a crystalline form of sufficient stability and purity suitable for parenteral admi-nistration.
Extensive development work on the antibiotic has afforded the O-formyl ester of cefamandole sodium salt in the gamma crystalline form as described in Belgian Patent 840179. This crystalline form of the O-formyl derivative of cefamandole sodium is suitable for pàrenteral administration;
however, it is best administered when formulated with a mild base such as sodium carbonate. Such formulations are described in U.S. Patent 3,928,592 issued December 23, 1975.
A stable, crystalline form of sodium cefamandole suitable for bulk preparation and administration would avoid the necessity of preparing the O-formyl derivative form and 3~ would thus simplify the pxoduction of the antibiotic.

" ~ .

'7 - -This inventi~n, in one aspect, provides a crystalline anhydrate of sodium cefamandole which is readily prepared and which possesses the stability characteristics desirable in formulations of the antibiotic.
This invention also provides a crystalline methanolate and, in a further aspect, a crystalline monohydrate of sodium ce$amandole. These forms are useful as intermediate crystalline _ structures in the preparation of the anhydrate crystals of sodium cefamandole.

The crystalline anhydrate of sodium cefamandole is prepared by removing the solvent from a crystalline sodium cefamandole solvate under reduced pressure~
The crystalline anhydrate of sodium cefamandole is a white microcrystalline solid which is best characterized by its x-ray powder diffraction pattern shown below. The diffraction pattexn was obtained with nickel filtered copper O . ~ .
radiation ~Cu:Ni) of wave length ~ = 1.5405A. The inter~
planar spacings are in the column headed by "d" and the ~ s relative intensities in the column headed "I/I~

SpacingRelative Intensity d /Il ;

14.2~ .61 12.70 .22 ~ ~
8.14 .15 ~ ~`
7.92 .23 -`
7 25 .71 .
6.60 .15 , 6.43 30 , 5.33 13 ;;~

' `~

X-4625 -3- -`

5O06 .12 ~.83 .S5 4.29 .29 4.17 .15 4.02 .26 3.64 .12 _ .
3.~0 .13 3.5~ . .12 3.50 .05 3.42 .06 3.28 07 3.20 .08 3.14 .06

2.96 .~9 2.87 .21 2.80 ..06 2.72 .15 2.67 ` .~8 -~
2.57 .~7 ;~
2.52 .~4 ~ :: :~
.
2.41 -.12 .2.29 .15 : :~ .

Stability studies carried out thus far on the :
crystalline anhydrate demonstrate substantially no loss in ~:
either antibiotic activity or in crystallinity when the salt ~ ; :
is maintained for one week a. 60C. . .
The crystalline ~nhydrate form of sodium cefamandole, and the process for.its preparation is also described in Canadian Applications No~ 266,112 and 34~,~o7, and is claimed in said -30 application No. 34~, ~ol , a divisional of the aforesaid:: :

Canadian Application No. 266,112.
This invention also provides the crys~alline methanolate ~ ~ .
and monohydrate forms of sodium cefamandole. Both o these -~
novel ~orms can be used to prepare the crystalline anhydrate i: - . . . .
as discussed hereina~ter.

3~
The crystalline methanolate, alternatively re-ferred to herein as the methanol solvate, is characterized by its x-ray powder diffraction pattern shown below. The pattern was obtained using nickel filtered copper radiation (Cu:Ni) of wave length ~1.5405A to calculate the intérplanar spacings and the relative intensities. --Spacing Relative Intensity d I/I
15.22 .06 14.24 1.00 12.g9 .25 8.75 .18 ~ -7.92 .19 7.65 45 ~:
7.16 .46 6.93 .25 ;
6.62 .18 ~.
5.48 .15 `
5.30 07 .~
5.11 .26 `

4.98 .47 `~
4.79 .40 ~.
4.64 .19 ~ `
4.22 .08 :
4.15 .07 3.76 .11 ;~
3.89 .28 ::
3.70 .18 . ~.
3.58 .19 .
3,49 .22 ~' ~'' , ,. ,. ., , .. :
;, -. .
.: - , , - - . - ~ . :
: . . , -, .

3.35 .13 3.12 .og 2.~3 .06 2.89 .17 2.79 .10 --2.76 .08 2.66 .09 2.56 .07 The methanolate form contains about 6.0 percent by weight of methanol which corresponds to a mole ratio of methanol to sodium cefamandole of 1~
The crystalline methanol solvate can be prepared by crystallizing substantially pure amorphous sodium cefamandole from methyl alcohol. Alternatively, the ~ .
m/3thanolate can be prepared with cefamandole acid by con- :
verting the acid in. methyl alcohol to sodium cefamandole : : .
.w.ith the sodium salt of a weak acid. The sodium cefamandole precipitates from solution as the crystalline methanolate.
Salts of weak acids which can be usecl include, for example, sodium acetate, sodium propionate, sodium 2-ethylhexanoate, and like sodium salts of weak carboxylic acids which are soluble.in methanol. ~ ..
The present invention, in one aspect, therefore, ~ -~
resides in a process for preparing the above-defined crystalline methanolate of sodium cefamandole which comprises carrying out one of the following procedures:

.. :,, ~ ., ':'~' ' ..

- ~ - . . , ~8~47 ~ (a) conversion of 7-(D-2-hydroxy-2-phenylacetamide)-3-(1-methyl-lH-tetrazole-5-ylthiomethyl)-3-Cephem-~ carbaxylate acid with methanol and the sodium salt of a weak acid at a temperature between about 0 and 50C., or (b) conversion of amorphous sodium 7-(D-2-hydroxy- --2-phenylacetamido)-3-(1-methyl-lH-tetrazole-5-ylthiomethyl~-3-cephem-4-carboxylate with methanol at a temperature between about 0 and 50C.; or ~ c) conversion of the crystalline anhydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1~-tetrazole-5-ylthiomethyl3-3-cephem-4-carboxylate with dry methanol; or (d) conversion of the crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-lH- ~
-tetrazol-e-5-y-~t-hiomethyl~-3-cephem-4-carboxylate with dry `-methanol. - . , -The crystalline methanolate form of sodium cefamandole and `~
the process for its preparation is also described, and is claimed, in Canadian Application No. 266,112, fi:Led November 10, 1976, of which the present application is a divisional.
The methanol solvate crystalline form is preferably ;~
prepared with substantially pure cefamandole in the free acid form as follows. The cefamandole acid is dissolved in methyl alcohol, and a solution of excess sodium acetate in methyl alcohol is added to the solution. The solution of sodium acetate is added slowly to avoid gel formation and addition is halted when the pH reaches about , .

-6a--:
- . ~ -.~ , . . . . . .
~ .

~s~ 7 6. The solution thus obtained (crystallization solution) is allo~ed to stand to complete crystallization. The crystals of methanol solvate are filtered and washed with a suitable dry organic solvent, for example ethanol or diethyl ether, and then are allowed to dry.
The crystallization procedure for the methanol solvate can be carried out at a temperature between about 0C. and 50C. The preferred temperature range of crystal-li2ation is between 15 and 40C. Over the preferred tem-perature range yields of the methanolate crystalline formare generally between about 90 and 95 percent. At tempera-tures much above 40C. the yields are usually lower. For example, at a crystallization temperature of about 50C., yields of methanolate are about 60 percent.
The crystallization of the methanol solvate is preferably carried out under substantially anhydrous con-ditions. Although trace or minor amounts of water in the crystallization solution have no deleterious effect on the yields o methanolate crystals, larger amounts can result in the formation of hydrated crystalline forms along with the methanol solvate form. Accordingly, for best results the crystallization is carried out with dry methanol and with ;~
anhydrous sodium acetate. Reagent grade methanol and an-hydrous sodium acetate are also preferred over less pure ; ~ `
grades.
The methanol solvate is obtained in highest yields from a concentra~ed crystallization solution. Therefore, concentrated solutions of cefamandole free acid in methanol and of anhydrous sodium acetate in methanol are used to form 3~ ~7 the concentrated crystallization solution of sodium cefaman-dole. A suitable concentration of cefamandole acid in methanol is about one gram of the antibiotic acid per 2 3 ml. of methanol. A concentrated solution of anhydrous sodium acetate in methanol containing about 1 g. o an-hydrous sodium acetate per 12 ml. of methanol can be con-veniently prepared at room temperature as follows. Excess anhydrous sodium acetate is stirred in methanol for several minutes and the undissolved salt is filtered. The filtrate can then be used to form the crystallization solution with the methanol solution of cefamandole free acid. -Methyl alcohol is unique in its ability to form a ;
crystalline solvate of sodium cefamandole. Attempts to prepare crystalline forms of sodium cefamandole with other alcohols have led to the formation of amorphous salt. For example, when in the above described preparation for the -;
ethanolate, methyl alcohol is replaced with ethyl ~lcohol, amorphous sodium cefamandole is obtained rather than an ethanol solvate.
The methanol solvate is the precursor crystalline form for both the anhydrate and monohydrate cr~stalline forms described herein. The methanol of crystallization of the methanolate form can be removed ln vacuo to provide the anhydrate crystalline form or, alternatively, the methanol of crystallization can be displaced by water to form the crystalline monohydrate form.
The crystalline monohydrate of sodium cefamandole contains about 4 percent by weight of water which corre-sponds to a ratio o water to sodium cefamandole of 1:1.

. ~

The monohydrate crystalline structure differs from that ofboth the anhydrate and the methanolate. The x-ray powder diffraction pattern of the monohydrate is shown belot~.
Again, nickel filtered copper radiation of wave length ~1.5405A was used.

Spacin~ Relative Intensity --d I/I1 -13.79 ~57 12.23 .40 ~0 8.23 .12 7.52 .09 7.21 40 7.02 .60 6.67 .15 6.19 .25

5.09 .1~

- 4.84 .42 4.70 .33 4.15 37 3.99 .26 3.84 .08 3.76 .09 3.65 .12 3.55 .10 3.40 .08 3.25 .10 3 07 .11 2.92 .06 2.76 .16 2.65 .11 ~-4625 -9~

:: ~

. . .
2.62 .os 2.49 .15 2.41 .o~
2.36 .07 -2.23 .11 -~

The monohydrate is prepared with the above~
described methanol solvate by allowing water to displace the methanol of crystallization in the methanolate crystals.
The preparation of the monohydrate is carried out by ex-posing the methanolate crystals to moist air. The displace~
ment of methanol with water occurs at a convenient rate at a relative humidity of between about 40 and 60 percent at a temperature between about 20 and 30C. The preferred conditions are 50 percent relative humidity at 25C. The ~ -preparation of the monohydrate crystalline form is con-veniently carried out in this manner in a humidity chamber.
The monohydrate is less stable than the anhydrate.
It becomes discolored and loses some antibiotic activity as . ~.
~ well as undergoing crystalline disfiguration in the standard stability test carried out at 60C. for one week.
The previously described crystalline anhydrate of sodium cefamandole can be prepared with either the monohy- ~
drate or preferahly with the methanol solvate. The water of ~ ;
crystallization of the monohydrate or the methanol of crystallization of the methanol solvate are removed under reduced pressure to providè the anhydrate crystalline form.
The conversion of the methanol solvate to the anhydrate crystalline form is carried out under vacuum at a temperature between about 25 and 45C. and preferably at about 40C.

3~ '7 The monohydrate crystalline form can be dehydrated under vacuum at a t~mperature between about 45 and 50C. to form the anhydrate. Preferably, a drying age~lt is placed in the vacuum oven to increase the rate of anhydrate formation.
The monohydrate will lose water at room tempera-ture at 0 percent relative humidity however, the rate is much slower than when dehydration is carried out as de-scribed above.
The anhydrate form of sodium cefamandole will rehydrate to the monohydrate crystalline form if exposed to moist air. For example, at a relative humidity of about 55 percent at about 25C., the anhydrate absorbs about 40 percent by weight of water in less than an hour. Accord-ingly, the anhydrate crystalline form is stored prior to use in sealed containers or in a dry atmosphere to prevent the formation of the less stable monohydrate form.
The anhydrate or the monohydrate can be converted to the methanolate crystalline form by crystallization from dry methyl alcohol.
The conversion of the three crystalline forms of sodium cefamandole into one another as discussed above is illustrated by the following triangular diagram. ;

Sodium Cefamandole-CH30H

C3303 ~ -CH30~ C 30H ~ ~2 Anhydrate \ Monohydrate ~ ;

' '```' ~ ~ '"' ~

.
;. . . : . : :, ~ :
- -. ., , ~ , ~ : .. .

The crystalline anhydrate can be stored in bulk form in closed containers for subsequent rormulation.
Alternatively, it can be prepared in unit dosage form in sealed ampoules for parenteral administration in the treat-ment of infectious diseases. The crystalline monohydrate and the crystalline methanol solvate are intermediate crystalline Porms useful for preparing the anhydrate form.
The following examples are provided to further illustrate the present invention.
Example 1 Sodium Cefamandole Methanolate To a solution of lO0 g. of cefamandole acid in approximately 200 ml. of methyl alcohol was slowly added a solution of 25 g. of anhydrous sodium acetate in 300 ml. of methyl alcohol until the pH of the solution reached pH 6.
The solution was allowed to stand at room temperature until crystallization of the methanolate crystalline form was complete. The crystals were har~ested by filtration through a Buchner funnel and were washed with dry ethyl alcohol and 20 with diethyl ether. ~;
Example 2 Sodium Cefamandole Anhydrate A solution of cefamandole acid in methanol was prepared by dissolving 4.0 kg. of cefamandole acid in 8.8 l. -~
of methyl alcohol with stirring. To the solution was added with vigorous stirring a solution of 0.98 kg. of anhydrous sodium acetate in 9.0 l. of methyl alcohol. The rate of addition of the sodium acetate solution was about 0.25 liters per minute. After addition was completed, the crystal ,.. . . - .:. -~ . - . ~ , - , - .
.

t~t7 slurry was stirred for one hour~ The crystals of methanol solvate were then harvested on a suchner funnel and were ~ashed with a mlxture of one liter of methanol and one liter of ethanol on the filter. The washed crystals were trans-ferred ~o drying pans and spread in a thin layer. The drying pans were placed in a Stokes oven and the crystals dried under vacuum (28 inches Hg.) at a temperature of about 40C. The dried crystals of anhydrate were transferred to amber glass jars which were sealed for storage.
Example 3 Sodium Cefamandole Monohydrate Ten grams of sodium cefamandole methanolate crystals, prepared as described by Example 1, were exposed at room temperature to approximately a 50 + 10 percent relative humidity for about 16 hours to provide 9.8 g. (quantitative yield) of sodium cefamandole monohydrate crystals.

. . .

'" '`~''; .
'` ' ~ ' X-4625 -13- ~
'' ~'' ~ . . , .. ,' ~ :.

Claims (5)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing the crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate which contains approximately 4 percent by weight of water and which has the following X-ray powder diffraction pattern obtained with nickel filtered copper radiation of .lambda.1.5405.ANG.
wherein .lambda. represents wave length, d represents the interplanar spacing, and I/I1 represents the relative intensity:

said process comprising either (a) exposing the crystalline methanol solvate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate to water at a relative humidity of between about 40 and 60 percent and at a temperature between about 20° and 30°C; or (b) exposing the crystalline anhydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate to water at a relative humidity of about 55 percent and at a temperature of about 25°C.

2. The process for preparing the crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate which comprises exposing the crystalline methanol solvate of sodium 7-(D-2-hydroxy-2-phenylacet-amido)-3-(1-methyl-1H-tetrazole-5-ylthiomethy)-3-cephem-4-carboxylate to water at a relative humidity of between about 40 and 60 percent and at a temperature between about 20° and 30°C.

3. The process for preparing the crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylate which comprises exposing the crystalline anhydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)3-cephem-4-car-boxylate to water at a relative humidity of about 55 percent and at a temperature of about 25°C.

4. The crystalline monohydrate of sodium 7-(D-2-hydroxy-2-phenylacetamido)-3-(1-methyl-1H-tetrazole

5-ylthiomethyl)-3-cephem-4-carboxylate which contains approximately 4 percent by weight of water and which has the following x-ray powder diffraction pattern obtained with nickel filtered copper radiation of .lambda.1.5405.ANG. wherein .lambda.
represents wave length, d represents the interplanar spacing and I/I1 represents the relative intensity, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.