CA1231941A - Cephalosporin derivatives - Google Patents

Abstract

ABSTRACT

Crystalline cephalexin hydrochloride mono-hydrate, a useful antibiotic, can be prepared by the hydration of novel crystalline cephalexin hydrochloride C1-4 alkanol solvates.

Description

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 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-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'~

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~

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.

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'~

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 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~

IR (KBr): 3290 cm~

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.

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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 25144 - ~ 2 0 ~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:

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 ~ ~ ~

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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 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~

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~

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~

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~

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.

Claims (7)

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

1. A process for preparing crystalline cephalexin hydrochloride monohydrate, which process comprises hydrating a crystalline cephalexin hydrochloride C1-4 alkanol solvate.

2. A process according to claim 1, in which a crystalline hydrochloride C1-2 alkanol solvate is hydrated.

3. A process according to claim 1, wherein the hydration is accomplished by exposing the solvate to an atmosphere having a relative humidity of from about 10% to about 50%.

4. A process according to claim 3, wherein the solvate is the ethanol solvate.

5. Crystalline cephalexin hydrochloride mono-hydrate, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.

6. Crystalline cephalexin hydrochloride mono-hydrate, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

7. The process of claim 3 wherein the solvate is exposed to an atmosphere having a relative humidity of from about 20% to about 45% and at a temperature of from about 20° to about 50°C.