CA1234799A - Cephalosporin derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Crystalline cephalexin hydrochloride monohydrate, a useful antibiotic, can be prepared by the hydration of novel crystalline cephalexin hydrochloride C1-4 alkanol solvates. The crystalline cephalexin hydrochloride C1-4 alkanol solvates are prepared by adding an excess of hydrogen chloride or hydrochloric acid to a suspension in a C1-4 alkanol of cephalexin hydrate.

Description

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
.

, 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 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 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 :

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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.

.
, ~.~, ., ;-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~

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).

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IT (KBr): 3290 cm 1 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.

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r ~23~799 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 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.

.
,.

., 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:

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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 _ CJ~ I
SHEA J h o 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 , 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 :
.

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 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

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

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

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 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.

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Claims (10)

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

1. A process for preparing a crystalline cephalexin hydrochloride C1-4 alkanol solvate which comprises adding an excess of hydrogen chloride or hydrochloric acid to a suspension in a C1-4 alkanol of cephalexin monohydrate.

2. A process as in claim 1 wherein an excess of gaseous hydrogen chloride is added to a methanolic or ethanolic suspension of cephalexin monohydrate.

3; A process as in claim 1 wherein an excess of aqueous hydrochloride acid is added to a suspension in a C3-4 alkanol of cephalexin monohydrate.

4. A process for preparing crystalline cephalexin hydrochloride ethanol solvate which comprises forming a suspension of cephalexin monohydrate in ethanol and then adding to said suspension an excess of gaseous hydrogen chloride.

5. A process for preparing crystalline cephalexin hydrochloride methanol solvate which comprises adding an excess of gaseous hydrogen chloride to a methanolic suspension of cephalexin monohydrate.

6. A crystalline cephalexin hydrochloride C1-4 alkanol solvate, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

7. A crystalline cephalexin hydrochloride C1-2 alkanol solvate, when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

8. A crystalline cephalexin hydrochloride C3-4 alkanol solvate, when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

9. Crystalline cephalexin hydrochloride ethanol solvate, when prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

10. Crystalline cephalexin hydrochloride methanol solvate, when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.