Antibiotic compositions.

Summary of the Invention

This invention relates to a novel, stable, non-hygroscopic solvate of cefbuperazone, cefbuperazone hemiacetonate, and to pharmaceutical compositions comprising physical mixtures of cefbuperazone free acid or cefbuperazone hemiacetonate and at least one of lysine, lysine acetate, arginine and arginine acetate.

Background and Description of the Prior Art

Cefbuperazone, a so-called "second generation" injectable cephalosporin, is disclosed in U.S. 4,263,292 issued to I. Saikawa et al. on April 21, 1981 and has the following structure. <chemistry id="chem0001" num="0001"><img file="EP0189941A2_D0001.tif" /></chemistry>

CEFBUPERAZONE

Patent 4,263,292 described the preparation of the dihydrate of cefbuperazone free acid (zwitterionic form), the lyophilized sodium salt of cefbuperazone and injectable pharmaceutical reparations containing the sodium salt.

European Patent Application No. 91,502, published October 19, 1983, discloses cephalosporin compositions for rectal administration which comprise one of a specific class of cephalosporins (including cefbuperazone), an ether type nonionic surfactant, an amino acid (including lysine and arginine) and an oleaginous base. The cephalosporins utilized are poorly absorbed when administered rectally. It is stated that, when administered in combination with an ether type nonionic surfactant, absorption is increased, but there is severe tissue damage. The addition of an amino acid to the composition reduces the rectal tissue damage. There is no suggestion of admixture of cefbuperazone and an amino acid without the surfactant and oleaginous base, no suggestion of an injectable form, and no discussion of pain on injection.

Although cefbuperazone is a useful antibiotic, the previously known forms have significant disadvantages. The free acid dihydrate is crystalline and stable in the dry state, but has a low solubility in water and therefore cannot be used to prepare aqueous injectable products having a reasonably useful cefbuperazone concentration. Also, the dihydrate is inconvenient to use for preparing pharmaceutical compositions because its water of hydration is very loosely bound, and its water content (and weight) varies with the ambient temperature and relative humidity. The lyophilized, amorphous sodium salt of cefbuperazone lacks sufficient stability for long-term storage, e.g. for periods in excess of one year, or for storage in areas of high ambient temperature. Moreover, injectable compositions of the sodium salt cause significant pain upon injection.

Brief Description of the Drawing

<ul id="ul0001" list-style="none"><li>Figure 1 shows the infrared spectrum of cefbuperazone hemiacetonate as a mineral oil mull.</li></ul>

Complete Description

In their attempt to find a form of cefbuperazone which is stable in the dry state, water soluble and having reduced pain upon injection, applicants prepared and examined the sodium, potassium, calcium and ammonium salts of cefbuperazone, and salts prepared from cefbuperazone and the following bases: lidocaine, ethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, nicotinamide, ethylenediamine, N-methylglucamine, L(+)-lysine and L(+)-arginine. None of these yielded a crystalline product, and none of the amorphous products obtained offered any advantage, with respect to stability in the dry state, over the sodium salt of cefbuperazone.

Applicants then, surprisingly, discovered a solvate of cefbuperazone, the hemiacetonate, which is crystalline, non- hygroscopic and very stable in the dry state. Applicants also have unexpectedly found that, although the lysine and arginine salts of cefbuperazone are not stable in the dry state, physical mixtures of crystalline cefbuperazone dihydrate with lysine, lysine acetate, arginine or arginine acetate, or mixtures thereof, are stable in the dry state and water-soluble, and produce little or no pain upon injection. Cefbuperazone hemiacetonate is also advantageously used in physical admixture with lysine, lysine acetate, arginine or arginine acetate, or mixtures thereof, in view of its ability to retain a constant weight (i.e., not gain or lose water) under varying conditions of ambient temperature and relative humidity, and its low level of pain upon injection.

Table 1, below, shows the stability in the dry state of sodium cefbuperazone, cefbuperazone free acid, cefbuperazone hemiacetonate, and of mixtures of the latter two with lysine, arginine, lysine acetate or arginine acetate. <tables id="tabl0001" num="0001"><img file="EP0189941A2_D0002.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0189941A2_D0003.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0189941A2_D0004.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0189941A2_D0005.tif" /></tables>

Table 1 demonstrates the low stability of sodium cefbuperazone in the dry state. Cefbuperazone free acid dihydrate and anhydrous cefbuperazone free acid are significantly more stable, but are insufficiently water-soluble to be useful as a dry fill for reconstitution with water. Cefbuperazone hemi- acetonate, and mixtures of cefbuperazone hemiacetonate, cefbuperazone free acid dihydrate or anhydrous cefbuperazone free acid with lysine, arginine, lysine acetate or arginine acetate, are shown to have good stability in the dry state, indicating excellent long-term shelf stability (e.g. greater than 1 year) under normal ambient conditions.

The amount of lysine, arginine, lysine acetate, arginine acetate, or mixtures thereof, to be mixed with cefbuperazone is not based on a molar equivalent basis, but is added in the amount necessary to produce a pH in the range of 4-7 when reconstituted with Sterile Water for Injection, U.S.P. The pH range preferably is in the range of 4-6 and most preferably is from about 4 to about 5.

It has been found that a pH of at least 3.5-3.7 upon reconstitution is necessary to insure complete solution of the dry mixture, it being preferable that the pH of the reconstituted mixture be at least about 4 to avoid the possibility of incomplete solution or possible crystallization in cool ambient conditions. The most preferred pH range of the reconstituted solution is about 4 to about 5, because pain upon injection normally increases with an increase of pH.

It will be appreciated that the purity (and hence, activity) of each batch of cefbuperazone will vary, whether dihydrate, anhydrous or hemiacetonate. Similarly, the purity of each batch of lysine, arginine, lysine acetate and arginine acetate will vary in purity (and hence, basicity). For this reason, it is not possible to give absolute gram amounts of cefbuperazone and lysine, arginine, lysine acetate and/or arginine acetate to produce a specific pH. The amount of each ingredient can readily be determined for individual batches of the two components by titration of the cefbuperazone with the other component. Table 2 shows typical results obtained when titrating cefbuperazone free acid dihydrate with L(+) lysine base. In this example, 264.4 mg of cefbuperazone free acid dihydrate (theoretically equal to 250 mg of cefbuperazone activity) was suspended in 10 ml of water and titrated with aqueous L(+) lysine. Solution of the cefbuperazone takes place at approximately pH 3.5. <tables id="tabl0005" num="0005"><img file="EP0189941A2_D0006.tif" /></tables>

It will be seen that, with these particular batches of the two components, 264.4 mg of the cefbuperazone free acid dihydrate requires about 64.1 mg of L(+) lysine to give a reconstituted material having a pH of 4, about 66.0 mg to give a pH of 4.4, etc.

Table 3, below, shows typical amounts of components, dilution volume (with Sterile Water for Injection, U.S.P.) and resulting pH of unit dosage forms containing 333 mg of cefbuperazone activity per ml. <tables id="tabl0006" num="0006"><img file="EP0189941A2_D0007.tif" /></tables>

The novel, crystalline cefbuperazone hemiacetonate provided by this invention has been characterized by x-ray powder diffraction pattern, infrared spectrum, nuclear magnetic resonance spectrum and differential scanning calorimetry.

The nuclear magnetic resonance confirmed the presence of cefbuperazone and showed the presence of one-half mole of acetone per mole of cefbuperazone. This was shown to be bound acetone (a solvate) rather than free acetone by the fact that the acetone was retained even when heated at 50°C in vacuo. Under these same conditions, cefbuperazone dihydrate lost water of crystallization.

The x-ray powder diffraction pattern was determined on a Rigaku X-ray Powder Diffractometer using a Cu 25 kv lamp operated at 20 ma, at a scan rate of 2° per minute from 40° to 5° using a chart speed of 10 mm per minute and a nickel filter. The d-spacings and relative intensity of the peaks are shown in Table 4. <tables id="tabl0007" num="0007"><img file="EP0189941A2_D0008.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0189941A2_D0009.tif" /></tables>

The infrared absorption spectrum of cefbuperazone hemiacetonate (as a mineral oil mull) is shown in Figure 1 hereof.

The differential scanning calorimeter curve of cefbuperazone showed endotherms at 163°C and 180°C, and an exotherm at 185°C.

The process for preparing cefbuperazone free acid hemiacetonate comprises <ul id="ul0002" list-style="none"><li>a) adjusting the pH of a slurry of cefbuperazone free acid in water to 3 - 6</li><li>b) adding acetone to the solution,</li><li>c) adjusting the pH to 1 - 3 and</li><li>d) isolating the product.</li></ul>

Preparation No.1

Preparation of Sterile Cefbuperazone Free Acid (Anhydrous Form)

<ul id="ul0003" list-style="none"><li>1. Slurry 10 g of hydrated cefbuperazone free acid in 25 ml of Water for Injection, U.S.P. (22-26°C).</li><li>2. With very rapid stirring, slowly add a 7.5% w/v solution of NaHCO₃ until a solution or near solution and a pH of 4.0-5.0 are obtained. Approximately 15 ml is required.</li><li>3. Add 10 ml of absolute ethanol. Stir for 5 minutes.</li><li>4. Using aseptic technique, pass the solution through an appropriate sterile, 0.22 micron pore size membrane filter and into an appropriate sterile container.</li><li>5. With very rapid stirring and over at least a 10-minute interval, add sterile, 6-12N HC1 to a pH of 2.5-3.0. Crystals form. Stir for 0.5 hours.</li><li>6. Vigorously stir the mixture for 1-2 hours at a maintained pH of 1.5-2.5 by addition of 6-12N HC1, if required.</li><li>7. Vacuum filter the crystals through an appropriate sterile filtration unit.</li><li>8. Tamp the crystals to smooth the filter cake and remove any cracks which may have formed.</li><li>9. Wash the crystals with two x 10 ml portions of 75% Sterile Water for Injection, U.S.P./25% ethanol, v/v. Assure that any cracks present in the filter cake are removed by tamping before each washing.</li><li>10. Remove all free liquid from the filter cake by tamping smooth under vacuum.</li><li>11. Wash the filter cake with three x 10 ml portions of sterile ethanol. Tamp the filter cake smooth after each washing.</li><li>12. Maintain vacuum until all free ethanol appears removed.</li><li>13. Vacuum dry the crystals aseptically at 55-65°C for 24 hours. Expected yield: 9.0-9.5 g of sterile cefbuperazone free- acid, anhydrous form.</li></ul>

Preparation No.2

Preparation of Sterile Cefbuperazone Free Acid "Dihydrate

<ul id="ul0004" list-style="none"><li>1. Repeat Steps 1-8 of Preparation No. 1.</li><li>2. Wash the resulting crystals with two x 10 ml portions of Sterile Water for Injection, U.S.P. Assure that any cracks present in the filter cake are removed by tamping before each washing.</li><li>3. Remove all free liquid from the filter cake by tamping smooth under vacuum.</li><li>4. Air dry the crystals aseptically at 20-25°C and relative humidity &gt;50% for 24 hours. Expected yield 9.5-9.7 g.</li></ul>

Preparation No. 3

Preparation of Sterile, Crystalline L-Arginine Free Base

<ul id="ul0005" list-style="none"><li>1. Dissolve 3 g of L-arginine free base in 30 ml of Water for Injection, U.S.P.</li><li>2. Using aseptic technique, pass the solution through a suitable sterile 0.22 micron pore size filter.</li><li>3. Add the filtered solution, over a 10-minute interval, to 400 ml of rapidly stirring, sterile isopropanol. Crystals form. Stir for 1 hour.</li><li>4. Isolate the crystals via a suitable aseptic vacuum filtration procedure.</li><li>5. Wash the crystals with 80 ml of sterile isopropanol.</li><li>6. Vacuum-dry the crystals under aseptic conditions at 65-70⁰C for 24 hours. Expected yield 2.7 g. Store in a suitable sterile container.</li></ul>

Preparation No. 4

Preparation of Sterile, Crystalline L-Arginine Acetate

<ul id="ul0006" list-style="none"><li>1. Slurry 10 g of L-arginine free base in 30 ml of Water for Injection, U.S.P.</li><li>2. With rapid stirring, add 12.2 ml (approximately 3 molar equivalents) of glacial acetic acid over a 5-minute interval. A solution or near solution is obtained. Cool to 20-25°C.</li><li>3. Using aseptic technique, pass the solution through a suitable sterile 0.22 micron pore size filter.</li><li>4. Add the filtered solution, over a 15-minute interval, to 500 ml of rapidly stirring, sterile absolute ethanol. Crystals form. Stir for 0.5 hour.</li><li>5. Isolate the crystals via a suitable aseptic vacuum filtration procedure.</li><li>6. Wash the crystals with 100 ml of sterile absolute ethanol.</li><li>7. Vacuum-dry the crystals under aseptic conditions at 65-75°_C for 24 hours. Expected yield: 10.1 g. Store in a suitable sterile container.</li></ul>

Preparation No. 5

Preparation of Sterile, Crystalline L-Lysine

<ul id="ul0007" list-style="none"><li>1. Slurry 50 grams of L-lysine base in 500 ml of methanol for 20 minutes at 20-25°C.</li><li>2. Remove the insolubles (mostly L-lysine carbonate) by suitable filtration technique. At this point, the filtrate may have a slight haze. Discard the filter cake.</li><li>3. With rapid stirring, add about 7.5 grams of decolorizing carbon to the filtrate of Step 2 and stir for 0.5 hour.</li><li>4. Remove the carbon by suitable filtration technique.</li><li>5. Wash the filter cake with 75 ml of methanol. Add the wash to the filtrate.</li><li>6. Pass the filtrate-wash through a suitable 0.22 micron Millipore filter to remove bacteria and particles. Collect the filtrate in suitable sterile, pyrogen-free containers (glass or stainless steel).</li><li>7. In a sterile environment, using sterile techniques, add, with very rapid stirring (air stirrer), 2 liters of sterile, pyrogen-free isopropanol over a one-hour interval to the sterile, pyrogen-free methanol solution of L-lysine base of Step 6. A heavy precipitate forms. Slurry an additional 15 minutes.</li><li>8. Remove the crystalline L-lysine base by suitable, sterile filtration techniques. Tamp the filter cake to remove cracks and fissures.</li><li>9. Wash the filter cake with 200 ml of sterile, pyrogen-free isopropanol and continue the vacuum until the cake appears dry.</li><li>10. High-vacuum dry the filter cake at 56°-65°C for 24 hours. Yield: approximately 40 grams.</li><li>11. Mill or screen the solids by sterile techniques to 40-60 mesh.</li><li>12. Re-dry the solids at high-vacuum, 56°-65°C for 24 hours.</li><li>13. Store the solids in sterile, pyrogen-free amber bottles.</li><li>14. If desired or required, the isopropanol used in Steps 7 and 9 may be substituted with equal volumes of sterile, pyrogen-free ethyl acetate.</li></ul>

Properties of Parenteral Grade L-Lysine Base

<ul id="ul0008" list-style="none"><li>1. IR - NMR: a. Consistent for structure b. Substantially free of methanol, ethyl acetate, isopropanol</li><li>2. % Water, Karl Fischer: 1-2%</li></ul>

Preparation No. 6

Preparation of Sterile, Crystalline L-Lysine Acetate

<ul id="ul0009" list-style="none"><li>1. Dissolve 10 g of L-lysine free base in 30 ml of Water for Injection, U.S.P.</li><li>2. With rapid stirring, add 12.2 ml (3 molar equivalents) of glacial acetic acid over a 5-minute interval. Cool to 20-25°C.</li><li>3. Using aseptic technique, pass the solution through a suitable sterile 0.22 micron pore size filter.</li><li>4. Add the filtered solution, over a 15-minute interval, to 500 ml of rapidly stirring, sterile isopropanol. Crystals form. Stir for 0.5 hour.</li><li>5. Isolate the crystals via a suitable aseptic vacuum filtration procedure.</li><li>6. Wash the crystals with 75 ml of sterile isopropanol.</li><li>7. Vacuum-dry the crystals under aseptic conditions at 65-75°C for 24 hours. Expected yield: 9.6 g. Store in a suitable sterile container.</li></ul>

Example 1

Dry Fill Mixture: Cefbuperazone Free Acid (Anhydrous) + L-Arginine Free Base for Parenteral Use

(Label claim per vial is 250 mg of cefbuperazone activity)

All work should be conducted under aseptic conditions at a relative humidity of below 50%, preferably at 30-35%. <tables id="tabl0009" num="0009"><img file="EP0189941A2_D0010.tif" /></tables>

MANUFACTURING INSTRUCTIONS

<ul id="ul0010" list-style="none"><li>1. The aseptic manufacturing area relative humidity must be less than 50%, preferably 30-35%.</li><li>2. Using aseptic technique, suitably blend the batch-weight requirements of the sterile cefbuperazone free acid (anhydrous) and L-arginine free base.</li><li>3. Drop the blend in a suitable sterile holding container. Submit for potency, sterility, blend uniformity and testing for other required parameters.</li><li>4. Aseptically fill the required amount^*** of bulk-blend into appropriate vials. Seal with appropriate rubber closures and aluminum shells.</li></ul>

^***The actual weight of fill can vary as a function of needle- vial-syringe retention and additional overfill required.

Example 2

Dry Fill Mixture: Cefbuperazone Free Acid 2H

2

0 + L(+) Lysine Base for Parenteral Use

(Label claim per vial is 250 mg of cefbuperazone activity)

All work should be conducted under aseptic conditions at a relative humidity of below 50%, preferably at 30-35%. <tables id="tabl0010" num="0010"><img file="EP0189941A2_D0011.tif" /></tables><maths id="math0001" num=""><img file="EP0189941A2_D0012.tif" /></maths>

^**This amount of L(+) lysine base is required to give a reconstituted pH of 4.0-6.0 (pH 4.6-5.4 preferred) in Sterile Water for Injection, U.S.P., qs to 1.0 ml. The actual amount of L(+) lysine free base required can vary as a function of its purity, desired pH and the potency of the cefbuperazone · 2H20 free acid.

MANUFACTURING INSTRUCTIONS

<ul id="ul0011" list-style="none"><li>1. The aseptic manufacturing area relative humidity must be less than 50%, preferably 30-35%.</li><li>2. Using aseptic technique, suitably blend the batch-weight requirements of the sterile, cefbuperazone free acid 2H₂0 and L(+) lysine free base.</li><li>3. Drop the blend in a suitable sterile holding container. Submit for potency, sterility, blend uniformity and testing for other required parameters.</li><li>4. Aseptically fill the required amount^*** of bulk-blend into appropriate vials. Seal with appropriate rubber closures and aluminum shells.</li></ul>

^***The actual weight of fill can vary as a function of needle- vial-syringe retention and additional overfill required.

Example 3

Dry Fill Mixture: Cefbuperazone Free Acid (Anhydrous) + L(+) Lysine Free Base for Parenteral Use

(Label claim per vial is 250 mg of cefbuperazone activity)

All work should be conducted under aseptic conditions at a relative humidity of below 50%, preferably at 30-35%.

FORMULA PER VIAL

<tables id="tabl0011" num="0011"><img file="EP0189941A2_D0013.tif" /></tables><maths id="math0002" num=""><img file="EP0189941A2_D0014.tif" /></maths>^**This amount of L(+) lysine base is required to give a reconstituted pH of 4.0-6.0 (pH 4.0-5.5 preferred) in Sterile Water for Injection, U.S.P. The actual amount of L(+) lysine free base required can vary as a function of its purity, desired pH and the potency of the cefbuperazone free acid.

MANUFACTURING INSTRUCTIONS

<ul id="ul0012" list-style="none"><li>1. The aseptic manufacturing area relative humidity must be less than 50%, preferably 30-35%.</li><li>?. Using aseptic technique, suitably blend the batch-weight requirements of the sterile cefbuperazone free acid (anhydrous) and L(+) lysine free base.</li><li>3. Drop the blend in a suitable sterile holding container. Submit for potency, sterility, blend uniformity and testing for other required parameters.</li><li>4. Aseptically fill the required amount^*** of bulk-blend into appropriate vials. Seal with appropriate rubber closures and aluminum shells.</li></ul>

^***The actual weight of fill can vary as a function of needle- vial-syringe retention and additional overfill required.

Example 4

Preparation of Sterile Cefbuperazone Hemi-Acetonate

<ul id="ul0013" list-style="none"><li>1. Slurry 10 g of hydrated cefbuperazone free acid in 25 ml of Water for Injection, U.S.P. (22-26°C).</li><li>2. With very rapid stirring, slowly add a 7.5% w/v solution of NaHCO₃ until a solution or near solution and a pH of 4.0-5.0 are obtained. Approximately 15 ml is required.</li><li>3. Add 10 ml of acetone. Stir for 5 minutes.</li><li>4. Using aseptic technique, pass the solution through an appropriate, sterile 0.22 micron pore size membrane filter and into an appropriate sterile container.</li><li>5. With very rapid stirring and over at least a 10-minute interval, add sterile, 6-12 N HC1 to a pH of 2.5-3.0. Crystals form. Stir for 0.5 hour.</li><li>6. Vigorously stir the mixture for 1-2 hours at a maintained pH of 1.5-2.5 by addition of 6-12 N HC1, if required.</li><li>7. Vacuum filter the crystals through an appropriate sterile filtration unit.</li><li>8. Tamp the crystals to smooth the filter cake and remove any cracks which may have formed.</li><li>9. Wash the crystals with 2 x 10 ml portions of 75% Sterile Water for Injection, U.S.P./25% sterile acetone, v/v. Assure that any cracks present in the filter cake are removed by tamping before each washing.</li><li>10. Remove all free liquid from the filter cake by tamping smooth under vacuum.</li><li>11. Wash the filter cake with 2 x 10 ml portions of sterile acetone. Tamp the filter cake smooth after each washing.</li><li>12. Slurry the acetone-damp crystals in 30-40 ml of acetone for 0.5 hour. Remove the crystals by vacuum filtration. Maintain vacuum until all free acetone appears removed.</li><li>13. Vacuum dry the crystals aseptically at 40-50°C for 24 hours. Expected yield: 9.0-9.5 g of sterile cefbuperazone hemi- acetonate.</li></ul>

In preparing the compositions of this invention, one may use racemic lysine or arginine (or their acetate) or their D(-) or L(+) isomers. Since the L(+) isomers are the commonly available, naturally occurring forms, we prefer to use the L(+) isomers. Preferably, the lysine or arginine (or their acetate) is substantially dry, i.e. containing less than about 1-2% water. In order to minimize the volume of solution to be injected, we prefer to reconstitute the compositions to a volume of about 300 to 350 mg of cefbuperazone activity per ml of solution. The compositions may be reconstituted with Sterile Water for Injection, U.S.P., or other common injection vehicles such as 5% glucose or normal saline.

The dosage of the compositions of this invention depend on the age, weight and general health of the patient, as well as the severity of the disease, and is within the discretion of the physician. Generally, however, the dosages are similar to other known injectable cephalosporins, e.g. from about 250 mg to about 1 g, administered every six hours. In very serious or life- threatening infections, up to about 10-12 grams per day may be administered.

Intravenous toxicity tests were conducted in Swiss-Webster mice using the sodium salt of cefbuperazone and the compositions of the present invention. The Lethal Dose50 (LD50) for each of the tested compositions is shown in Table 5. In each case, the dosing solution contained 333 mg of cefbuperazone activity per ml. <tables id="tabl0012" num="0012"><img file="EP0189941A2_D0015.tif" /></tables><tables id="tabl0013" num="0013"><img file="EP0189941A2_D0016.tif" /></tables>

The compositions of this invention were assessed for pain on injection by a modification of the rat-paw lick test described by E. Gelozzi et al., Journal of Pharmacological Methods, 4, 285-9 (1980). The test animals were weanling female Sprague-Dawley rats. The test solutions were injected into the subplantar tissue of the right or left hind paw, using a syringe with a 27 gauge, 1/2-inch needle. The injection volume in each case was 0.1 ml, using a solution reconstituted with Sterile Water for Injection, U.S.P. to a concentration of 333 mg of cefbuperazone activity per ml. The paw-lick response, an indicator of the pain caused by the injection, was recorded for each rat for three minutes following the injection. A paw-licking episode is defined as a licking response followed by a turning of the head away from the paw or five seconds of uninterrupted licking. The results of the tests are shown in Table 6. <tables id="tabl0014" num="0014"><img file="EP0189941A2_D0017.tif" /></tables>

It should be noted that, at a given pH of the reconstituted solution, no difference in pain level would be expected between compositions made from dry mixes containing cefbuperazone free acid dihydrate, anhydrous cefbuperazone free acid or cefbuperazone free acid hemiacetonate. This is because the first two are identical in aqueous solution, while the third differs only in that the aqueous solution will contain a trace of acetone.