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IE59222B1 - Cephalosporin salts and injectable compositions - Google Patents

Cephalosporin salts and injectable compositions

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Publication number
IE59222B1
IE59222B1 IE207886A IE207886A IE59222B1 IE 59222 B1 IE59222 B1 IE 59222B1 IE 207886 A IE207886 A IE 207886A IE 207886 A IE207886 A IE 207886A IE 59222 B1 IE59222 B1 IE 59222B1
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Ireland
Prior art keywords
salt
crystalline
admixture
acid addition
methyl
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IE207886A
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IE862078L (en
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Bristol Myers Squibb Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cephalosporin Salts and Injectable Compositions Crystalline sulfuric, di-nitric, mono-hydrochloric, dihydrochloric, and di- and sesqui-orthosphosphoric acid addition salts of 7-¢.alpha.-(2-aminothiazol-4-yl)-.alpha.-(Z)-methoxyimino-acetamido!-3-¢(1-methyl-1-pyrrolidinio)-methyl!-3-cephem-4-carboxylate are stable even at elevated temperatures. The crystalline sulfuric acid addition salt is made by forming an admixture of (a) at least one molar equivalent of sulfuric acid with (b) zwitterion in an amount so as to be present in the admixture at a concentration of greater than 25 milligrams/ml, causing crystallization, separating the crystals, washing and drying. The crystalline monohydrochloride, dihydrochloride, and orthophosphate salts are prepared by dissolving the zwitterion in the appropriate amount of acid, causing crystallization by adding acetone and isolating the crystal. Physical admixtures of the salts with certain bases in proportions to give a pH ranging from about 3 5 to about 7 on dilution with water provide injectable compositions on dilution. Brief Description of the Drawing Figure 1 is a graphical representation of the infra red absorption spectrum of crystalline 7-¢.alpha.-(2-aminothiazol-4-yl)-.alpha.- (Z)-methoxyiminoacetamido!-3-¢(1-methyl-1-pyrrolidinio)methyl!-3-cephem-4-carboxylate sulfate salt measured on a KBr dilution thereof. BMY-28142.H2SO4 - IR Spectrum. [CA1284994C]

Description

The invention relates to cephalosporin salts and injectable compositions.
Crystalline sulfuric, di-nitric, mono-hydrochloric, dihydrochloric, and di- and sesqui-orthophcsphcric· acid addition Basing of 7-[e-<2-aminothiarol-4-yl)-a-(Z$-me thoxy iminoacetamidoJ-3-[ U-methyl-l-pyrrolidinioS-saethyl3-3"cephem-4carboxylste are stable ©ven at elevated temperatures» The crystalline sulfuric acid addition salt is made by forming an admixture of |a| at least one molar equivalent of sulfuric acid with (bi gwitterion in an amount bo as to b@ present in th® admixture at a concentration of greater than 25 milligrams /ml, causing crystallisation, separating the crystals, washing and drying. The crystalline monohydrochloride, dihydrochloride, and orthophosphate salts are prepared by dissolving th® gwitterion in the appropriate amount of acid, causing crystallisation by adding acetone and isolating th® crystals» Physical admixtures of the ©alts with certain bases in proportions to give a pH ranging from about 3„S to 7 on dilution with water provide injectable compositions on dilution,.
Figure 1 is a graphical representation-of the infra red absorption spectrum of crystalline 7-(a-<2-aminothiazol-4-ylS-®" (2Ji -methoxyiminoacetamido] -3-1 (1-methyl-l-pyrrolidinioi snethylJ-3cephem-4-carboxylate sulfate salt measured on a KBr dilutionthereof» Figure 2 is a graphical representation of the infra red absorption spectrum ox the crystalline sesquiphosphate salt of 7"(a-(2-arainothiazol-4-yl)-x-(Z)-methoxyiminoacetamidol 3- [ (1-methyl-l-pyrrelidinio) -methyl3 -3-cephem-4-earboxylate measured on a KBr dilution thereof.
Figure 3 is a graphical representation of the infra red absorption spectrum of the crystalline diphosphate salt of 7-[σ~(2-aminothiazol-4-yl)-x-(Z)-methoxyiminoacetamido] -3-[ (1-methyl-l-pyrrolidinio)-methyl3-3-cephem-4-earboxylate measured on a KBr dilution thereof.
This invention is directed to temperature stable semisynthetic cephalosporin salt® whose preparation fess not been described in the literature, to the preparation ©ί such salts, and to admixtures containing these salt®. v Aburaki et al. U.S. Patent Uo. 4,406,399 discloses 7(a- (2-aminothiasol-4-yl)-O-(ti-nethoixy iminoacetamido)-3i (l-methyl-I-pyrrolidinio) -methy13-3-eephem-4-carboxylate in the zwitterion form and mentions corresponding acid addition salts (which are present in the rwitterion form in injectable composi10 tions) and shows that the switterion form has broader spectrum activity than ceftazidime and cefotaxime.
However, the aforementioned Aburaki et al. cephalosporins ar© stable only for a few hours as injectable compositions and the zwitterion form even as a dry powder is unstable at room temperature and loses 30% or more of its activity on storage st elevated temperatures (e.g. 45 deg. C and above) for even on© week and therefore requires special insulated packaging and/or refrigeration and is at a packaging and storage disadvantage compared to ceftazidime and cefotaxime.
While Aburaki et al. mentions acid addition salts, th© patent does not state how to sabs these or state which if any of these salts have good stability in dry powder form. Kessler et ©1., Comparison of a Sew Cephalosporin, BK¥ 23142, with Other Broad-Spectrum β-lactam Antibiotics, Antimicrobial Agents and Chemotherapy, Vol. 27, So. 2, pp. 207-216, February 1985 mentions the sulfate salt, but does not disclose how to prepare such or that this salt has room temperature stability and good elevated temperature stability ia dry powder form.
It has been discovered herein that certain crystalline acid addition salts ©f 7- These acid addition salts are the crystalline salts of 7" Is- <2-aminothiazol-4-yl)-a- iZbrnethoxyiminoacetamidoj-s[ (l-methyl-l-pyrrolidinio) -methyl 3 ",3"C®phem"4"CaAboxyl ate selected from the sulfuric, di-nitric, mono-hydrochloric, and di-hydrochloric acid addition salts and orthophosphoric acid addition salts <1.5-2 moles of orthophosphoric acid per mole of salt, e.g. a range of from the sesqui- to the di-orthophosphoric acid salts I, or solvates thereof., The term crystalline is used, herein to mean at least some characterising arrangement of molecules. While the sulfuric, di-nitric, di-hy dr ©chloric and orthophosphor ic acid addition salts herein axe prepared in clearly crystalline fox® The acid addition salts herein when formed into aqueous injectable compositions provide the zwitterion in solution. The zwitterion has the structure The broad spectrum utility against various organisms of the gwitterion form, and thus ©£ aqueous compositions mad® up from the ©alts herein, is shewn hy the data in Aburaki et al. 9„§m 4,406,899.
Aqueous composition© made up from the acid addition ©alts herein simply hy th® addition of sterile water provide acidic solutions which provoke unacceptable irritation on intravenous administration to rabbit© and unacceptably painful sensation on intramuscular administration to rabbits. The sulfuric acid and di-nitrie acid addition salt© hav.
A preferred salt herein is the crystalline sulfuric acid addition salt. It is preferred because its low solubility in water (25 mg /ml 3 allows high recovery from aqueous medium on crystallisation.
The crystalline sulfuric acid addition salt is readily prepared by a process comprising the steps of (a) forming an aqueous admixture of (i> at least 1 molar equivalent of sulfuric acid and (iii gwitterion in an amount so as to be present in the admixture at a concentration greater 'than 25 mg/ml, (bi causing crystallisation of the sulfuric acid addition salt to occur, and (¢) isolating crystalline sulfuric acid addition salt.
The crystalline salts herein (hereinafter referred to simply •s the salts herein) have excellent stability at room temperature and have a potency loss (as determined by HPLC), of less than 1% ** on storage for a month at room temperature. These salts also feave excellent stability at elevated temperatures and have a potency loss (es determined by HPLC) of less than 15¾ on storage for a month at 45-56 deg. C.
The sulfuric acid addition salt is a preferred salt herein. It has a potency loss of less than 10% on storage for a month a 45-56 deg- C. Very importantly, it has a low solubility in water, i.e. about 25 mg/ml, and therefore is crystallized from water with minimized residual loss.
The di-nitric acid addition salt herein also has a low solubility in water, i.e. about SO mg/ml, and therefore also provides low residual loss on crystallization from water.
The mono-hydrochloric, di-hydr©chloric and sesaui- or di-orthophosphoric acid addition salts have water solubilities greater £han 200 mg/ml., and therefore are preferably crystallised from organic solvents, rather than from water, in order to obtain good yields.
We turn now to the preparation of the salts herein.
As previously indicated the sulfuric acid addition salt herein is prepared by a process comprising th® steps of (a) forming an aqueous admixture of at least one molar equivalent of sulfuric acid and (ii| switterion corresponding to said salt in ' an amount ®o as to be present in the admixture at a concentration ©f greater than 25 mg/ml, (b) causing crystallization to occur, ' and Preferably the zwitterion is used in step (a) in aa amount so bs to be present in the admixture at a concentration ranging fro® about 100 sg/al to 200 mg/ml, and step Step (a) is readily carried out either by adding solid zwitterion to sulfuric acid solution (e.g. IN 9^50*) with rapid stirring to form a solution. Alternatively step (a) can be carried by dissolving solid zwitterion in water and slowly adding sulfuric acid with stirring to form a solution.
Step in an amount so as to be present in the admixture in an amount less than 25 mg/ml, organic solvent, preferably acetone, must b© included in the crystallization medium to provide reasonable recovery. When acetone is used, it is appropriately used in amounts of 0.S to 20 volumes per volume of .'aqueous crystallization medium.
Step The method herein for forming the sulfuric acid addition salt result© in the purification of the gwitterion form because of the limited solubility ©f the sulfuric acid addition salt compared to the gwitterion form and can be used to purify gwitterion without isolating it as.a solid. 2£ it is desired to obtain substantially pure gwitterion (free-base) from the formed sulfuric acid addition salt, this can be carried out by dissolving the salt in water, adding Ba(OH)2-BB^Q in an amount of 90-100% of theory at a pH of less than 6.5 to precipitate 3aS04, filtering to remove the BaSO^ and recovering the filtrate containing the gwitterion dissolved therein and utilising it as a solution or isolating solid zwitterion (free-base) by lyophilizing it or by adding acetone to precipitate amorphous gwitterion followed by isolating solid gwitterion by vacuum filtration, washing e.g. with acetone, and vacuum drying. Alternatively, the sulfuric acid addition ©alt is converted to the free-base utilizing ion exchange resins, e.g. Dowex WGR (a weak base anion exchange resin) and Dowex XU-40090.Ol (a strong acid cation exchange resin) with subsequent lyophilization.
Turning now to the preparation of the crystalline di-nitric acid addition salt herein, this is obtained by admixing (i) at least two molar equivalents, of nitric acid and (ii) zwitterion corresponding to said salt ©o to be present in the admixture at a concentration greater than 200 mg/ml, and then inducing crystallisation' by seeding or rubbing with a glass rod, diluting with 2-propanol and cooling. The crystalline di-nitric acid addition salt is recovered e.g. by filtering, washing sequentially, e.g. with 2-propanol-H^O (504 v/v), 2-propanol, and ether, and then vacuum drying at 50 deg. C for 2 hours.
The mono-hydrochloric acid addition salt herein is prepared by dissolving zwitterion in approximately one molar (equivalent of hydr©chloric acid and causing crystallization by adding acetone with stirring and continuing to stir, followed by isolating crystal®, e.g. by vacuum filtration followed by washing with acetone and vacuum drying. Alternatively the aono-hydrochloric acid addition salt is formed from the di-hydrochloric acid addition salt by slurrying the di-hydrochloric acid addition salt in methylene chloride and adding 1 mole equivalent of triethylamine followed by slurrying to form the mono-hydrochloric acid addition salt which is isolated, e.g. by vacuum filtration, followed by washing with methylene chloride and vacuum drying.
The crystalline di-hydrochloric acid addition salt herein is prepared by dissolving zwitterion in at least two molar equivalents of hydrochloric acid, then causing crystallization by adding acetone, then isolating crystals e.g. by vacuum filtration, washing with acetone and vacuum drying.
Th© crystalline di-orthophosphorie acid addition salt herein is prepared by dissolving the zwitterion in at least 2 solar equivalents of phosphoric acid, causing crystallization by adding acetone, and isolating crystals by e.g. by vacuum filtration followed by washing first with acetone and then with ether and then vacuum drying. Th© crystalline sesqui-or thcphosphoric acid addition ©alt is formed by this same procedure except that about 2.5 molar equivalents of phosphoric acid is used.
The ©alts herein are formed into injectable compositions by diluting with sterile water and buffering to a pS of 3.5-7 to form an injectable concentration of 2 mg/ml up to 400 mg/ml of zwitterion. Suitable buffering agents include, for example, trisodium orthophosphate, ©odium bicarbonate, sodium citrate, N-methylglucamine, Χ.Ή) lysine and b<+) arginine. For intramuscular or intravenous administration to aa adult human, a totsi 1 dosage of from about 750 to about 3000 sag per day in divided doses is normally sufficient.
The salts herein are not desirably formed into injectable compositions simply by the addition of sterile water because the sulfuric and di-nitric acid addition salts ar© not sufficiently soluble to form compositions of normal concentration for adminis5 tretion and because th® salts herein when dissolved provide very low pH compositions (1.8-2.5) which provide painful sensation on ** injection. As indicated above, it has been found herein that «? these shortcomings are overcome by forming the salts herein into a physical, i.e. solid, admixture with pharmaceutically acceptable, normally solid non-toxic organic or inorganic bases in proportion© to provide a pH ranging from about 3.5 to 7, preferably from about 4 to 6, ©n dilution of the admixture with water to injectable concentration of 1 mg/ml up to 400 mg/ml of zwitterion, e.g. switterion activity of 250 mg/ml as 2.5 determined by HPLC assay.
The exact proportions of ingredients in th® physical admixture vary from lot to lot of the ©alt since th® purity of the salt varies from lot to lot. The proportions of ingredients are established for a particular lot by pretitrating in respect to a sample to obtain a ©elected pH within the aforementioned range.
The physical admixture is readily stored and shipped in solid form thereby taking advantage of the stability of the salts herein and is readily converted into an injectable composition simply by addition of water, e.g. by a nurse or doctor,just prior to us®.
The physical admixture is prepared by blending the salt and the base into a uniform blend, e.g. utilizing a standard blender in a dry atmosphere, and is then preferably filled into a vial or other container, all under aseptic conditions.
The base® for use in the admixture include, for example, ‘ trisodium orthophosphate, sodium bicarbonate, sodium citrate, tf-otethylglucamine, LC+J lysine and 1(-1-1 arginine. L<+) lysine •nd L'HS arginine are preferred sine© admixtures containing these are reconstituted to provide injectable compositions which on injection provide less pain in animals than composition© derived from admixture© containing other base©. The ΜΉ lysine is very preferably utilised in a proportion to provide · pH of 3.5-6 on dilution of the admixture with water to provide a composition with a zwitterion activity of 250 mg/ml (as determined by HPLC assayI.
The salts herein and substantially dry physical admixtures containing them can be stored without refrigeration or insulated packaging and still retain high potency,.
Xn several of the preparations herein the unstable zwitterion is used as the starting material. The preparation of this is described in Examples 1-3 of Aburaki et al. U.S. 4,406,899. Th© zwitterion is referred to in Aburaki et al. as 7- ί ¢2)-2-me thoxy imino-2- (2-aminothiazol-4-yl)acetamido-3-i ¢1me thy 1-1 -py rrol idin ium) me thyl) -3-c@phem- 4-carboxyl ate.
The invention is illustrated in the following working examples.
Example I Preparation_of the Sulfuric Acid Addition Salt 1.5 g of switterion are added slowly to 10 ml of rapidly stirred IN ¢1.59 molar equivalents) at 20-26 deg. C. A solution is obtained. Crystallisation is then induced by seeding with crystalline sulfuric acid addition salt and the crystalline mass is slurried for 0.5 hours. Th© crystals are then separated by vacuum filtration, washed with 3 ml of 50% acetone/water (V/V) and with two 5 al portions of acetone, and vacuum 3 A typical! yield Is 2.3 g of sulfuric acid addition salt. Analysis: Calculated for "®2SO4s *C39*H» 4.53; »», 24.52; %S, 16.62; tB^O, none. Founds 1C, 3Θ.92; 1H( 4.57? IN, 14.64; %S, 16.72; IS^O, 2.42.
Example II Preparation of the Sulfuric Acid Addition Salt 1.5 g of zwitterion are dissolved in 5 ml of water. 5 ml of IH HgS04 as-e slowly added to this solution with stirrlnq. Crystallization is then induced by seeding with crystalline acid addition salt and the crystalline mass is slurried for 0„5 hours. The crystals are then separated by vacuum filtration, washed with 3 »1 of 50% acetone/water (V/V) and with two 5 sal portions of acetone, and vacuum dried at 40-50 deg. C overnight.
A typical yield is 1.3 g of sulfuric acid addition salt.
Example III Preparation of the (HWO^)^ Acid Addition Salt 300 mg of zwitterion are dissolved in 2M nitric acid (0-5 al). The solution is rubbed with a glass rod, diluted with 2-propanol (0.4 sill and cooled. The crystalline title compound is collected and is sequentially washed with 0-4 ml of 2-propanol BQ (1:1), 2-propanol and then ether to afford 127 mgs of the <& dinitrate salt.
Analysis: Calculated for C, lISNO^s %C, 37.52; %H, 4.32; %N, 18.47; %S, 20.57. Founds %C, 36.92; %H, -4.10; %K, 18.08: IS, 10-67; (BjO content 0.90%). 4 Example SV Prepa,ration of the Monohydrochlorlde Acid Addition Salt g of zwitterion i® dissolved in 2.08 ml of IN SCI (1 molar equivalent) at 20-25 deg. C. Thirty ml of acetone are added with rapid stirring ewer a 15 minute period whereby crystals form. Stirring is continued for 1 hour. The crystals &xe isolated by vacuum filtration, washed with 10 ml of acetone and vacuum dried at 50 deg. C for 2 hours.
A typical yield is 0.9 g of crystalline monohydrochloride salt. Analysis; Calculated for C^B^N.OjSj.SCls SC, 41.37? %H, 4.75? IN, 35.2? %S, 11.63? %C1, 12.86. Founds %C, 39.32? %H, 4.88? 6N, 13.95? %S, 11.28? ICl, 12.44? SH^O, 4.5.
(Corrected for H,Os %C, 41.17? %N„ 14.61? %S, 11.82? %C1, 13.03).
Example V Preparation of the Dihydrochloride Acid Addition Salt and Preparation of the Monohydrochloride Acid ._*_Addition Salt From It__ 350 mg of zwitterion are dissolved in 2 ml of 1W-HC1. 10 ml of acetone are added to the resultant solution* with rapid stirring and over a 5 minute interval* whereby crystals form. Stirring is continued for 5 additional minutes. Then 10 additional ml of acetone are added and stirring is carried out for 0.5 hours. The crystals ar© removed by vacuum filtration, washed with two 5 al portions of acetone and vacuum «dried at 40-45 deg. C for 24 hours.
A typical yield is 300 mg of crystalline Sihydrochloride acid addition ©alt. Analysis Calculated for C19B24KS°^S22SCXs 4Ϊ’3Θ? <"75; *N' aS· 2'" 1S* **-62; BCl, 12.βζ *Found: 1C, 40.78; IH, 4.98; IN, 14.7; IS, 11.25; tBgO, 1.25» (Corrected for B2©s 1C, «1.1; IN, 14.88; IS, 11.39; ICI, 11.94). 1 g of dihydrochloride ©alt prepared as above is ©lurried ia ml of methylene chloride at 3()--25 deg. C in a sealed flask and 0.28 ml of triethylamine is added over a 15 minute interval. The crystalline mass is then slurried for 5 hours. The resultant mohohydrochlorid® crystals are then isolated by vacuum XO filtration, washed with two 5 ml portions of methylene chloride and vacuum dried at 50 deg. C for 2 hours. A typical yield is 800 mg.
Example VI Preparation of the Di-orthophosphoric it Acid Addition Salt g of zwitterion is dissolved in 3.4 ml of 144 mg/ml BgFOg (2.2 molar equivalents) at 15 deg. C. Th® resulting solution is suitably filtered to clarify it. 12 ml ot acetone are added to the clarified solution, with rapid stirrino and over a minute period a,whereby crystal© form. Stirring is continued for 10 minutes. Then 30 ml of acetone are added over a 10 minute period, and stirring is continued for an additional 15 minutes. The crystals are collected by vacuum filtration, washed with two 5 al portions of acetone ©nd two 5 ml portions of ether and dried under high vacuum for IS hours.
A typical yield for this type of preparation was 1.1 g of crystalline di-orthophosphoric acid addition salt. Analysis: Calculated for %C, 33.72; IH, 4.47; IN, 12.42» Found: 1C, 33^43? IH, 4.65; IN, 12.02; 1.82. 3Q (Corrected for fi^O: 1C, 34.0; IN, 12.2).
@ The Besgui-cs·thcphosphoric acid addition salt is formed as above except that 1.5 molar equivalents of Η,ΡΟ^ are used instead of 2.2 solar equivalents.
Example Vll Stabilities at Elevated Temperatures Elevated temperature stabilities were determined by storing the preparation© in dry containers at temperatures and for time periods as denoted below and potency losses or gains were determined by HPLC. A % potency gain is indicated by a plus sign in front of a figure. A less than 10% potency loss over a 2 to 4 week period at 45-5S d®g. C is usually indicative of less than 10% potency loss over a 2-3 year period at room temperature.
PERCENT .LOSS 45 Deg. C 56 Beg. C 3DD Beo. £ (Km k«) (SJisekK) (Bays 1 Forsa 1 3 4 5 1 a 4 3 xvl «lesion SIT 51 71 - 57 - - 300 SgSO ft* H 3.4 to «5 3 *5 1.4 5 to *3 0 to *£ 0-10 eaaseo3»a s»n ΙΒ.Θ 3.4 D.S8 10.3 3.7 2.4 - MCI Salt 4.8 2.3 e.o 6.4 6.4 - - - «ecu, s*:u β - 7.4 - 0 7.2 15.4 (a3P04»2 Salt 0 3.0 3.0 - 2.7 5.0 » - Example VIII Testing of Physical Admixtures Physical admixtures were made up of crystalline sulfuric acid salt ’4iii (a) trisodii^n orthophosphate „ (b) sodium bicarbonate(c) L(+) lysine, and (d) 1.(-=-) arginine. The bases were added in proportions to provide pH’s on dilution of the admixture with water to a zwitterion activity of 250 mg/ml (as determined by HPLC assay) as follows: trisodium orthophosphate (to provide a pH of 6.0); sodium bicarbonate (to provide a pH of S.O); L(->) lysine (to provide a pH of S.O); LG.) arginine (to provide a pH ©f 6.0). Injectable compositions were made up by reconstituting with sterile water to a zwitterion activity of 250 mg/ml as determined by BPIC essay. There were no solubility problems. Injections ¢100 sg/kg) were carried out intramuscularly cm rabbits with pain within acceptable thresholds. The least pain, was with the arginine containing composition.
Similar result© of good solubility and acceptable pain on intramuscular injection are obtained on use of the other salts herein in th© physical admixtures with th© above bases.
Figure 1 is the infra red absorption spectrum of the crystalline sulfate salt prepared as described in Examples X or II pelletised in the crystalline form with potassium bromide.
The X-ray powder diffraction pattern of the crystalline £5 sulfate salt of ?- Is-(2-aminothia$ol"4"yll-iS-(z) -methoxyiminoacetamido)-3-1 (l-methyl-l-pyrrolidinio) -methyl]-3-c®ph©m-4carboxylate prepared as described in Example ϊ or II was determined with a stigaku Powder Diffractometer using a copper target X-ray tube, a nickel filter, and th® sample contained in a glass dish. The scan rate was 2 deg./min. over the rang® from 5 deg. to 40 deg. and a chart was mechanically recorded to show the angles of maximum diffraction. Frost this the (d) spacings and relative intensities (1/2°) were calculated. They ar® listed below. ο ο d spacinq (A! Ϊ/Ι 9.20 200 V 6.30 50 5.50 28 5 5.09 22 4.50 38 4.41 44 4.19 63 3.78 38 20 3.64 44 a ϊο O& & of •*>IL die qgp 3.31 an bW t£> 3., 15 47 EXAMPLE IX PREPARATION OF THE SESOUIPHOSPHATE SALT The zwitterion, 0.70 g., is dissolved with rapid stirring in from 2.2 to 2.4 ml. of 85% phosphoric acid (2.1 to 2.2 molar equivalents) which has been diluted 1:10 (v/v) with water. The solution is clarified by filtration through a 0.22-0.45 micron pore-size membrane filter. From 5 to 7 parts by volume (15-20 ml) of methanol is added to the filtrate with rapid stirring during a 30 to 60 min. period. Crystals form during this operation, and rapid stirring is continued for 1.5 to 2 hours. The crystalline product is recovered by vacuum filtration. The product is washed on the filter first with 6 to 8 ml of 1:1 (v/v) methanol:acetone taking care to maintain a tightly packed filter cake, and then with acetone. The product is dried in vacuo at 50° C for 2 hours; typical yield 0.7 to 0.75 g.
Infrared Interpretation (See Figure 2) (IR, KBr pellet) Peak Position (cm~b Functional Group 2800-3400 1780 NH,NH3’,carboacyl OH β-lactam C=O 1680 Carboxyl C=O 1660 Amide C=O 1630 C=N,C=C 1550 Amide OH 980,1040 Behavior On Heating An exotherm is shown at 171.8°C in the differential scanning calorimeter tracing.
X-Ray Diffraction Pattern The X-ray powder diffraction pattern of the foregoing sesquiphosphate salt was measured with a Rigaku Powder Diffractometer in the same fashion as described above with respect to sulfate salt with the following results. d Ι/Γ 11.04 - 32 9.2 - 16 7.89 - 24 7.02 - 42 S.7 - 32 .5 - 26 4.64 - J00 4.456 - 53 4.3 - 58 3.88 - 26 3.75 - 89 3.56 - 21 3.35 - 2G 3.05 - 16 .) NMR Interpretation (~H 90 MHz NMR, D2O solution) 2® Chemical Shift (pom δ vs. TSP) Description Integral Assignment 2.0-2,4 Multiplet "3 14CH2, 14’CH2 3.04 Singlet 3 12CH3 3„ 3-3., 5 Multiplet 5 2CH, 13CH2, 13’CH2 3.94 Doublet 1 2CH 10 4.12 Singlet • 3 20CH3 4.12 Doublet 1 11CH 4.8 Doublet 1 11CH 5.42 Doublet 1 SCH 5.88 Doublet 1 7CH 15 7.21 Singlet 1 18CH S’ 3 Stability Time-Temperature % Loss 1 day; 100°C - 10.9 3 days; 70°C - 0 7 days; 70°C - . 1.9 1 week; 56°C - 1.0 2 weeks; 56’C - 1.4 4 weeks; 56’C - 0 1 week; 45’C - 0 2 weeks; 45°C - 1.4 4 weeks; 45°C - 0.7 8 weeks; 45’C - 1.6 1 month; 37’C - 2.5 Elemental Analysis (percent by weight) Found Dry Basis Theory (Sesauiphosphate) C 35.44 36.3 36.4 H •4 o S S 4.41 • 4.7 N 12.88 13.2 13.4 ί« O 2.29* - monohydrate = 2.8% 20 23.06 23.6 23.6 a vl Fischer Method

Claims (12)

1. » A temperature stable crystalline salt oi 7-()0-(2*minothiatol«4“yl)-e- 5 the sulfuric, di-nitric, mono-hydrochloric, and di“hydrochloric acid addition ©alts, and ortbophospboric acid addition ©alts containing 1.5-2 molar (equivalents of H,PO^, ora solvate thereof.
2. The crystalline ©alt of Claim 1 selected from -0 the sulfuric, mono-hydrochloric, di-hydrochloric and ortbopbospboric acid addition ©alts, or a solvate thereof.
3. A physical admixture of the ©alt of Claim 1 or 2 with a pharmaceutically acceptable non-toxic organic or inorganic base in proportions to provide a pH of about 3.5 to 7 on 15 dilution of the admixture with water to injectable concentration.
4. A physical admixture as recited in Claims wherein the salt and the base are present in proportions to provide a pS of about 4 to 6 on dilution of the admixture with water to injectable concentration. 20 5. A physical admixture as recited in Claim 3 or 4 wherein the base is b(4j lysine. 6. A physical admixture as recited in Claim 3 or 4 wherein the base is 1,(4) arginine. ( 7, A method for making the sulfuric acid addition salt of Claim 1 ©caprising the steps of ,*s (·> forming an Squsous admixture of (i) at least 1 molar equivalent of esslfuric acid aad (ii) zwitterion corresponding to said salt,
5. HO (c) isolating crystalline sulfuric acid addition salt.
6. The method as recited in Claim 7 wherein step (b) is carried out in an aqueous medium free of organic solvent.
7. 9. The method as recited in Claim 7 or 8 wherein the zwitterion is «used in step (a) in an amount so as to be present in the 15 admixture at a concentration less than S00 mg/ml. 2,0,, The method a© recited in ary one of elate 7, 8 cx 9 wherein the amount of switterion employed in step (a) is such that it is present in the admixture at a concentration greater than S3 mg/ml. 2 6 11. The method as recited in Claim 8 wherein the zwitterion is used in step (a) in an amount sc as to be present in the admixture at a concentration ranging from about 100 mg/ml to 200 mg/ml. 12. The crystalline sulfuric acid addition salt of Claim 1. 13. Crystalline 7- [ α - (2-aminothiazol -4-yl)-a-(Z)methoxyiminoacetamido]-3- [ (1-methyl-l-pyrrolidinio)- . methyl]-3-cephem-4-carboxylate sulfate salt having the following X-ray powder diffraction pattern: ccina (A) 1 /1 (t) 9.20 100 6.86 50 5.5 0 28 5.09 22 4.50 38 4.43 44 4.19 63 3.78 38 3.64 44 3.39 25 3.31 31 3.15 47 14. The crystalline orthophosphoric acid addition. salt of Claim 1, or a hydrate thereof. 15. Crystalline 7-(0.-( 2-asiinothiaaoI-4-yl) -a- (2)methoseyiminoacetamido )-3-(( 1-methyIpyrrolidinio) 5 methyl]-3-e@phem~4-earboxylate phosphate having the following X-ray powder diffraction pattern: d 1/1° 11.04 - 32 9.2 - 16
8. 10 7.89 - 24 702 - 42 6.7 - 32 5.5 - 26 4.64 - 100
9. 15 4.456 - 53 4.3 - 58 3.88 - 26 3.75 - 89 356 - 21 20 3.31 - 26 3.05 - 16 2 8
10. 16. A method for making © salt or solvate as claimed in claim 1, substantially as described in any of Examples I to VI or Example IX
11. 17. A salt or solvate as claimed in Claim 1, made by a method as claimed in any of Claims 7 to IX, or Claim IS.
12. 18. A composition comprising a salt or solvate as claimed in claim 17 in physical admixture with a pharmaceutically acceptable normally solid non-toxic organic or inorganic base.
IE207886A 1985-08-05 1986-08-01 Cephalosporin salts and injectable compositions IE59222B1 (en)

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US4883868A (en) * 1984-12-27 1989-11-28 Banyu Pharmaceutical Co., Ltd. 7-amino-3-(substituted isoindolinium)methyl-3-cephem derivatives
US4959469A (en) * 1984-12-27 1990-09-25 Banyu Pharmaceutical Company, Ltd. Crystalline cephalosporin compounds
US5244891A (en) * 1985-08-05 1993-09-14 Bristol-Myers Squibb Company Injectable compositions of cefepime dihydrochloride hydrate
US4910301A (en) * 1985-08-05 1990-03-20 Bristol-Myers Company Cefepime cephalosporin salts
US4808617A (en) * 1985-12-18 1989-02-28 Bristol-Myers Company Lyophilized or precipitated cephalosporin zwitterion and salt combination
EP0321562B1 (en) * 1987-06-25 1993-11-24 Banyu Pharmaceutical Co., Ltd. Crystalline cephalosporin compounds, process for their preparation, and intermediates for their preparation
JPH02101081A (en) * 1988-10-08 1990-04-12 Meiji Seika Kaisha Ltd Crystalline dihydrochloride of cephalosporin derivative and production thereof
CA2011116C (en) * 1989-03-06 1999-11-16 Murray A. Kaplan Lyophilized bmy-28142 dihydrochloride for parenteral use
CA2101571A1 (en) * 1992-09-08 1994-03-09 Elizabeth A. Garofalo Crystalline dihydrate of a cephalosporin dihydrate salt and injectable compositions thereof
EP0638573A1 (en) * 1993-08-10 1995-02-15 Lucky Ltd. Crystalline hydrates of cephalosporin and process for preparation thereof
EP1699804B1 (en) 2003-12-23 2008-02-06 Sandoz Gmbh Process for production of intermediates for use in cefalosporin synthesis
WO2008056221A2 (en) * 2006-11-06 2008-05-15 Orchid Chemicals & Pharmaceuticals Limited Crystalline sulfate salt of cephalosporin antibiotic
DE102012101680A1 (en) * 2012-02-29 2013-08-29 Aicuris Gmbh & Co. Kg Pharmaceutical preparation containing an antiviral dihydroquinazoline derivative

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