NO881413L - WATER SOLUBLE COMPLEX OF A POLY (VINYLPYRROLIDON) COPOLYMER AND D-TREO- (1,1'-DIHYDROXY-1-P-NITROPHENYLISOPROPYL) DICHLORACETAMIDE. - Google Patents
WATER SOLUBLE COMPLEX OF A POLY (VINYLPYRROLIDON) COPOLYMER AND D-TREO- (1,1'-DIHYDROXY-1-P-NITROPHENYLISOPROPYL) DICHLORACETAMIDE.Info
- Publication number
- NO881413L NO881413L NO881413A NO881413A NO881413L NO 881413 L NO881413 L NO 881413L NO 881413 A NO881413 A NO 881413A NO 881413 A NO881413 A NO 881413A NO 881413 L NO881413 L NO 881413L
- Authority
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- Norway
- Prior art keywords
- approx
- dihydroxy
- copolymer
- threo
- dichloroacetamide
- Prior art date
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- WCGGWVOVFQNRRS-UHFFFAOYSA-N dichloroacetamide Chemical compound NC(=O)C(Cl)Cl WCGGWVOVFQNRRS-UHFFFAOYSA-N 0.000 title claims description 33
- 229920001577 copolymer Polymers 0.000 title claims description 22
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 title claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 12
- -1 alkyl methacrylates Chemical class 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000000178 monomer Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- OSSNTDFYBPYIEC-UHFFFAOYSA-N 1-ethenylimidazole Chemical compound C=CN1C=CN=C1 OSSNTDFYBPYIEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 4
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 230000000249 desinfective effect Effects 0.000 claims 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 229960005091 chloramphenicol Drugs 0.000 description 13
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XQBHAZDVLGNSOJ-UHFFFAOYSA-N 1-(4-ethenylphenyl)-n,n-dimethylmethanamine Chemical compound CN(C)CC1=CC=C(C=C)C=C1 XQBHAZDVLGNSOJ-UHFFFAOYSA-N 0.000 description 1
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 1
- GAVHQOUUSHBDAA-UHFFFAOYSA-N 3-butyl-1-ethenylaziridin-2-one Chemical compound CCCCC1N(C=C)C1=O GAVHQOUUSHBDAA-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Compositions Of Macromolecular Compounds (AREA)
Description
D-treo-(l,l' - dihydroksy-l-p-ni tr of enylisopropylisopropyl )-dikloracetamid er et velkjent antibakterielt middel som har bakteriocide egenskaper. Det er omfattende "benyttet for å bekjempe hudinfeksjoner og i antibiotiske oftalmologiske preparater og er markedført under betegnelsen kloramfenikol. Administrasjon av denne forbindelsen i oppløsning kompliseres imidlertid av dens ekstreme vannuoppløselighet. P.g.a. dens anvendelse på farmasøytiske områder er det viktig at intet oppløsningsmiddel som har toksiske eller andre skadelige bivirkninger benyttes for dens medisinske bruk. D-threo-(l,l'-dihydroxy-l-p-nitr of enylisopropylisopropyl)-dichloroacetamide is a well-known antibacterial agent that has bactericidal properties. It is widely "used to combat skin infections and in antibiotic ophthalmological preparations and is marketed under the name chloramphenicol. However, administration of this compound in solution is complicated by its extreme water insolubility. Due to its application in pharmaceutical areas, it is important that no solvent having toxic or other harmful side effects are used for its medicinal use.
Det er følgelig et formål med foreliggende oppfinnelse å tilveiebringe D-treo-(l,l'-dihydroksy-l-p-nitrofenyl-isopropyl)dikloracetamid i en sterkt vannoppløselig form som ikke har noen uheldige bivirkninger. It is therefore an object of the present invention to provide D-threo-(1,1'-dihydroxy-1-p-nitrophenyl-isopropyl)dichloroacetamide in a highly water-soluble form which has no adverse side effects.
Et annet formål med oppfinnelsen er å tilveiebringe en kom-mersielt gjennomførbar fremgangsmåte for fremstilling av D-treo-(l ,1 '-dihydroksy-l-p-nitrofenylisopropylisopropyl) - dikloracetamid i sterkt vannoppløselig form. Another object of the invention is to provide a commercially feasible method for the production of D-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropylisopropyl)-dichloroacetamide in highly water-soluble form.
Disse og andre formål ved oppfinnelsen vil fremgå<;>fra det nedenstående. These and other objects of the invention will appear <;>from the following.
Ifølge foreliggende oppfinnelse er det tilveiebragt et kompleksdannet, vannoppløselig produkt oppnådd fra omsetnin-gen mellom en N-vinyl-2-pyrrolidon-kopolymer eller N-vinyl-2-kmaprolaktam-kopolymer og D-treo-(1,1'-dihydroksy-l-p-ni trofenylisopropyl)dikloracetamid. Dette produktet er et virkelig kompleks som inneholder gjentagende enheter av den struktur som kan dannes gjennom hydrogenbinding som vist hvor R er CH2- eller —C2H4- og er fortrinnsvis —CH-. Det skal imidlertid forstås at den ovenfor angitte formel bare representerer en av de mulige hydrogenbundede strukturene som kan dannes i løpet av reaksjonen. Det er også mulig at kompleksdannelse finner sted ikke bare ved hydrogenbinding, men også ved hydrofob binding og/eller ved hjelp av Van der Waals krefter i større eller mindre grad. According to the present invention, a complexed, water-soluble product obtained from the reaction between an N-vinyl-2-pyrrolidone copolymer or N-vinyl-2-maprolactam copolymer and D-threo-(1,1'-dihydroxy- 1-p-nitrophenylisopropyl)dichloroacetamide. This product is a real complex containing repeating units of the structure that can be formed through hydrogen bonding as shown where R is CH2- or —C2H4- and is preferably —CH-. However, it should be understood that the formula given above only represents one of the possible hydrogen-bonded structures that can be formed during the reaction. It is also possible that complex formation takes place not only by hydrogen bonding, but also by hydrophobic bonding and/or with the help of van der Waals forces to a greater or lesser extent.
Foreliggende oppfinnelses omfang skal ikke begrenses av teo-retiske betraktninger m.h.t. beskaffenheten av kompleks-bindingen siden det vil bli forstått at forbindelsens evne til å kompleksdannes og oppløseliggjøres av poly(vinyllaktam) The scope of the present invention shall not be limited by theoretical considerations regarding the nature of the complex bond since it will be understood that the ability of the compound to complex and solubilize poly(vinyl lactam)
i stor grad avhenger av forbindelsens kjemiske, fysikalske og morfologiske egenskaper, hydrofil-hydrofob-forholdet for dens strukturelle elementer, typen av og den relative posisjon til dens substituenter, voluminøsiteten til molekylet generelt og substituentene spesielt. Små forskjeller i noen av de ovenfor angitte faktorer kan i betydelig grad endre den opp-løseliggjørende evne. Mens forbindelsens evne til å kompleksdannes med poly(vinyllaktam) til en viss grad kan forutsies på grunnlag av dens substituenters kjemiske karak-ter, kan dens oppløselighet ikke forutsis på grunnlag'av dens strukturelle likheter alene. Isteden må en kombinasjon av ovennevnte faktorer som samvirker i forbindelsen som skal kompleksdannes, tas i betraktning. Hver forbindelse må så-ledes betraaktes og testes individuelt for en bestemmelse av dens oppløselighet. largely depends on the chemical, physical and morphological properties of the compound, the hydrophilic-hydrophobic ratio of its structural elements, the type and relative position of its substituents, the bulkiness of the molecule in general and the substituents in particular. Small differences in some of the above-mentioned factors can significantly change the solubilizing ability. While the ability of the compound to complex with poly(vinyl lactam) can be predicted to some extent on the basis of the chemical nature of its substituents, its solubility cannot be predicted on the basis of its structural similarities alone. Instead, a combination of the above-mentioned factors that interact in the compound to be complexed must be taken into account. Each compound must therefore be considered and tested individually for a determination of its solubility.
Det kompleksdannede produkt Ifølge oppfinnelsen kan også inneholde en mindre mengde av ikke-kompleksdannede laktam-steder. En faktor som påvirker antallet av ikke-kompleksdannede steder er mengden vinyllaktam som inneholdes i kopolymeren. For foreliggende oppfinnelses formål bør følgelig mengden av vinyllaktam i kopolymeren være mellom ca. The complexed product according to the invention may also contain a smaller amount of non-complexed lactam sites. One factor that affects the number of uncomplexed sites is the amount of vinyl lactam contained in the copolymer. For the purposes of the present invention, the amount of vinyl lactam in the copolymer should therefore be between approx.
50 og ca. 95 vekt-$, idet mellom ca. 70 og ca. 85 vekt-# er foretrukket. Kopolymerens antallsmidlere molekylvekt bør være større enn 1000 og fortrinnsvis mellom 10.000 og 500.000. Slike kopolymerer er i stand til å kompleksdanne den vannuoppløselige kloramfenikol til en høy grad slik at ca. 8$, opp til 30$ av de laktam-kompleksdannende steder, er omsatt med kloramfenikol gjennom kompleks-binding. 50 and approx. 95 weight-$, since between approx. 70 and approx. 85 weight # is preferred. The number average molecular weight of the copolymer should be greater than 1,000 and preferably between 10,000 and 500,000. Such copolymers are capable of complexing the water-insoluble chloramphenicol to a high degree so that approx. 8$, up to 30$ of the lactam-complexing sites, are reacted with chloramphenicol through complexation.
Vinyllaktam-kopolymeren ifølge oppfinnelsen inneholder N-vinyl-2-pyrrolidon-monomer eller N-vinyl-2-kaprolaktam-monomer og en komonomer valgt fra gruppen av et di-laverealkylaminolaverealkylakrylat eller -metakrylat, f.eks. di-metylaminoetylakrylat eller -metakrylat, en di-lavere-alkylaminolaverealkylstyren, f.eks. dimetylaminometylstyren eller N-vinylimidazol. De ovenfor angitte kopolymerer kan være ikke-kvaterniserte eller kvaterniserte som i tilfelle for GAFQUAT-734 (den 50$ kvaterniserte kopolymeren av 80$ N-vinyl-2-pyrrolidon og 20% dimetylaminoetylmetakrylat i alkoholoppløsning). The vinyl lactam copolymer according to the invention contains N-vinyl-2-pyrrolidone monomer or N-vinyl-2-caprolactam monomer and a comonomer selected from the group of a di-lower alkylaminolower alkyl acrylate or methacrylate, e.g. dimethylaminoethyl acrylate or methacrylate, a di-lower-alkylamino-lower-alkylstyrene, e.g. dimethylaminomethylstyrene or N-vinylimidazole. The above copolymers can be non-quaternized or quaternized as in the case of GAFQUAT-734 (the 50% quaternized copolymer of 80% N-vinyl-2-pyrrolidone and 20% dimethylaminoethyl methacrylate in alcohol solution).
De kompleksdannede enhetene i polymeren kan forekomme i blokkvis, vilkårlig eller vekselvis fordeling. I ethvert tilfelle Inneholder det resulterende produkt minst 5% kompleksdannede enheter, fortrinnsvis minst 9% kompleksdannede enheter, i produktet, slik at egeneksaper' som er forbundet med kloramfenikolforbindelsen bibeholdes. The complexed units in the polymer can occur in a blockwise, arbitrary or alternating distribution. In any case, the resulting product contains at least 5% complexed units, preferably at least 9% complexed units, in the product, so that intrinsic properties associated with the chloramphenicol compound are retained.
Kloramfenikol kompleksdannet med kopolymeren er mest foretrukket til stede i en mengde mellom ca. 8 og ca. 115 vekt-#. Kloramfenikol kompleksdannet på denne måten viser i det minste en 50-gangers økning i vannoppløselighet i forhold til den ikke-kompleksdannede forbindelsen. Chloramphenicol complexed with the copolymer is most preferably present in an amount between approx. 8 and approx. 115 weight #. Chloramphenicol complexed in this way shows at least a 50-fold increase in water solubility over the uncomplexed compound.
Den kompleksdannede tilstand til kloramfenikol har blitt fastslått ved forsøk som viser at ved gradvis fortynning fra 2% til 0,01$ i vann, så utskilles intet fritt kloramfenikol fra den vandige oppløsningen. Dersom legemiddelet ikke var kompleksdannet, så ville det utfelles fra den vandige opp-løsningen ved en konsentrasjon i dette området. At materia-let forblir i oppløsning ved relativt høy fortynning, betydelig over oppløselighetsgrensen for ikke-kompleksdannet kloramfenikol (mindre enn 1 mg i 1 ml HgO ved romtemperatur), er virkelig uventet. The complexed state of chloramphenicol has been established by experiments which show that on gradual dilution from 2% to 0.01$ in water, no free chloramphenicol is separated from the aqueous solution. If the drug was not complexed, it would precipitate from the aqueous solution at a concentration in this range. That the material remains in solution at relatively high dilution, significantly above the solubility limit of uncomplexed chloramphenicol (less than 1 mg in 1 ml of HgO at room temperature), is truly unexpected.
Mens kompleksene ifølge oppfinnelsen er stabile under normale betingelser, utsettes de for in vivo hydrolytiske krefter og andre fysikalske kjemiske effekter som leder til langsom dissosiasjon. Disse kompleksene har derfor virke som sys-temer med langsom frigjøring egnet for langvarig utlevering av legemiddeldelen i komplekset ved medisinske og veterinær-anvendelser. While the complexes according to the invention are stable under normal conditions, they are exposed to in vivo hydrolytic forces and other physicochemical effects which lead to slow dissociation. These complexes therefore act as slow-release systems suitable for long-term delivery of the medicinal part of the complex in medical and veterinary applications.
Kloramfenikolkomplekset ifølge oppfinnelsen fremstilles ved hjelp av en relativt enkel og direkte fremgangsmåte som innebærer separat oppløsning av kloramfenikol og N-vinyllaktam-kopolymeren i en C^-C5alkohol, fortrinnsvis etanol, for tilveiebringelse av oppløsninger som har en konsentrasjon av de respektive reaktanter mellom ca. 5 og ca. 25 vekt-#. Generelt foretrekkes oppløsninger med fra ca. 8 til ca. 115 vekt-# reaktive komponenter. Oppløsningene kombineres deretter i et vektforhold av kopolymer til syre mellom ca. 1:1 og ca. 10:1, fortrinnsvis i et forhold 4-7:1, og'blandes grundig under atmosfærisk trykk eller superatmosfærisk trykk opp til 446,1 KPa, ved en temperaur over 3°C, og under kokepunktet for alkoholoppløsningsmiddelet, hvilket innbefatter et område mellom ca. 4 og ca. 100°C, fortrinnsvis mellom ca. 10 og ca. 40°C. Blandingen omrøres under disse betingelser i en periode fra ca. 5 min. til ca. 3 timer, mer ofte mellom ca. 10 og ca. 30 min., for å bevirke den kompleksdannende reaksj on. The chloramphenicol complex according to the invention is produced using a relatively simple and direct method which involves separately dissolving chloramphenicol and the N-vinyl lactam copolymer in a C₁-C₅ alcohol, preferably ethanol, to provide solutions that have a concentration of the respective reactants between approx. 5 and approx. 25 weight #. In general, solutions with from approx. 8 to approx. 115 wt-# reactive components. The solutions are then combined in a weight ratio of copolymer to acid between approx. 1:1 and approx. 10:1, preferably in a ratio of 4-7:1, and is thoroughly mixed under atmospheric pressure or superatmospheric pressure up to 446.1 KPa, at a temperature above 3°C, and below the boiling point of the alcohol solvent, which includes a range between about. 4 and approx. 100°C, preferably between approx. 10 and approx. 40°C. The mixture is stirred under these conditions for a period from approx. 5 min. to approx. 3 hours, more often between approx. 10 and approx. 30 min., to effect the complex-forming reaction.
Etter fullføring av reaksjonen blir den resulterende blanding omfattende en flytende alkoholfase og en fast produktfase behandlet for å fjerne oppløsningsmiddel på en hvilken som helst konvensjonell måte, slik som rotasjonsfordampning eller frysetørking. Rotasjonsfordampning utføres i vakuum, f.eks. under et trykk fra ca. 2 til ca. 40 mm Hg, fortrinnsvis høyst 25 mm Hg. De resterende faste stoffer utvinnes og tørkes ved en temperatur mellom ca. 45 og ca. 100°C, fortrinnsvis mellom ca. 50 og ca. 63°C, i vakuum i en periode på 1-24 timer. After completion of the reaction, the resulting mixture comprising a liquid alcohol phase and a solid product phase is treated to remove solvent by any conventional means, such as rotary evaporation or freeze drying. Rotary evaporation is carried out in vacuum, e.g. under a pressure from approx. 2 to approx. 40 mm Hg, preferably no more than 25 mm Hg. The remaining solids are extracted and dried at a temperature between approx. 45 and approx. 100°C, preferably between approx. 50 and approx. 63°C, in vacuum for a period of 1-24 hours.
Det tørkede produktet oppnådd ved fremgangsmåten lar seg lett oppløse i vann, og vannoppløseligheten til kloramfenikolforbindelsen i denne kompleksdannede form er øket fra 0,01 til minst 5$ ved romtemperatur. The dried product obtained by the process is easily soluble in water, and the water solubility of the chloramphenicol compound in this complexed form is increased from 0.01 to at least 5% at room temperature.
Følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Ekempel 1 D-treo-(l,1'-dihydroksy-l-p-nitrofenylisopropyl )kloracetamido (10 g) ble oppløst i 90 g etanol og helt i en skylletrakt. GAFQUAT-736 (60 g) ble oppløst i 540 g etanol og helt i en separat skilletrakt. De to oppløsningene ble gradvis blandet i løpet av 15 min. ved romtemperatur og atmosfæretrykk under god omrøring i en 2000 ml kolbe. Blandingen ble omrørt i ytterligere 10 min., og kolben ble deretter overført til en rotasjonsfordamper under et trykk på ca. 20 mm Hg for å fjerne etanoloppløsningsmidddelet. Etter inndampning ble det resterende faste stoffet tørket i vakuum ved 60°C natten over. 24 g av det faste stoffet ble ovverført til en beholder med skrulokk hvor det ble blandet med 20 g destillert vann på en horisontal rysteanordning i 6 timer ved romtemperatur. Etter denne perioden var oppløsningsmiddelet fullstendig oppløst, og oppløseligheten til D-treo-(1,1'-dihydroksy-l-p-nitro-fenylisopropyl)dikloracetamid i vann ble funnet å være 16,69*. Example 1 D-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropyl)chloroacetamido (10 g) was dissolved in 90 g of ethanol and poured into a rinsing funnel. GAFQUAT-736 (60 g) was dissolved in 540 g of ethanol and poured into a separate separatory funnel. The two solutions were gradually mixed during 15 min. at room temperature and atmospheric pressure with good stirring in a 2000 ml flask. The mixture was stirred for a further 10 min., and the flask was then transferred to a rotary evaporator under a pressure of approx. 20 mm Hg to remove the ethanol solvent. After evaporation, the remaining solid was dried in vacuo at 60°C overnight. 24 g of the solid was transferred to a container with a screw cap where it was mixed with 20 g of distilled water on a horizontal shaker for 6 hours at room temperature. After this period the solvent was completely dissolved and the solubility of D-threo-(1,1'-dihydroxy-1-p-nitro-phenylisopropyl)dichloroacetamide in water was found to be 16.69*.
Som en kontroll ble 1 g D-treo-(1,1'-dihydroksy-l-p-nitro-fenylisopropyl)dikloracetamid anbragt i en beholder med skrulokk sammen med 99 g destillert vann og agitert i en horisontal rysteanordning i 24 timer ved romtemperatur. Opp-løseligheten til det ikke-kompleksdannede D-treo-(1,1'-dihydroksy-l-p-nitrofenylisopropyl)dikloracetamid ble funnet å være 2,5 mg i 1 ml vann. As a control, 1 g of D-threo-(1,1'-dihydroxy-1-p-nitro-phenylisopropyl)dichloroacetamide was placed in a screw cap container together with 99 g of distilled water and agitated in a horizontal shaker for 24 hours at room temperature. The solubility of the uncomplexed D-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropyl)dichloroacetamide was found to be 2.5 mg in 1 ml of water.
Eksempel 2 Example 2
Eksempel 1 ble gjentatt med unntagelse for at poly(N-vinyl-2-pyrrolidon)homopolymer ble benyttet istedenfor GAFQUAT-734 og forholdet for polymeren til D-treo-(1,1'-dihydroksy-l-p-nitrofenylisopropylisopropyl)dikloracetamid var 5:1. Den resulterende kompleksdannede forbindelse ble funnet å være bare 3,7$ oppløselig i vann. Example 1 was repeated with the exception that poly(N-vinyl-2-pyrrolidone) homopolymer was used instead of GAFQUAT-734 and the ratio of the polymer to D-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropylisopropyl)dichloroacetamide was 5: 1. The resulting complexed compound was found to be only 3.7% soluble in water.
Eksempel 1 representerer en foretrukken utførelse av foreliggende oppfinnelse, men mange variasjoner og modifika-sjoner av de kompleksdannede produkter vil imidlertid fremgå fra det ovenstående. F.eks. kan andre alkoholoppløsnings-midler benyttes, samt de andre ovennevnte poly(N-vinyl-pyrrolidon)- eller poly(N-vinylkaprolaktam-kopolymerene for tilveiebringelse av komplekser hvor kloramfenikolforblndelsen viser betydelig forøket vannoppløselighet. Example 1 represents a preferred embodiment of the present invention, but many variations and modifications of the complex-formed products will however be apparent from the above. E.g. other alcohol solvents can be used, as well as the other above-mentioned poly(N-vinyl-pyrrolidone) or poly(N-vinylcaprolactam) copolymers for the preparation of complexes where the chloramphenicol mixture shows significantly increased water solubility.
Claims (15)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/902,535 US4666992A (en) | 1986-09-02 | 1986-09-02 | Water soluble complex of a poly(vinylpyrrolidone) copolymer and D-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropyl) dichloroacetamide |
PCT/US1987/001819 WO1988001627A1 (en) | 1986-09-02 | 1987-07-30 | Water soluble complex of a poly(vinylpyrrolidone) copolymer and d-threo-(1,1'-dihydroxy-1-p-nitrophenylisopropyl) dichloroacetamide |
Publications (2)
Publication Number | Publication Date |
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NO881413L true NO881413L (en) | 1988-03-29 |
NO881413D0 NO881413D0 (en) | 1988-03-29 |
Family
ID=26776057
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO881413A NO881413D0 (en) | 1986-09-02 | 1988-03-29 | WATER SOLUBLE COMPLEX OF A POLY (VINYL-PYRROLIDON) COPOLYMER AND D-TREO- (1,1'-DIHYDROXY-1-P-NITROPHENYLISOPROPYL) DICHLORACETAMIDE. |
Country Status (1)
Country | Link |
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NO (1) | NO881413D0 (en) |
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1988
- 1988-03-29 NO NO881413A patent/NO881413D0/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO881413D0 (en) | 1988-03-29 |
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