CA2021441A1 - Process for the manufacture of parenteral application formulations - Google Patents
Process for the manufacture of parenteral application formulationsInfo
- Publication number
- CA2021441A1 CA2021441A1 CA002021441A CA2021441A CA2021441A1 CA 2021441 A1 CA2021441 A1 CA 2021441A1 CA 002021441 A CA002021441 A CA 002021441A CA 2021441 A CA2021441 A CA 2021441A CA 2021441 A1 CA2021441 A1 CA 2021441A1
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- active substance
- process according
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- solvent
- salt
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
Abstract Parenterally administerable solutions of strongly acidic or strongly basic salts of pharmaceutically active substances are prepared by combining such a salt with a neutralizing solvent.
Description
2 0 2 1 ~
The preparation of parenterally admini6terable solution6 of pharmaceutically active sub6tances i6 frequently as60ciated with technical difficulties. Such difficulties occur, for example, when the solution6 which are prepared are not sufficiently stable to guarantee a lengthy storage, if necessary below normal room temperatures (precipitation of the active substance) or above normal room temperatures (decomposition of the active 6ubstance). Attempt6 have been made to circumvent such difficulties by preparing the 601ution6 in situ, i.e.
immediately prior to use. The dissolution rate of the active substance is, however, often unsatisfactory, especially when the concentration of the active substance in the desired solvent volumes is close to the saturation limit. The problem is even greater when the active substance to be dissolved is not lyophilizable and mu6t be present a6 a sterile powder. One remedy can be found in the case of ionizable active 6ub6tance6 by preparing a 6alt which is sufficiently soluble and which i6 stable in the dry 6tate. Salts of very weak bases or very weak acids with strong acid6 or, respectively, strong base6 give, 25 however, 6uch acidic (pH < 3) or, respectively, 6trongly - ~. . .r ba6ic solutions (pH > 9.5) that their parenteral u6e i6 -not pos6ible or i6 pos6ible only after neutralization to phy6iological pH value6. Thu6, for the preparation of ~ -parenteral 601ution6 of metronidazole, the hydrochloride 30 of which di6solve6 in water with a 6trong acidic reaction, - `~
a commercial preparation, two operations are required for the preparation of the finished 601ution. Firstly, the ;-~
hydrochloride i6 dis601ved in water, whereupon in a 6econd operation the aqueou6 solution obtained in neutralized to ~~~
a physiological pH value. This procedure i6 not only very . ., , -Grn/12.6.90 ' 202~4~1 laborious and susceptible to contamination, but also holds the danger of the neutralization of the strongly acidic solution being inadvertently omitted.
It ha~ now surprisingly been found that the preparation of physiologically compatible parenterally admini6terable solutions from such strongly acidic or ~-strongly basic 6alts of pharmaceutically active substance6 can be realized directly, i.e. in only one single step. In accordance with the invention there i8 provided a proces6 for the direct preparation of physiologically compatible -parenterally administerable solutions from ~trongly acidic or strongly ba6ic salts of pharmaceutically active substance6, which comprises bringing a sufficiently soluble salt of such an active substance into contact with a sufficient volume of a neutralizing solvent and, if necessary, bringing resulting and transiently--precipitating active substance base or active substance acid as the case may be into solution by slight shaking.
The term "strongly acidic or strongly basic salts of pharmaceutically active substances" used here is intended to denote salts of pharmaceutically active substances which have a pKs of < 4 (very weak bases) or, respectively, > 8-9 (very weak acids). The solutions of these salts have pH values of < 2.5 and, respectively, > 9.5, which are far removed from the physiologically acceptable pH range of 4 to 8. 5-Fluorocytosine and , metronidazole are exam21es of very weak bases. Flurazepam, levodopa, flunitrazepam, bromazepam and the like are further examples. 5-Fluorouracil, allobarbital, - ~-acetaminophen, butabarbital, hexobarbital, paracetamol, --~- -pentobarbital, phenobarbital, phenytoin and the like are examples of very weakly acidic active sub~tances.
-- 2021~1 .
All pharmaceutically usable bases come into consideration as bases for the neutralization of strongly acidic solutions. There are preferably used bafie6 with which, during the neutralization, an optimal iso--osmotizing effect is obtained, such a6 e.g. disodium monohydrogen phosphate, tristhyd~oxymethyl)-aminomethane, L-arginine or L-lysine, preferably in admixture with sodium hyd~ogen cacbonate, which liberates C02 in the neutcalization reaction and thereby substantially accelerates the proces~ for the dissolution of the active substance base or acid which may result and precipitate.
All pharmaceutically usable acids can come into consideration as acids for the neutralization of strongly basic solutions of such active substance salts. There are preferably used acids with which, during the neutraliza-tion, an optimal iso-osmotizing effect is obtained, such as e.g. citric acid, acetic acid, monosodium dihydrogen phosphate, lactic acid and the like. The sodium hydrogen ~--carbonate, which is preferably used for accele~ating the dissolution process, can be admixed with the active substance salt in this case.
",'' :~',':' The solutions obtainable in acco~dance with the ~-invention can also contain usual pharmaceutical adjuvants such as agents for isoosmotization or pH-adjustment, as well as buffers and/or stabilizers. The~e adjuvants can be admixed with the active substance salt or can be present dissolved in the solvent.
~ .
~; In a preferred embodiment the invention i8 concerned with the p~epacation of parenteral solutions of 5-fluoro-cyto~ine, whereby 5-fluorocytosine monohydrochloride is 3S used as the salt.
.
-~ 20214~
~. ~
The preparation of parenterally admini6terable solution6 of pharmaceutically active sub6tances i6 frequently as60ciated with technical difficulties. Such difficulties occur, for example, when the solution6 which are prepared are not sufficiently stable to guarantee a lengthy storage, if necessary below normal room temperatures (precipitation of the active substance) or above normal room temperatures (decomposition of the active 6ubstance). Attempt6 have been made to circumvent such difficulties by preparing the 601ution6 in situ, i.e.
immediately prior to use. The dissolution rate of the active substance is, however, often unsatisfactory, especially when the concentration of the active substance in the desired solvent volumes is close to the saturation limit. The problem is even greater when the active substance to be dissolved is not lyophilizable and mu6t be present a6 a sterile powder. One remedy can be found in the case of ionizable active 6ub6tance6 by preparing a 6alt which is sufficiently soluble and which i6 stable in the dry 6tate. Salts of very weak bases or very weak acids with strong acid6 or, respectively, strong base6 give, 25 however, 6uch acidic (pH < 3) or, respectively, 6trongly - ~. . .r ba6ic solutions (pH > 9.5) that their parenteral u6e i6 -not pos6ible or i6 pos6ible only after neutralization to phy6iological pH value6. Thu6, for the preparation of ~ -parenteral 601ution6 of metronidazole, the hydrochloride 30 of which di6solve6 in water with a 6trong acidic reaction, - `~
a commercial preparation, two operations are required for the preparation of the finished 601ution. Firstly, the ;-~
hydrochloride i6 dis601ved in water, whereupon in a 6econd operation the aqueou6 solution obtained in neutralized to ~~~
a physiological pH value. This procedure i6 not only very . ., , -Grn/12.6.90 ' 202~4~1 laborious and susceptible to contamination, but also holds the danger of the neutralization of the strongly acidic solution being inadvertently omitted.
It ha~ now surprisingly been found that the preparation of physiologically compatible parenterally admini6terable solutions from such strongly acidic or ~-strongly basic 6alts of pharmaceutically active substance6 can be realized directly, i.e. in only one single step. In accordance with the invention there i8 provided a proces6 for the direct preparation of physiologically compatible -parenterally administerable solutions from ~trongly acidic or strongly ba6ic salts of pharmaceutically active substance6, which comprises bringing a sufficiently soluble salt of such an active substance into contact with a sufficient volume of a neutralizing solvent and, if necessary, bringing resulting and transiently--precipitating active substance base or active substance acid as the case may be into solution by slight shaking.
The term "strongly acidic or strongly basic salts of pharmaceutically active substances" used here is intended to denote salts of pharmaceutically active substances which have a pKs of < 4 (very weak bases) or, respectively, > 8-9 (very weak acids). The solutions of these salts have pH values of < 2.5 and, respectively, > 9.5, which are far removed from the physiologically acceptable pH range of 4 to 8. 5-Fluorocytosine and , metronidazole are exam21es of very weak bases. Flurazepam, levodopa, flunitrazepam, bromazepam and the like are further examples. 5-Fluorouracil, allobarbital, - ~-acetaminophen, butabarbital, hexobarbital, paracetamol, --~- -pentobarbital, phenobarbital, phenytoin and the like are examples of very weakly acidic active sub~tances.
-- 2021~1 .
All pharmaceutically usable bases come into consideration as bases for the neutralization of strongly acidic solutions. There are preferably used bafie6 with which, during the neutralization, an optimal iso--osmotizing effect is obtained, such a6 e.g. disodium monohydrogen phosphate, tristhyd~oxymethyl)-aminomethane, L-arginine or L-lysine, preferably in admixture with sodium hyd~ogen cacbonate, which liberates C02 in the neutcalization reaction and thereby substantially accelerates the proces~ for the dissolution of the active substance base or acid which may result and precipitate.
All pharmaceutically usable acids can come into consideration as acids for the neutralization of strongly basic solutions of such active substance salts. There are preferably used acids with which, during the neutraliza-tion, an optimal iso-osmotizing effect is obtained, such as e.g. citric acid, acetic acid, monosodium dihydrogen phosphate, lactic acid and the like. The sodium hydrogen ~--carbonate, which is preferably used for accele~ating the dissolution process, can be admixed with the active substance salt in this case.
",'' :~',':' The solutions obtainable in acco~dance with the ~-invention can also contain usual pharmaceutical adjuvants such as agents for isoosmotization or pH-adjustment, as well as buffers and/or stabilizers. The~e adjuvants can be admixed with the active substance salt or can be present dissolved in the solvent.
~ .
~; In a preferred embodiment the invention i8 concerned with the p~epacation of parenteral solutions of 5-fluoro-cyto~ine, whereby 5-fluorocytosine monohydrochloride is 3S used as the salt.
.
-~ 20214~
~. ~
5-Fluorocyto6ine monohydrochloride ha6 hithe~to nowhere been de6cribed and i6 likewi~e an object of the invention. The compound can be produced as de6cribed below in more detail by adding ethanol to an aqueous olution of the 5-fluorocyto6ine 6alt prepared in ~itu with hyd~o-chloric acid.
The parenteral 601ution6 which can be prepared in a 6ingle 6tep in accordance with the invention are conveniently prepared immediately prior to u6e. The invention is therefore al60 concecned with a kit, i.e. an article con6i6ting of individual unit6, compri6ing: -a) a container in which i6 located a 6trongly acid or 6trongly basic 6alt of a phacmaceutically active 6ub6tance which i6 6ufficiently 60luble and which i6 ~ ~ -6table in the dry 6tate:
b) a containec in which i6 located a sufficient volume of a neutralizing 601vent which can di6601ve the -~
re6ulting active 6ub6tance ba6e or active 6ubstance acid; and ,..: ~ ., c) a connecting piece which i6 6uitable for tran~ferring the active 6ub6tance 6alt into the neutralizing -;
601vent.
For 6uch an article thece can be used e.g. the infu6ion 6y6tem which i6 commercialized under the name ~ADD-Vantage~ (Abbot Labcratoties, North Chicago, Ill.
USA). -. .-The invention i6 illu6trated by the following Example6.
~ .
~: ' .
2 0 2 1 ~
ExamDle 1 5 A. Active 6ub6tance -~
5-Fluorocyto6ine monohydrochloride 3.21 g The active 6ubstance i6 introduced into a 20 ml gla vial which i8 clo6ed with a rubber 6topper.
B. Solvent -~ ; ~
Sodium hydrogen carbonate 1.375 g ~ ~ ;
Disodium monohydrogen pho6phate dodecahydrate 3.275 g HCl lN ad pH 8.0 q.6.
Water for injection q.~. ad 250.0 ml , .''.,',.'',',"''',. ~
The 601vent i6 filled under a vacuum into a 500 ml infu6ion bag, e.g. an infu~ion bag of the ADD-Vantage ~ -infu6ion 6y6tem.
For the preparation of the fini6hed infu6ion 601ution.
the active 6ub6tance 6alt i6 tran6fecred into the ;~
neutralizing 601vent in which the 5-fluorocyto6ine base which re6ults therein can be di6601ved to give a clear 601ution in les6 than 1 minute by 61ight 6haking. The ~olution obtained contain6 2.5 g of 5-fluorocyto6ine in 250 ml and ha6 a pH value of about 5.9-6Ø The non--neutralized 601ution of 5-fluorocytosine monohydro-chloride would have a pH value of about 1.5.
The complete dis601ution of micronized 5-fluoro-cyto6ine base in 250 ml of a commercial infusion solution wou~ld require a vigorou~ shaking for considerably more than 8 minute6, which obviou61y doe6 not come into consideration for practical use.
~: ~
.
2Q2~ ~41 ExamPle 2 ~.
A. Active 6ubstance Mi~onidazole hydrochloride 590.6 mg ~-tcorr. to 500 mg of misonidazole) ;~
B. Solvent Sodium hydrogen carbonate 0.55 g Disodium monohydrogen phosphate dodecahydrate 1.31 g HCl lN ad pH 7.5 q.s.
Water for injection q.s. ad 100.0 ml The solvent iB filled under a vacuum into a commercial -PVC infu~ion bag.
For the preparation of the finished infusion 601ution, the misonidazole hydrochloride is fir~tly suspended in a portion of the solvent with the aid of a suitable ;-connecting piece (e.g. a so-called transfer needle). The suspension obtained is then introduced into the infusion bag where finally the resulting misonidazole dissolves.
The pH value of the solution, which contain~ 100 mg of ~ -misonidazole in 100 ml, amounts to about 6.9. The non- `
-neutralized ~olution would have a pH value of ~ 2.
ExamDle 3 A. Active sub~tance Flurazepam dihydrochloride 17.B2 mg (corresponding to 15 mg of flurazepam) The active substance 6alt is introduced into a 10 ml glas6 vial which is closed with a rubber stopper.
:'.. '::'`.
2~21~
B. Solvent L-Arginine 6.5 mg Sodium chloride 85.0 mg Water for injection q.6. ad 10.0 ml The solvent i6 filled into a sterilized 10 ml PE vial. `~
,~,.",:",~,~"......
For the preparation of the finished injection ~ -10 solution, the partially neutralizing solvent is ~;
transferred with aid of a transfer needle into the active substance vial where the flurazepam is dissolved in the form of the resulting monohydrochloride by slight shaking.
The pH value of the solution obtained, which contains 15 mg of flurazepam in the form of the monohydrochloride in 10 ml, amounts to 7.4. The non-neutralized solution of the corresponding dihydrochloride would have a pH value of about 2.4.
ExamDle 4 :
A. Active substance ~`
5-Fluorouracil 250.0 mg NaOH lN 1.923 ml ; ` `
Water for injection q.s. ad 5.0 ml This sodium salt solution prepared in situ is filled into a 20 ml glass vial and lyophilized as usual.
B. Solvent Citric acid monohydrate 40.0 mg Water for injection 5.0 ml The solvent is filled into a sterilized 10 ml PE vial.
',' ' ' ~
--` 202~
For the preparation of the finished injection solution, the solvent is transferred with the aid of a transfer needle into the active 6ub6tance vial where the 5-fluorouracil which results to some extent i~ di6601ved by slight 6haking.
The pH value of the solution obtained, which contains 10 250 mg of 5-fluorouracil tonly to some extent in the form ~ t~
of the sodium salt), amounts to 8.4. The non-neutralized solution would have a pH value of more than 10. ~ ~
ExamPle 5 ~ ! '~ ' '. . -The 5-fluorocytosine monohydrochloride can be prepared as follows:
200 g of 5-fluorocytosine are dis601ved in 720 ml of 25% hydrochloric acid at 70C. Subseguently, 8 1 of ethanol are added dropwise to the 601ution while cooling ;~
in an ice bath and stirring. Theceafter, the crystallizing mixture i5 stirred at 5C for a further hour. The crystal~
are filtered off under suction, washed with ethanol and dried at 80C.
; ' ', ' " '' ,,., '"..'.:"' ~ ~
The parenteral 601ution6 which can be prepared in a 6ingle 6tep in accordance with the invention are conveniently prepared immediately prior to u6e. The invention is therefore al60 concecned with a kit, i.e. an article con6i6ting of individual unit6, compri6ing: -a) a container in which i6 located a 6trongly acid or 6trongly basic 6alt of a phacmaceutically active 6ub6tance which i6 6ufficiently 60luble and which i6 ~ ~ -6table in the dry 6tate:
b) a containec in which i6 located a sufficient volume of a neutralizing 601vent which can di6601ve the -~
re6ulting active 6ub6tance ba6e or active 6ubstance acid; and ,..: ~ ., c) a connecting piece which i6 6uitable for tran~ferring the active 6ub6tance 6alt into the neutralizing -;
601vent.
For 6uch an article thece can be used e.g. the infu6ion 6y6tem which i6 commercialized under the name ~ADD-Vantage~ (Abbot Labcratoties, North Chicago, Ill.
USA). -. .-The invention i6 illu6trated by the following Example6.
~ .
~: ' .
2 0 2 1 ~
ExamDle 1 5 A. Active 6ub6tance -~
5-Fluorocyto6ine monohydrochloride 3.21 g The active 6ubstance i6 introduced into a 20 ml gla vial which i8 clo6ed with a rubber 6topper.
B. Solvent -~ ; ~
Sodium hydrogen carbonate 1.375 g ~ ~ ;
Disodium monohydrogen pho6phate dodecahydrate 3.275 g HCl lN ad pH 8.0 q.6.
Water for injection q.~. ad 250.0 ml , .''.,',.'',',"''',. ~
The 601vent i6 filled under a vacuum into a 500 ml infu6ion bag, e.g. an infu~ion bag of the ADD-Vantage ~ -infu6ion 6y6tem.
For the preparation of the fini6hed infu6ion 601ution.
the active 6ub6tance 6alt i6 tran6fecred into the ;~
neutralizing 601vent in which the 5-fluorocyto6ine base which re6ults therein can be di6601ved to give a clear 601ution in les6 than 1 minute by 61ight 6haking. The ~olution obtained contain6 2.5 g of 5-fluorocyto6ine in 250 ml and ha6 a pH value of about 5.9-6Ø The non--neutralized 601ution of 5-fluorocytosine monohydro-chloride would have a pH value of about 1.5.
The complete dis601ution of micronized 5-fluoro-cyto6ine base in 250 ml of a commercial infusion solution wou~ld require a vigorou~ shaking for considerably more than 8 minute6, which obviou61y doe6 not come into consideration for practical use.
~: ~
.
2Q2~ ~41 ExamPle 2 ~.
A. Active 6ubstance Mi~onidazole hydrochloride 590.6 mg ~-tcorr. to 500 mg of misonidazole) ;~
B. Solvent Sodium hydrogen carbonate 0.55 g Disodium monohydrogen phosphate dodecahydrate 1.31 g HCl lN ad pH 7.5 q.s.
Water for injection q.s. ad 100.0 ml The solvent iB filled under a vacuum into a commercial -PVC infu~ion bag.
For the preparation of the finished infusion 601ution, the misonidazole hydrochloride is fir~tly suspended in a portion of the solvent with the aid of a suitable ;-connecting piece (e.g. a so-called transfer needle). The suspension obtained is then introduced into the infusion bag where finally the resulting misonidazole dissolves.
The pH value of the solution, which contain~ 100 mg of ~ -misonidazole in 100 ml, amounts to about 6.9. The non- `
-neutralized ~olution would have a pH value of ~ 2.
ExamDle 3 A. Active sub~tance Flurazepam dihydrochloride 17.B2 mg (corresponding to 15 mg of flurazepam) The active substance 6alt is introduced into a 10 ml glas6 vial which is closed with a rubber stopper.
:'.. '::'`.
2~21~
B. Solvent L-Arginine 6.5 mg Sodium chloride 85.0 mg Water for injection q.6. ad 10.0 ml The solvent i6 filled into a sterilized 10 ml PE vial. `~
,~,.",:",~,~"......
For the preparation of the finished injection ~ -10 solution, the partially neutralizing solvent is ~;
transferred with aid of a transfer needle into the active substance vial where the flurazepam is dissolved in the form of the resulting monohydrochloride by slight shaking.
The pH value of the solution obtained, which contains 15 mg of flurazepam in the form of the monohydrochloride in 10 ml, amounts to 7.4. The non-neutralized solution of the corresponding dihydrochloride would have a pH value of about 2.4.
ExamDle 4 :
A. Active substance ~`
5-Fluorouracil 250.0 mg NaOH lN 1.923 ml ; ` `
Water for injection q.s. ad 5.0 ml This sodium salt solution prepared in situ is filled into a 20 ml glass vial and lyophilized as usual.
B. Solvent Citric acid monohydrate 40.0 mg Water for injection 5.0 ml The solvent is filled into a sterilized 10 ml PE vial.
',' ' ' ~
--` 202~
For the preparation of the finished injection solution, the solvent is transferred with the aid of a transfer needle into the active 6ub6tance vial where the 5-fluorouracil which results to some extent i~ di6601ved by slight 6haking.
The pH value of the solution obtained, which contains 10 250 mg of 5-fluorouracil tonly to some extent in the form ~ t~
of the sodium salt), amounts to 8.4. The non-neutralized solution would have a pH value of more than 10. ~ ~
ExamPle 5 ~ ! '~ ' '. . -The 5-fluorocytosine monohydrochloride can be prepared as follows:
200 g of 5-fluorocytosine are dis601ved in 720 ml of 25% hydrochloric acid at 70C. Subseguently, 8 1 of ethanol are added dropwise to the 601ution while cooling ;~
in an ice bath and stirring. Theceafter, the crystallizing mixture i5 stirred at 5C for a further hour. The crystal~
are filtered off under suction, washed with ethanol and dried at 80C.
; ' ', ' " '' ,,., '"..'.:"' ~ ~
Claims (13)
1. A process for the preparation of physiologically compatible parenterally administerable solutions from strongly acidic or strongly basic salts of pharmaceu-tically active substances, which process comprises bringing a sufficiently soluble salt of such an active substance into contact with a sufficient volume of a neutralizing solvent and, if necessary, bringing resulting and transiently-precipitating active substance base or active substance acid as the case may be into solution by slight shaking.
2. A process according to claim 1, wherein the pharmaceutically active substances are very weak bases (pKs < 4) or very weak acids (pKs > 8-9).
3. A process according to claims 1-2, wherein the active substance is 5-fluorocytosine.
4. A process according to claims 1-3, wherein the active substance salt is 5-fluorocytosine monohydro-chloride.
5. A process according to claims 1-4, wherein the solvent for the neutralization of the strongly acidic or strongly basic salt contains one or more pharmaceutically usable bases or, respectively, acids.
6. A process according to claim 5, wherein the pharmaceutically usable base is disodium hydrogen phosphate, L-arginine or tris(hydroxymethyl)aminomethane.
7. A process according to claim 5, wherein the pharmaceutically usable acid is citric acid, acetic acid or sodium dihydrogen phosphate.
8. A process according to claims 1-7, wherein additional pharmaceutically usable adjuvants for isoosmotization, pH-adjustment, buffering and stabilizing the active substance, mixed with the active substance salt and/or dissolved in the solvent, are used.
9. A process according to claims 1-8, wherein sodium hydrogen carbonate is used as the adjuvant.
10. A kit for the preparation of parenterally administerable solutions, comprising:
a) a container in which is located a strongly acid or strongly basic salt of a pharmaceutically active substance which is sufficiently soluble and which is stable in the dry state;
b) a container in which is located a sufficient volume of a neutralizing solvent which can dissolve the resulting active substance base or active substance acid: and c) a connecting piece which is suitable for transferring the active substance salt into the neutralizing solvent.
a) a container in which is located a strongly acid or strongly basic salt of a pharmaceutically active substance which is sufficiently soluble and which is stable in the dry state;
b) a container in which is located a sufficient volume of a neutralizing solvent which can dissolve the resulting active substance base or active substance acid: and c) a connecting piece which is suitable for transferring the active substance salt into the neutralizing solvent.
11. 5-Fluorocytosine monohydrochloride.
12. 5-Fluorocytosine monohydrochloride for use in the preparation of parenteral solutions.
13. The invention as described hereinbefore, especially with reference to the Examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH301589 | 1989-08-18 | ||
| CH3015/89 | 1989-08-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2021441A1 true CA2021441A1 (en) | 1991-02-19 |
Family
ID=4246725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002021441A Abandoned CA2021441A1 (en) | 1989-08-18 | 1990-07-18 | Process for the manufacture of parenteral application formulations |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0413246A3 (en) |
| JP (1) | JPH0390019A (en) |
| AU (1) | AU6095090A (en) |
| CA (1) | CA2021441A1 (en) |
| IE (1) | IE902991A1 (en) |
| NZ (1) | NZ234872A (en) |
| ZA (1) | ZA906356B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002257602A (en) * | 2001-02-28 | 2002-09-11 | Yazaki Corp | Vehicle-mounted meter an dial used for the same |
| JP4700291B2 (en) * | 2003-04-28 | 2011-06-15 | 武田薬品工業株式会社 | Injectable composition |
| ES2686898T3 (en) * | 2003-04-28 | 2018-10-22 | Takeda Pharmaceutical Company Limited | Composition for injection |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2364414A1 (en) * | 1973-01-03 | 1974-07-11 | Compaselect Gmbh | ADDITIVE AND PROCESS FOR PREPARING SOLUTIONS FOR INFUSION |
| DE3538771A1 (en) * | 1985-10-31 | 1987-05-07 | Nattermann A & Cie | PARENTERAL APPLICABLE FORMS OF AMITRIPTYLINOXIDE |
| FR2598081B1 (en) * | 1986-04-30 | 1990-02-02 | Chauvin Blache Lab | PROCESS FOR THE PREPARATION OF AN AQUEOUS PHARMACEUTICAL SOLUTION OF AN ACTIVE INGREDIENT CONSTITUTED BY AN ORGANIC ACID |
-
1990
- 1990-07-18 CA CA002021441A patent/CA2021441A1/en not_active Abandoned
- 1990-08-08 EP EP19900115215 patent/EP0413246A3/en not_active Withdrawn
- 1990-08-10 ZA ZA906356A patent/ZA906356B/en unknown
- 1990-08-13 NZ NZ234872A patent/NZ234872A/en unknown
- 1990-08-13 AU AU60950/90A patent/AU6095090A/en not_active Abandoned
- 1990-08-15 JP JP2214448A patent/JPH0390019A/en active Pending
- 1990-08-17 IE IE299190A patent/IE902991A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0390019A (en) | 1991-04-16 |
| AU6095090A (en) | 1991-02-21 |
| EP0413246A2 (en) | 1991-02-20 |
| EP0413246A3 (en) | 1991-06-05 |
| NZ234872A (en) | 1992-08-26 |
| IE902991A1 (en) | 1991-02-27 |
| ZA906356B (en) | 1991-04-24 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Dead |