EP0153370A1 - Procede de preparation d'un systeme reactif sec unitaire contenant des produits chimiques heterogenes - Google Patents

Procede de preparation d'un systeme reactif sec unitaire contenant des produits chimiques heterogenes

Info

Publication number
EP0153370A1
EP0153370A1 EP19840903145 EP84903145A EP0153370A1 EP 0153370 A1 EP0153370 A1 EP 0153370A1 EP 19840903145 EP19840903145 EP 19840903145 EP 84903145 A EP84903145 A EP 84903145A EP 0153370 A1 EP0153370 A1 EP 0153370A1
Authority
EP
European Patent Office
Prior art keywords
solid
reagent system
reagents
lithium hydroxide
suspension
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19840903145
Other languages
German (de)
English (en)
Inventor
Robert L. Bodden
Richard B. Edwards
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
American Hospital Supply Corp
Original Assignee
American Hospital Supply Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Hospital Supply Corp filed Critical American Hospital Supply Corp
Publication of EP0153370A1 publication Critical patent/EP0153370A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine

Definitions

  • This invention is directed to a method, a composition of matter and a process. More specifically, the invention described hereinafter is directed to a method for the isolation of heterogeneous reagents by encapsulation of one or more of such reagents; a unitary solid reagent system prepared by the foregoing method; and a process for conducting an assay of biological fluid sample utilizing the foregoing reagent system.
  • Such interactions generally take the form of reduced shelf-life, and in extreme cases, in the rendering of one of the reagents ineffective for performance of a particular assay.
  • One such reagent system which is susceptible to this type of interaction is used in the determination of creatinine levels via a Jaffe reaction.
  • the Jaffe reaction requires the use of an alkali hydroxide and an alkali salt of picric acid in the performance of a creatinine assay.
  • These two reagents react with one another in solution and, thus, any solution formed from these materials is of. limited stability.
  • these reagents are isolated from one another until immediately prior to use and, even then, they are generally added to the sample sequentially.
  • the reagents notably the alkali hydroxide and picric acid or picrate salt
  • the reagents are initially isolated from one another by storage in separate containers. If there were a failure to take such preventative measures, it would result in the type of instability alluded to previously.
  • the alkali hydroxide and picric acid solutions are prepared as two separate liquids and these liquids stored in separate dispensing stations, thus requiring coordination of handling and precision on-site mixing. Once these two solutions are combined, their shelf life is limited, generally less than 14 days.
  • solid reagent systems are used, they require the solid be reconstituted as a liquid prior to performance of the assay.
  • the need to reconstitute the solids as liquids which must then be mixed in certain proportions introduces the potential for variability into the assay as mentioned above.
  • One possible alternative for elimination of human error and the variability which flows from such manipulation would be to have all reagents premeasured in a single granular or tabletted form.
  • the reagent could then be simply introduced in the reaction vessel, either prior to or subsequent to diluent, followed by dissolution and the addition of patient sample. Under certain conditions, the sample itself may serve as the diluent.
  • This system would eliminate or reduce the potential for variability in measurement and/or dispensing of reagents and, thus, increase the reliability and repeatability.
  • An automatic clinical analyzer of advan ⁇ ed design which is adapted to make use of a unitary dry reagent system is the PARAMAX Automated Clinical Analyzer developed by American Dade Division of American Hospital Supply Corporation.
  • the PARAMAX instrument system uses a tabletted reagent for the perfor ⁇ mance of clinical assays on patient's samples.
  • the specifications of tabletted reagents used in this system are that they must be stable up to six (6) months; capable of dispensation from a container of a type described in U.S. Patent application 284,980 (30-DA); and, be capable of rapid dissolution to form an optically clear solution.
  • the object of this invention is to remedy the above as well as related deficiencies in the prior art.
  • the above and related objects are achieved by providing a method for preparation of a unitary dry solid from a heterogeneous reagent system.
  • the method of this invention can be exemplified with the reagents which are used in the conduct of the creatinine assay via a Jaffe reaction.
  • a solid reagent system for a creatinine assay via a Jaffe reaction, an alkali salt of picric acid is isolated in a solid form.
  • lithium hydroxide is isolated in the solid form.
  • the phrase "solid reagent system” is inclusive of not only the reactive components of the solid but also tabletting aids (i.e., hulking agents, lubricants and the like).
  • Either one of the foregoing reagents is thereafter coated with an encapsulation effective amount of an agent which is otherwise compatible with the physical specifications of the solid (i.e., tablet) and the chemical constituent of the sample to be analyzed.
  • this agent can be any agent which is otherwise compatible with the physical specifications of the solid (
  • a WIP be another reagent of the reagent system which is inert relative to the encapsulated component; or a bulking agent used in the formation of the solid; or a combination of reagent and bulking agent.
  • the purpose and extent of such encapsulation is to effectively isolate the encapsulated material and thereby prevent its premature interaction with another of the reagents used in the conduct of the particular assay.
  • various reagents, including the encapsulated material are com ⁇ bined in the relative proportions into a unitary solid form.
  • the solid can take the form of free flowing material (i.e., powder or granule) or be compressed in a tablet of precise dimension and weight.
  • This invention describes a method for preparing a stabilized dry reagent system for use in bioassays requiring the isolation of one or more dry components to prevent their premature interaction.
  • a representative rea ⁇ gent system requiring isolation of their key chemical component from one another are the chemical constituents used in the Jaffe analytical protocol for creatinine determination.
  • the Jaffe analytical protocol involves the following reaction:
  • LiOH adduct a Janowsky-type adduct (a colored complex of picrate + creatinine)
  • the procedure involves provid ⁇ ing an alkali salt of picric acid in solid form as one of the reagents.
  • lithium hydroxide also in solid form, is twice-coated with an encapsulating agent.
  • This agent can preferably be any nonpolymeric binding agent compatible with a tabletted system, i.e., one which retains its optical 5 clarity in reconstituted solution, permits a rapid dissolution capability; and, which is non-reactive in the solid form with respect to the other components in the reaction system.
  • This initial encapsulation process can be followed, in one of the preferred embodiments of this invention, by further encapsulation sequence with a detergent/surfactant.
  • the above encapsulation procedure 0 effectively prevents the interaction of the lithium hydroxide with the picrate when placed in a unitary solid state. After encapsulation of the lithium hydroxide, the picrate salt and the coated lithium hydroxide can then be combined. Formulation of a unitary dry solid in the foregoing manner will maintain the stability of the reagent system by preventing their interaction, 5 while retaining the requisite optical clarity of the reconstituted solution.
  • this procedure is equally applicable to isolation of the picrate salt by coating it rather than the lithium hydroxide.
  • sucrose is used as a bulking agent for Q tabletting purposes.
  • Picric acid must be neutralized by forming the alkali salt so as to prevent the acid catalyzed hydrolysis of the sucrose to produce glucose and fructose.
  • the picric acid normally acts as a catalyst for this reaction, both in aqueous solution and the solid phase.
  • Glucose is a substance which interferes with the Jaffe reaction and the elimination of this is 5 accomplished by using the neutralized picrate.
  • the alkali salt ⁇ of picric acid can be formed by introducing lithium hydroxide to an aqueous solution of picric acid, followed by the addition of sucrose to the picrate solution and subsequent lyophilization of the resultant mixture.
  • the lyophilization step is preferably conducted in stainless steel or glass trays .since the picrate
  • OMP solution is reactive towards certain materials (i.e., reacts with aluminum to produce intensely red product).
  • Coated lithium hydroxide can be obtained by preparing a solution of lithium hydroxide in isopropanol and to the stirred solution is added an aqueous solution of sucrose. Adding sucrose dropwise, by fine spraying • throughout the bulk of the suspension, or any other metered controlled addition technique is acceptable so long as the even distribution of sucrose solution throughout the lithium hydroxide is accomplished. Because the sucrose is not soluble in isopropanol, it crystallizes out using the lithium hydroxide particles as nuclei around which to grow, hence the coating of lithium hydroxide. The resulting product is washed, .dried and sieved in preparation for a second layer of sucrose to be applied by the same procedure.
  • a spray-drying apparatus can be employed to effect the controlled addition of sucrose wherein the solid lithium hydroxide is suspended by air currents in a spray-drying chamber and an aqueous solution of the appropriate solute is sprayed into the chamber at a controlled rate and droplet size. This results in the condensation of the sucrose around the lithium hydroxide, and the product is followed by rapid drying.
  • the encapsulated lithium hydroxide can be added to warmed methanol and to the suspension which is formed is added dodecyl sodium sulfate (hereinafter "SDS"), followed by evaporation of the methanol leaving the product which is then dried and sieved.
  • SDS is an ionic detergent that reduces protein interference during the Jaffe reaction, and acts as a clarifying agent keeping the protein in solution. Furthermore, the SDS acts as a lubricant and mold-releasing agent reducing the amount of sticking of the mixture to the equipment used in the tabletting process.
  • the tablet can be formed from this free-flowing solid material prepared by the above manner, blending the lyophilized picrate and coated lithium hydroxide with sucrose or similar substance (as a bulking agent) in the proper relative proportions followed by a compression of the blend into wafers which are then granulated and tabletted.
  • g JRE OMPI This procedure can be adapted to any reagent system which contains two or more heterogeneous reagents which must be kept isolated from one another during storage.
  • An example of another such reagent system are the heterogeneous chemicals used to measure magnesium levels in blood serum.
  • Calmagite available from Eastman Chemicals, Tennessee, which has the generic name of 1-(1- hydroxy-4-methyl 2-phenylaza)-2-napthal-4-sulfonic acid
  • the alkaline reagent used is tribasic sodium phosphate.
  • This reagent is that it has the tendency to absorb water, which decreases the linearity of measurements observed and also decreases the reagent system stability.
  • the reagent system can be contained in a single unitary dry solid for use in an automatic chemical analyzer.
  • the procedure for manufacturing a single solid reagent involves three basic steps:
  • Lithium picrate is prepared as described in Example 1.
  • To prepare the coated lithium hydroxide suspend 65g of lithium hydroxide in 1000 ml of isopropanol, while stirring vigorously at a temperature of 40-50C.
  • prepare a mannitol solution by dissolving 26g mannitol in 45 ml of warmed water and adding dropwise to the suspension, while stirring. Collect the precipitated 5 product by vacuum filtration, wash with isopropanol and dry. Sieve this product through a 40 mesh stainless steel screen and continue with a second layer of mannitol in the same manner described above, using 86g mannitol- coated lithium hydroxide with a solution of 24g mannitol in 40 ml of water.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

Procédé de préparation d'un système réactif unitaire stable, sous forme solide, contenant des réactifs hétérogènes. Le système réactif isole efficacement des agents réactifs hétérogènes les uns des autres en encapsulant sélectivement un ou plusieurs de ces réactifs avant leur formation en tablette ou granule unitaire. Les systèmes réactifs solides préparés de cette façon permettent d'exécuter diverses analyses chimiques cliniques, dont l'analyse de créatinine par une réaction de Jaffe.
EP19840903145 1983-08-26 1984-08-13 Procede de preparation d'un systeme reactif sec unitaire contenant des produits chimiques heterogenes Withdrawn EP0153370A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52764083A 1983-08-26 1983-08-26
US527640 1983-08-26

Publications (1)

Publication Number Publication Date
EP0153370A1 true EP0153370A1 (fr) 1985-09-04

Family

ID=24102327

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19840903145 Withdrawn EP0153370A1 (fr) 1983-08-26 1984-08-13 Procede de preparation d'un systeme reactif sec unitaire contenant des produits chimiques heterogenes

Country Status (4)

Country Link
EP (1) EP0153370A1 (fr)
JP (1) JPS60502168A (fr)
CA (1) CA1229292A (fr)
WO (1) WO1985001107A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5086001A (en) * 1989-12-01 1992-02-04 Baxter International, Inc. Automated test method for evaluating the physical compatibility of intravenous drugs in solutions
US5464777A (en) * 1994-09-26 1995-11-07 Miles Inc. Dry reagent for creatinine assay

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA544029A (fr) * 1957-07-23 H. Reman Gerrit Matieres solides d'enduisage divisees finement
DE1648977A1 (de) * 1967-07-20 1970-08-13 Merck Anlagen Gmbh Farbreagenz zur Bestimmung von Kreatinin
US3705013A (en) * 1970-01-05 1972-12-05 Xerox Corp Analytical procedures and compositions therefor
US3988010A (en) * 1975-02-20 1976-10-26 Monsanto Company Apparatus for the continuous agglomeration of aqueous latices
US4279691A (en) * 1979-12-12 1981-07-21 Matsushita Electric Industrial Co. Method of making boron cantilever

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8501107A1 *

Also Published As

Publication number Publication date
CA1229292A (fr) 1987-11-17
WO1985001107A1 (fr) 1985-03-14
JPS60502168A (ja) 1985-12-12

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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Inventor name: EDWARDS, RICHARD, B.

Inventor name: BODDEN, ROBERT, L.