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
  • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
  • G01N33/521—Single-layer analytical elements
  • G01N33/523—Single-layer analytical elements the element being adapted for a specific analyte
• • 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
  • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors

Definitions

• This invention relates generally to a method and means for qualitatively and quantitatively detect ⁇ ing the presence of certain drugs of abuse, namely barbiturates, amphetamines and morphine-like compounds as a group as well as individual narcotics, specifical- ly heroin, morphine, cocaine, dilaudxd and codeine in physiological fluids.
• This invention more specifically relates to a combination of special, unique formulations of shemicals and special carrier matrix, test paper or dipsticks, for the qualitative and/or quantitative analysis of body fluids such as whole blood, serum, urine or saliva for the presence of drug abuse compound residues by use of said test matrix, paper or dipsticks.
• the chemical formulations and matrix used in such test strips are unique and the chemical formulations lie within very narrow limits of concentrations of chemical compounds. Further, the resulting products do not require ion-exchange resins or color intensifiers for reactivities 1,000 to 10,000 times more sensitive than the reactivities of the formulations utilized in thin layer chromatography.
• OMPI OMPI
• methadone, morphine-like drugs and tranquilizers from caffeine and nicotine, alkaloids which are very commonly found in addicts as well as the general population.
• the intensifying agent intensifies all the alkaloid staining reactions equally well. Although these formulations are useful for clinical laboratory purposes, they fail to offer the methadone and rehabilitation centers a simple and accurate method which can be used by untxaxned personnel to screen for drugs of abuse.
• Another object of this invention is to provide a method and means for rapid qualitative and quantita ⁇ tive identification of particular species of drug residues in the 0.5 microgram to 500 micrograms per drop range.
• Yet another object of the present invention is to provide a unique combination of a carrier matrix having specific physical characteristics and dry chemical staining agents, absorbed from solutions containing a narrow range or narrow ranges of specific chemicals, deposited in inter ⁇ stices in the carrier matrix whereby to provide a matrix dipstick of high sensitivity to specific abuse- type drug residues found in the physiological fluid of users; such dipstick being quite insensitive to the pH factor of the fluids being tested and providing a semi-permanent qualitative and quantitative color intensity record of the drug residue in such fluids.
• Still another object of the present invention is to provide processes for the preparation and production of abuse-type drug staining agents having sufficient sensitivity to permit use without the requirement of an ion-exchange resin or color intensifier.
• physiological fuids refers most commonly to urine but is also applicable to whole blood, serum, plasma, sweat and tears.
• classes of drug residues referred to include those most commonly found in addict or rehabilitation patient physiological fluids, namely: amphetamines, barbiturates, morphine-like substances and cocaine, and tranquilizers of the diazepam type structure.
• the particular species of such drug residues include, all derivatives of barbiturates and amphetamines; methadone, morphine, cocaine, codeine, dilaudid and derivatives of the diazepam type structure.
• a carrier matrix comprises a chemically treated, disposable test paper or dipstick which may be of any suitable shape or form.
• paper refers to any material (paper, fibers, plastics, etc.) having the requisite physical properties as hereinafter stated and the necessary lack of chemical reactivity to the system.
• the carier body is limited to certain types of bibul- ous paper which will maintain the chemical com ⁇ ponents within its matrix and allow sufficient poros ⁇ ity and absorbance for the staining reaction to occur effectively with one or more drops of the physiological fluid.
• This carrier body is impreg- nated by an immersion process with the essential drug-reactive components.
• test papers or dipsticks Only very specific solvents and combinations of chemicals may be used to produce a dipstick with characteristics which are stable (as to color and re- activity) over a period of months.
• Such formulations impregnated in the test papers or dipsticks can only be prepared under special conditions of immersion into the specified formulations. These conditions involve pretreatment of chemicals (dissolution, ageing) im- mersion time, drying time and drying conditions. In some instances a stabilizing bath is required after initial immersion.
• SUBSTITUTE SHEET fURE yield an intense and relatively permanent color record of the specific drug residues found in the physiological fluids tested.
• a test paper or dipstick is pro-ucked for a particular purpose, i.e. to identify a particular class of drugs or specific drug.
• diphenylcarbazone and mercuric chloride are the active staining reagents for the barbiturate class of drugs and derivatives; Ninhydrin is the active staining reagent for amphetamine class of drugs and derivatives and a modified Dragendorff stain (platinum, bismuth, and iodide) is used for the narcotic class reactions for methadone, morphine ⁇ like compounds and tranquilizers.
• test paper is determined by its intended use, i.e. as a screening agent or confirmation for a particular class or specific drug residue to be identified.
• the stains themselves do not normally react with other substances in the body fluids other than those within the class category except as herein ⁇ after stated.
• the class reactions are summarized in Table 3.
• Table 2 is a summary of test papers developed and their color reactions with drug residues.
• the quantitative characteristics of the stain ⁇ ing reactions may be utilized by one of three methods:
• OMPI (1) a color comparison chart developed by using, standard incremental spiked urine samples to standard dipsticks; (2) the use of a densitometer to measure the color absorbancy; (.3) the use of urine samples from incrementally dosed animals or humans. Color in ⁇ tensity is measured as a function of concentration following Beer's Law for each class or specific drug residue. In the case of the barbiturates a slightly different procedure is used since the staining reaction is a blanching effect (white spot) of an already colored test paper (.purple) . In this case the diameter of the white spot produced is proportional to the concentra ⁇ tion of the drug.
• ⁇ UiSTSTUTE SHEET As a qualititive screen for drugs of abuse (the most common application for these test papers) these test papers have been designed to monitor drug residues at the concentration levels most fre- quently encountered with drug addicts in rehabilit ⁇ ation centers.
• concentration levels of 0.05— 50 micrograms of drug residue/drop can be increased or decreased by one of three ways: (1) using a more or less sensitive formulation of the chemicals in the test paper; (2) increasing the number of drops of body fluid placed on the test paper; (3) im ⁇ mersing the paper a plurality of dips with drying between each dip. The most effective formulations for these concentration levels are being used.
• the amphetamine and barbiturate tests can be used as a "Yes” or “no", i.e. positive or negative screen.
• This test is conducted by placing one or more drops of the body fluid (usually urine) on the test paper from a pipet or medicine dropper.
• the test paper is designed to react with .05 micro- gram of drug residue/drop of test fluid. Larger numbers of drops or dipping directly into the fluid is generally superfluous.
• One drop of liquid from a Pasteur pipet is adequate to obtain the desired results.
• SUBSTITUTE SHEET will distort the reading and interpretation of results. With the one or two drops of liquid, the drug residues migrate at different rates re ⁇ acting with chemicals in the paper to yield a colored pattern easily discernable.
• the rings, bands and spots for the Narcotic "G" test paper are given in Figure 1. All of the test papers have been designed to yield positive test reactions at the levels of concentration of drug residues most commonly found in addict body fluids based on hundreds of tests performed at rehabilitation centers.
• OMPI inert plastic materials on-woven fabrics
• wood or even metals with similar characteristics may be used but have not been found as satisfactory as paper.
• Whatman Filter Paper #3 contains the ideal characteristics and the minimum character ⁇ istics are:
• Filter paper of lesser porosity (Whatman #2) will yield a test paper that will give the necessary re ⁇ actions but not at the sensitivity required to pro ⁇ vide quantitative as well as qualitative results. Also, it is possible to employ a hard matrix with a porous coating of the porosity characteristics set forth above. The results obtained are acceptable but not as good as when using the type of paper described.
• any volatile organic solvent that will dissolve 3 or more grams per 100 ml of Ninhydrin reagent may be used as the immersion liquid.
• Each solvent may impart a slightly different color reaction to positive and negative tests.
• selection of the solvent is based on the color dif ⁇ ferentiation desired.
• Various higher alcohols yield different shades of blue for negative and positive
• the method of preparation of the amphetamine test paper involves completely immersing the filter paper in the liquid for 5 to 10 seconds and removing. Immersing for less than 5 seconds gives uneven dis— tribution of chemicals within the paper.
• the paper may be dried in air or with gentle heat Cno greater than 60°C) .
• the test papers when dry are stable to light and air and. have a shelf life of 1 year. Test papers may be cut with any paper cutter to any size. One inch squares have been found more than adequate for a single drop urine test.
• OMPI positive and negative tests The use of methyl alcohol or acetone with an added coloring agent for adding background color to the paper is the only feasible method. High concentrations of Ninhydrin are limited by solubility which is 6%. The color reaction with one drop or more of urine will only occur with a highly absorbent paper or matrix such as a Whatman #3 paper. Other types of paper or ion exchange resin papers will not give this color change or sensitivity of reaction with ⁇ out the use of an intensifying agent.
• the amphetamine test paper is manufactured by immersion for at least 5 seconds a testpaper having the requisite wet strength and absorbance in a 5% to 6% solution of Ninhydrin in methyl alcohol or acetone.
• any volatile organic solvent that is able to dissolve greater than 0.1 gm of S-diphenylcarbazone and 4 gm of mercuric chloride in solution may be utilized as the immersion liquid.
• cupric chloride may be substituted for mercuric chloride in some formulations.
• color differentiation was im- paired and a time delay in reactivity occurred making these formulations less than satisfactory.
• Other salts have been tested with equally poor results.
• No substitute has been found for S-diphenylcarbazone. Differing ; solvents yield differing colors of test papers from pale blues to deep purples.
• CMPI In preparation 0.25 gm (0.20 gm to 0.25 gm range) of S-diphenylcarbazone is added and mixed with preferably 5 gm (4.5 gm to 5 gm range) of mercuric chloride dissolved in 100 ml of methanol. Actually quantities of the S-diphenylcarbazone and mercuric chloride (HgCl) are employed to preferably produce a saturated solution for sensitivity.
• test paper Since the reaction with a drop of physio ⁇ logical fluid (primarily urine) yields a blanching or whitening effect, the crimson or dark purple color of the test paper is more desirable. Using methanol or acetone imparts such a desired deep purple color to the test paper- When freshly prepared, this test paper has a sensitivity of 0.25 micrograms of barbiturates per drop of body fluid.
• physio ⁇ logical fluid primarily urine
• test papers deep purple
• These test papers are still functional for up to 30 days after manufacture and will give characteristic reactions. If sealed in an airtight wrapping, the paper is stable for approximately 60 days. A negative barbiturate fluid turns the paper a deep purple, while a positive barbiturate fluid blanches the paper to a whitish grey.
• a negative barbiturate fluid turns the paper a deep purple
• a positive barbiturate fluid blanches the paper to a whitish grey.
• the disadvantages of a test paper that changes color in spite of the fact that the test paper itself is still functional makes its commercial use question ⁇ able.
• a second immersion of the paper is made in a solu— tion of 4.5% (3% to 5% range) polyvinyl alcohol (aqueous) of the test paper for extended periods of time. The paper is completely functional as a qualitative test
• the 4.5% of polyvinyl alcohol cannot be incorporated into the S-diphenylcarbazone, mercuric chloride solution.
• the manufacturing process must proceed in a two step immersion with air drying between and after. As with the preparation of amphetamine test papers, gentle heat may be. used in the drying process but is not required and, in fact, more sensitive test papers are obtained by drying in air. Methanol is the solvent of choice for the barbiturate test paper. With volatile organic solvents properly vented, drying times do not exceed 10 to 15 minutes for pilot production runs. With the use of S-diphenylcarbazone and mercuric chloride drying and immersion of papers must be achieved in a properly vented air space.
• test paper incorporating polyvinyl alcohol is not sufficiently sensitive to conduct more than a qualitative or at best a semi-quantitative test and should not be used for quantitative tests. If it is desired to perform a quantitatxve test, the polyvinyl alcohol must be excluded. As indicated
• test papers have a shelf life of about 60 days if individually wrapped and sealed.
• a positive reaction results in the formation of black spots within 12 to 24 hours depending upon concentration of the residue in the body fluid tested.
• test paper must be readable in a reasonably short period of time (30 minutes) .
• the test papers should preferably have a shelf life of no less than six months.
• test papers should offer a semi ⁇ permanent record such that the stained test papers can be referred to in three to six months for document- ation purposes.
• a formulation that meets those criteria has very stringent limits placed on the bismuth nitrate concentration, the acetic acid concentration, the chloroplatinate concentration, the iodide concentration and the normality of hydrochloric acid used.
• Table 1 lists the allowable ranges of concentr ⁇ ations that yield an acceptable test paper according to the above criteria.
• the test papers must be pre ⁇ pared under special conditions or the test papers will not be satisfactory.
• the platinum solutions must be prepared two to ten days prior to immersion and aged during that period. Fresh platinum solutions or those kept longer than 10 days are non-functional.
• the bismuth and platinum salts must be dissolved in an aqueous potassium iodide solution and then diluted to working concentration. Other methods of preparation are ineffective. A double immersion is required for the platinum solution.
• the bismuth subnitrate is dissolved at the necessary concentration level in the exact and necessary concentration of acetic acid.
• test paper is then immersed for 5 to 10 seconds in this solution and allowed to air dry under light (about 24 hours)
• Glacial acetic acid 17.5 ml (17.5%)
• Solution 1 and allowed to dry in light and air for 24-48 hours.
• Solution 1 must age for 2—10 days prior to use; i.e. application to the carrier matrix.
• the carrier matrix must dry in light and air after immersion in Solution 2.
• This paper is more sensitive than the first stated Narcotics "G” paper by about 10 fold (i.e.
• the paper is opaque to caffeine and nicotine.
• the percent concentrations in the U-paper formul ⁇ ations are based upon grams weight per 100 ml of liquid solution.
• the carrier matrix is immersed into each of the solutions 1 and 2 with a drying step effected in between. Once dry after the second dip, the impregnated carrier matrix is placed into a humidity chamber as discussed below.
• WIFO Solution 2 must be within the acceptable concentr ⁇ ation limits described in Table 1. Similar conditions apply to the preparation of platinum sol ⁇ utions and the air and light drying. A summary of the formulations and procedures for manufacture of the various test papers is pro ⁇ vided in Table 4.
• Morphine-like Drugs inner blue-purple rings or bands with buff or yellow center
• Morphine solid blue spot fills entire area with a superimposed dark blue peripheral ring
• Cocaine orange-brown or orange spot with white halo
• the solution must be aged, 2-10 days, prior to use.
• This test paper requires only 1 dip in the above solution and is dried in light and air. A positive reaction yields a purple violet color .
• Bismuth subnitrate 1.5%/100 ml of 15% acetic acid is mixed with an equal volume of 2-10 day aged iodoplatinate solution as follows:
• Solution 2 must be aged for 2-10 days prior to use.
• the matrix is dipped in the first solution and allowed to dry in light and air and then dipped in the second solution and allowed to dry in light and air. All Purpose Alkaloid Detection Paper
• This test paper is reactive to all alkaloids and cannot distinguish between the various narcotic residues. This paper is used as a broad base screen.
• the platinum solution is aged for 2-10 days before use.
• the matrix is dipped once and allowed to dry in light and air.
• This test paper is not opaque to caffeine and nicotine and provides the same blue-purple color reaction to all alkaloids.
• narcotic (S) One dip into a solution formed by dissolving 0.250 gm H 2 PtCl g , plus 2.0 gm KI in 50 ml of H 2 0. Bring to
• test Specimens Two drops of a body fluid specimen is the most required for any given test paper. Thus, for a full screen, 1 ml of a body fluid sample of urine, blood, serum or saliva is adequate. Since most testing for drug abuse offenders is performed on urine samples, the test papers to be described are specifically targeted for urine testing. However, the formulations and applications are equally satisfactory for other body fluids as well.
• the quantity of liquid in a drop varies from liquid to liquid as a function of such parameters as
• the dipstick of the invention- is operative over a range of at least 0.05 to 0.3 milliliters of body fluid specime .
• Urine samples should be used as soon after voiding as possible, preferably within 24 hours. Urine samples do not have to be refrigerated nor preservatives added. Urine samples left unattended for three days at room temperatures show no difference in reactivity.. Specimens left over a week at room temperature do not give characteristic normal re ⁇ actions for blank urine although urine with drugs gives comparable drug reactions. Testing of urines allowed to stand for long periods of time should be avoided. Although preservatives in urine do not appear to influence normal or drug reactions with specimens, preference is given to freshly voided urine.
• the drug abuse test appears to operate in- dependently of the pH of the urine within a range of pH 3-10. Changing the pH of the urine will not affect the reactivity or color changes of the test papers with normal urine or drug urine. Interfering Substances The chemistry of the drug abuse test papers is comparable to the staining reactions of the thin-layer chromatography procedures except magnified 1,000 to
• the individual staining reactions are based on stains reacting with specific classes of drugs.
• the stains themselves do not usually react with other substances than those within the class category. See Table 3.
• the amphetamine test with Ninhydrin reagent is a more general test for amines and covers a broader category of reactions than amphetamines commonly found in urine samples. In the methadone center study no cross reactions were observed and a 100% correlation with the thin layer chromatography tests was noted.
• False positives can only be encountered with contamination from highly acid materials. Acidity below pH 2.5 is never encountered in urine specimens. False negatives would be rarely encountered since even in very low concentrations (nanogram amounts) a small white ring will form after 10 minutes. Adding one or two additional drops of urine will bring out this positive reaction. This type of
• the urine may give a false positive.
• a normal blank urine ' will show an immediate blanching and the formation of a large white or buff area 1 wherein the two drops or urine contacted the test paper. The area 1 has dispersed brown periphery. .With the blank urine, this picture will remain until the test paper dries (less than 30 minutes) and fade very slowly thereafter.
• QUTI_ pinkish inner ring 2 of tranquilizers will form if the drugs are present. These bands and rings will often start forming within 3 or 4 minutes after the test paper is wetted. In the case of high con— centration of drugs as often found in addicts' urine, color formation and rings and bands will often faintly appear instantaneously as the test paper is wetted. As the paper dries the colors and rings intensify. Water samples on addict urine where water has been falsely substituted will give an instant ⁇ aneous deep black characteristic spot.
• a dark purple or black outer peripheral band or ring 5 is characteristic of both normal (negative) and addict (containing drugs) urines and is always formed.
• a methadone band or ring 4 in the presence of methadone residue will always form in contact with the outer peripheral band or ring 5.
• the shape of a ring or band will vary depending on concentra ⁇ tion of the drug. Also, the color will vary from deep purple to azure blue depending on concentration. 3.
• Morphine-like drugs band or ring 3 will always form separated from the outer peripheral ring 5 and methadone rings 4. Colors will vary from purple to blue and shape will vary from bands to rings.
• a blue tranquilizer ring or band 2 will form around the inner spot which will be intensified blue-pink depending on concentration.
• the inner spot 1 may be a blanched white area or buff colored spot in normal (negative) urines. In addict urines the inner spot may be blanched or highly colored often yellow depending on concentration of drugs present. With methadone, the inner spot will usually be blanched or buff. Rarely, with high concentrations, it will be a purple or grey spot. With cocaine, the "inner spot” will be orange at high concentrations. With morphine ⁇ like drugs, the “inner spot” will be purple at high concentrations, but blanched or buff at low concen- trations. With a tranquilizer, a deep blue and/or pinkish at high concentrations for the "inner spot” but blanched or buff at low concentrations. Sensitivity Control
• the processing is effected by placing the staining agent impregnated carrier matrix into a humidity controlled atmosphere for a sufficient length of time so as to improve the reactivity of the test indicator
• EET strip with respect to indicating the presence of abuse-type drugs as discussed herein.
• Test papers made in accordance with the formulations of the narcotic G papers disclosed hereinabove were allowed to stand in a controlled humidity atmosphere for various periods of time. The time periods tested existed from a period of hours up through a period of several weeks.
• the narcotic G test paper which was brown in color following its production in accordance with, the above formulations was held in the controlled atmosphere for an amount of time sufficient to change the color to green. It was found that green papers which were produced after two weeks of saturation in a controlled water vapor atmosphere became ultrasensitive to abuse- type drugs. This sensitivity was sufficient to pick up caffeine rings resulting from the person having drunk a cup of coffee. Thus, the sensitivity of the indicator strip was down in the hundredths of thousandths of a nanogram of the drug per millileter of physiological liquid test solution.
• narcotic S papers Both the narcotic G and S papers were hung in a closed box in which the humidity was controlled for different lengths of time.
• the test included the use of a physiological liquid test solution containing very small amounts of a drug. A test solution was placed on regular narcotic G paper and no reaction would be obtained on the test indicator strip when a drop of the test solution was applied thereto. That is, there
• OMPI would be no rings appearing on the test indicator strip at very low levels of abuse-type drugs down to about 2 nanograms per millileter of solution. It was known that there was enough chromophoric material in the interstices of the test indicator strip so that there should have been some kind of a reaction in obtaining that color. However, no such reaction was taking place. However, the test indicator strips made in accordance with the form— ulations for narcotic G papers was held in a humidity controlled environment for a period of time to increase the reactivity of the chromophoric materials and sub ⁇ sequently dry. When the same test solution was then placed on the narcotic G paper, the color reaction was changed and the rings were now present.
• the particular mechanism for the increased sensitivity is not completely understood. However, it was found that the sensitivity of the narcotic test strip papers was greatly enhanced simply by maintaining the test papers in a humidity controlled atmosphere from anywhere from one day to two weeks.
• the narcotic G papers were placed in a humidity chamber that was maintained at a curing temperature of from about 15°C to about 45°C. An airflow was established in the humidity chamber from zero to about 8 cubic feet per minute. The head pressure and the exhaust was then turned on and the temperature and airflow adjusted to reach an appropriate equilibrium.
• the racks of paper were placed in the environmental chamber and the temperattire was monitored and recorded on a regular basis.
• the narcotic G test papers which were treated in the humidity controlled environment are referred to as the U-papers (ultrasensitive papers) .
• the standard size of these papers is one inch square.
• a further paper referred to as UP-paper (ultra ⁇ sensitive proficiency paper) was processed exactly the same as the U-paper but is cut in a six inch square. That is, either a large piece either 6 x 6 inches or 8 x 8 inches was used for determining the presence of abuse-type drugs in a physiological liquid test solution.
• the larger piece of test indicator strip is then saturated with a large amount of the test solution. For example, 5 ml of urine con- taining various abuse-type drugs is placed on the larger piece of test paper.
• a further advantage of using the capillary pipet method is that there is a constant amount of fluid that can be maintained from one test to another. In this fashion, there is a greater accuracy of compar ⁇ ing test papers which have the same amount of the chromophoric material in them and standard comparisons can be more readily made in the field at the site of taking the fluid test specimen from the person being monitored.
• the drug abuse indicator devices as described herein distinguish over the earlier U.S. Patent 3,915,639 because the staining agent is im ⁇ pregnated rather than formed as a coating. Further ⁇ more, there is no necessity of ion-exchange resins or color intensifiers as the result of using the formulations and procedures as described herein.

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• 1983
  • 1983-12-06 IT IT24086/83A patent/IT1167682B/it active
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  • 1983-12-07 WO PCT/US1983/001920 patent/WO1984002397A1/en active Application Filing
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• 1984
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