U.S. patent application number 10/858591 was filed with the patent office on 2007-03-08 for stable isotopic identification and method for identifying products by isotopic concentration.
Invention is credited to John P. Jasper.
Application Number | 20070054402 10/858591 |
Document ID | / |
Family ID | 23372162 |
Filed Date | 2007-03-08 |
United States Patent
Application |
20070054402 |
Kind Code |
A1 |
Jasper; John P. |
March 8, 2007 |
Stable isotopic identification and method for identifying products
by isotopic concentration
Abstract
A stable isotopic identification comprising a mathematical or
numerical array of concentrations of isotopes found in a batched
product, said mathematical or numerical array being presented in a
machine readable form and comparable to analytical results whereby
the product can be distinguished from other similar products, said
machine readable form also being indexed through stored product
information. The stored product information may be displayed when
desired. By the stable isotopic identification of the invention, a
product may be securely traced through manufacturing of a product,
marketing of a product and the use of a product.
Inventors: |
Jasper; John P.; (Niantic,
CT) |
Correspondence
Address: |
David A. Lundy;KRIEG DEVAULT LUNDY LLP
825 Anthony Wayne Bldg.
203 E. Berry St.
Fort Wayne
IN
46802
US
|
Family ID: |
23372162 |
Appl. No.: |
10/858591 |
Filed: |
June 2, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09349380 |
Jul 9, 1999 |
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10858591 |
Jun 2, 2004 |
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Current U.S.
Class: |
436/56 ;
436/57 |
Current CPC
Class: |
Y10T 436/13 20150115;
G07F 7/086 20130101; Y10T 436/24 20150115 |
Class at
Publication: |
436/056 ;
436/057 |
International
Class: |
G01N 37/00 20060101
G01N037/00 |
Claims
1. An identification for a batched product comprising a
mathematical array of concentrations of isotopes, said
concentrations of isotopes being the result of an analysis of a
plurality of the naturally occurring stable isotopes of said
batched product in their isotopically unaltered concentrations,
said mathematical array being presented in a readable form, said
readable form being comparable to analytical results of the
naturally occurring isotopes of unknown products, whereby unknown
products can be identified with and differentiated from said known
products, said readable form being indexed to stored product
information, whereby products can be securely traced through
manufacturing and the marketplace and distinguished from unknown
products.
2. The isotopic identification of claim 1 wherein said
concentrations of isotopes are chosen from the group of isotopic
concentrations consisting of concentrations of isotopes,
concentrations of isotopes and their errors, ratios of isotope
concentrations, ratios of isotope concentrations and their errors,
and combinations thereof.
3. The isotopic identification of claim 1 wherein said readable
form is chosen from the group of readable forms consisting of
serial numbers, bar codes, and other numerical and alphabetical
indicia.
4. The isotopic identification of claim 1 wherein said mathematical
array is chosen from the group of mathematical arrays consisting of
a list of a plurality of concentrations, a list of a plurality of
isotopic ratios, a list of a plurality of mathematical products of
isotopic concentrations, a list of a plurality of mathematical
products of isotopic ratios, groups of any such lists, groups of
any such mathematical products, groups of any such ratios, groups
of any such concentrations, mathematical products of any such
concentrations plus or minus their error added, mathematical
products of any such ratios plus or minus their error added, any
such concentrations, ratios, lists, groups, and mathematical
products in quadrature, isotopic ratios of any such mathematical
products, ratios of said concentrations plus or minus their errors
added, any of such concentrations plus or minus their errors added,
factor analysis of any such concentrations, ratios, lists, groups,
mathematical products and any determinants and combinations
thereof.
5. The isotopic identification of claim 1 wherein the isotopes
available are any of the 252 existing stable isotopes of known
elements that have two or more isotopes.
6. The isotopic identification of claim 1 wherein said isotopes are
of any of the 13 stable isotopes of the group of elements
consisting of carbon, hydrogen, oxygen, nitrogen, sulfur and
combinations thereof.
7. The isotopic identification of claim 1 wherein the error of the
identification is chosen by the mathematical array chosen, the
number of concentrations of isotopes utilized in said array, and
the portion of said array compared with the isotopic analysis of
said unknown product.
8. The isotopic identification of claim 1 wherein the batched
product from which the concentrations of isotopes are analyzed and
formed into a mathematical array is chosen from the group of
batched products consisting of active pharmaceutical ingredients,
excipients of drug products, impurities in drug products, raw
materials and drug products, combustible fuels, additives to
combustible fuels, environmental and naturally occurring products,
explosives products, ammunition, gun powder, crude oil, petroleum
distillates, hazardous waste, paper, ink, tire materials, paints
and other coatings, other synthetic materials, and combinations
thereof.
9. The isotopic identification of claim 1 wherein said
concentrations of isotopes are chosen from the group of
concentrations of isotopes consisting of bulk phase analysis and
specific compound analysis.
10. The isotopic identification of claim 9 wherein said bulk phase
analysis includes off-line dual inlet isotope ratio mass
spectrometry (irMS) and on-line combustion coupled with high
resolution isotope ratio monitoring/mass spectrometry (irmMS).
11. The isotopic identification of claim 9 wherein specific
compound analysis includes gas chromatography coupled with irMS
(irmGCMS) and liquid chromatography coupled with irMS
(irmLCMS).
12. The isotopic identification of claim 1 wherein said analyses
includes nuclear magnetic resonance.
13. The isotopic identification of claim 1 wherein said readable
form is a machine readable form that is comparable to other machine
readable forms derived from the analysis of known products and
their product information stored in memory on a machine together
with an index, said machine readable forms, index, and product
information being interlinked, said machine readable forms once
identified through the index presents stored product information in
displayed form.
14. The isotopic identification of claim 13 wherein said product
information may be scrolled through.
15. The isotopic identification of claim 13 wherein said product
information may be printed.
16. The isotopic identification of claim 13 wherein said product
information may be accessed through said index from said machine
readable form of said mathematical array.
17. An identification for a composition comprising an arrangement
of empirical information derived from an analysis of a plurality of
the naturally occurring stable isotopes of said composition after
batching in their isotopically unaltered concentrations, said
arrangement comprising a numerical array of said empirical
information in a readable form.
18. The identification of claim 17 wherein said empirical
information further comprises the tolerable error of said
analysis.
19. The identification of claim 17 wherein said composition is a
substance manufactured in an industry chosen from the group of
industries consisting of the chemical, petroleum, pharmaceutical,
biomedical, biochemical, environmental, paint, explosive material
and combustible fuel industries.
20. The identification of claim 1 wherein said readable form is
comparable to numerical arrays of isotopic concentrations from the
analyses of said naturally occurring stable isotopes of unknown
products, whereby said unknown products can be identified with and
differentiated from said known batched products.
21. The identification of claim 1 wherein said readable form is
indexed to stored product information, whereby products can be
securely traced through manufacturing and the marketplace and
distinguished from said unknown products.
22. The isotopic identification of claim 17 wherein said empirical
information is chosen from the group of empirical information
consisting of concentrations of isotopes, concentrations of
isotopes and their errors, ratios of isotope concentrations, ratios
of isotope concentrations and their errors and combinations
thereof.
23. The isotopic identification of claim 17 wherein said readable
form is chosen from the group of readable forms consisting of
serial numbers, bar codes, and other numerical and alphabetical
indicia.
24. The isotopic identification of claim 17 wherein said
mathematical array is chosen from the group of mathematical arrays
consisting of a list of a plurality of concentrations, a list of a
plurality of isotopic ratios, a list of a plurality of mathematical
products of isotopic concentrations, a list of a plurality of
mathematical products of isotopic ratios, groups of any such lists,
groups of any such mathematical products, groups of any such
ratios, groups of any such concentrations, mathematical products of
any such concentrations plus or minus their error added,
mathematical products of any such ratios plus or minus their error
added, any such concentrations, ratios, lists, groups, and
mathematical products in quadrature, isotopic ratios of any such
mathematical products, ratios of said concentrations plus or minus
their errors added, any of such concentrations plus or minus their
errors added, factor analysis of any such concentrations, ratios,
lists, groups, mathematical products and any determinants and
combinations thereof.
25. The isotopic identification of claim 17 wherein said isotopes
are any of the 252 existing stable isotopes of known elements that
have two or more isotopes.
26. The isotopic identification of claim 17 wherein said isotopes
are of any of the 13 stable isotopes of the group of elements
consisting of carbon, hydrogen, oxygen, nitrogen, sulfur and
combinations thereof.
27. The isotopic identification of claim 18 wherein the error of
the identification is chosen by the mathematical array chosen, the
number of concentrations of isotopes utilized in said array, and
the portion of said array compared with the isotopic analysis of
said unknown product.
28. The isotopic identification of claim 17 wherein the composition
from which the concentrations of isotopes are analyzed and formed
into a mathematical array is chosen from the group of batched
products consisting of active pharmaceutical ingredients,
excipients of drug products, impurities in drug products, raw
materials, combustible fuels, additives to combustible fuels,
environmental and naturally occurring products, explosives
products, ammunition, gun powder, crude oil, petroleum distillates,
hazardous waste, paper, ink, tire materials, paints and other
coatings, and other synthetic materials.
29. The isotopic identification of claim 22 wherein said
concentrations of isotopes are chosen from the group of
concentrations of isotopes consisting of bulk phase analysis and
specific compound analysis.
30. The isotopic identification of claim 29 wherein said bulk phase
analysis includes off-line dual inlet isotope ratio mass
spectrometry (irMS) and on-line combustion coupled with high
resolution isotope ratio monitoring/mass spectrometry (irmMS).
31. The isotopic identification of claim 29 wherein specific
compound analysis includes gas chromatography coupled with irMS
(irmGCMS) and liquid chromatography coupled with irMS
(irmLCMS).
32. The isotopic identification of claim 17 wherein said analyses
includes nuclear magnetic resonance.
33. The isotopic identification of claim 17 wherein said readable
form is a machine readable form that is comparable to other machine
readable forms derived from the analysis of known products and
their product information stored in memory on a machine together
with an index, said machine readable forms, index, and product
information being interlinked, said machine readable forms once
identified through the index presents stored product information in
displayed form.
34. The isotopic identification of claim 33 wherein said product
information may be scrolled through.
35. The isotopic identification of claim 33 wherein said product
information may be printed.
36. The isotopic identification of claim 33 wherein said product
information may be accessed through said index from said machine
readable form of said mathematical array.
37. An identification for a batched product comprising an
arrangement of empirical information derived from an analysis of a
plurality of naturally occurring stable isotopes of said batched
product in their isotopically unaltered concentrations, said
arrangement comprising a numerical array of said empirical
information in a readable form.
38. An identification for a batched product comprising empirical
information derived from an analysis of a plurality of naturally
occurring stable isotopes of said batched product in their
isotopically unaltered concentrations, said empirical information
being arranged in a numerical array, said array being in a readable
form, said readable form being comparable to the empirical
information of said naturally occurring isotopes of an unknown
product, said readable form being indexed to stored product
information, whereby unknown products can be identified with and
differentiated from said known products.
39. The method of claim 1 wherein said batched product is a sample
of a product larger in volume than said sample, and said sampling
of said larger in volume product is more precise than the precision
of said analysis of a plurality of the naturally occurring stable
isotopes of said batched product.
40. The identification of claim 1 wherein each of said analysis of
a plurality of the naturally occurring stable isotopes of said
batched product has a dynamic range equal to the observed range
divided by the 1-sigma standard deviation.
41. The identification of claim 40 wherein the precision of each of
said analysis of a plurality of the naturally occurring stable
isotopes of said batched product is the 1-sigma standard deviation
of the analysis performed divided by the square root of the number
of observations of said analysis.
42. The identification of claim 40 wherein the dynamic range is the
range of values expected for an analysis divided by the 1-sigma
standard deviation of that analysis.
Description
THE BACKGROUND OF THE INVENTION
[0001] This application is a divisional application of application
Ser. No. 09/349,380, filed on Jul. 9, 1999.
[0002] The present invention relates to a stable isotopic
identification and method for identifying products using naturally
occurring isotopic concentrations or isotopic ratios in products,
especially in the pharmaceutical industry, and more particularly to
an identification and a method utilizing such isotopic
concentrations or ratios in a machine readable form for identifying
products and tracking products through manufacturing, marketing and
use of a product, and readily indexing product information to the
product.
[0003] The stable isotopic composition of matter has been
recognized since about 1945 as a criterion for differentiating one
material from another with the same elemental composition. In the
field of geochemical oil exploration and prospecting, measurement
of the isotopic compositions of large numbers of individual organic
compounds of oil samples from various oil reservoirs have assisted
in clarifying the origin of specific compounds correlating the
organic compounds with particular petroleum sources, recognizing
the existence of multiple petroleum sources, examining the
mechanisms of petroleum generation, and improving the sensitivity
of petroleum migration studies. This information, particularly in
connection with seismological data, can be used to predict
locations of other oil reservoirs to which oil may have migrated
from a common source of generation or formation.
[0004] Isotope ratio monitoring has further applications in the
biomedical field, wherein non-radioactive and stable isotopes are
used as tracer labels in drug metabolism and other biomedical
studies where natural variations in isotopic abundances may also
carry additional information regarding sources and fates of
metabolites. Current radioactive and stable isotopic labeling
apparatus and methods in the medical fields employ typically costly
labeled compounds having isotope ratios much different than those
found in natural abundance. Since the inception of these
techniques, improvements in isotope ratio monitoring sensitivity
and precision, and a reduction in sample size and the required
amount of the taggant material have occurred. In some cases, the
relative concentration of the minor isotope versus the major
isotope of naturally occurring isotopic ratios is so small that
monitoring the isotope ratio has been problematic. It is therefore
highly desirable to provide a new and improved stable isotopic
identification and a method of identifying products utilizing a
stable isotopic identification. It is also highly desirable to
provide a new and improved stable isotopic identification and a
method for identifying products utilizing the same which is fully
operational utilizing naturally occurring variations in isotopic
abundance, thus eliminating costly taggants in some
applications.
[0005] In the combustible fuel, environmental, foods, explosive and
ammunition and paint industries, the new and improved stable
isotope identification can be used.
[0006] In the pharmaceutical industry, there is a need to trace
ingredients through the manufacturing process, through the
marketplace, and into various usages. Products such as active
pharmaceutical ingredients (APIs), excipients of drug products,
impurities in drug products, raw materials and drug products are
included in those products which a pharmaceutical manufacturer may
wish to trace. The ready identification of products in the
marketplace allows a pharmaceutical manufacturer to monitor its
products for quality purposes as well as to act as an impediment
against fraudulent "knock-offs" or counterfeits. It is therefore
highly desirable to provide a new and improved stable isotopic
identification which can be used in the pharmaceutical industry for
APIs, drug products, excipients of drug products, and/or impurities
of drug products and a new and improved method of identifying and
using such an identification. It is also highly desirable to
provide a new and improved stable isotopic identification utilizing
the intrinsic or ambient variability of the stable isotopic
compositions or ratios of the product (not artificially altered or
"tagged") thereby eliminating the need for relatively expensive
taggants and the resultant dilution or contamination by impurities
of the product, and a method utilizing such isotopic concentrations
or ratios in a machine readable form for identifying products, and
tracking products through manufacturing, marketing and use of a
product, and readily indexing product information to the
product.
[0007] New techniques for measuring highly precise on-line isotopic
ratios are now available. The probability of isotopic compositions
of two batches from independent sources being the same is inversely
proportional to the product of the dynamic ranges of each type of
isotopic analysis undertaken, whether bulk or compound specific
analyses. The "dynamic range" is defined herein as the range of
values expected for a given type of measurement divided by the
1-sigma standard deviation of that measurement. All products such
as APIs, drug products, excipients of drug products and/or
impurities of drug products have intrinsic or ambient measurable
amounts of stable isotopes of common light elements such as carbon,
hydrogen, oxygen, nitrogen sulfur, and chlorine. It is therefore
highly desirable to provide a new and improved stable isotopic
identification derived from stable isotopic compositions or ratios
of common light elements of the product and a method of identifying
the products and indexing product information to the product
utilizing the same. It is also highly desirable to provide a new
and improved stable isotopic identification for APIs, drug
products, excipients of drug products and/or impurities of drug
products which can be readily determined by either on-line or
off-line analysis of the intrinsic, ambient or naturally occurring
stable isotopic compositions or ratios of the common light elements
in such products and a method for identifying and tracing such
products throughout the manufacturing process, the marketplace and
use and potential misuse.
[0008] Finally, it is highly desirable to provide a new and
improved stable isotopic identification and method for utilizing
the same including all of the above features throughout the
chemical, petroleum, pharmaceutical, biomedical, food,
environmental, paint, explosive-ammunition, and combustible fuel
industries.
SUMMARY OF THE INVENTION
[0009] It is therefore an object of the invention to provide a new
and improved stable isotopic identification, and a method of
identifying batched products utilizing stable isotopic
identification.
[0010] It is also an object of the invention to provide a new and
improved stable isotopic identification, and a method for
identifying batched products utilizing the same which is fully
operational utilizing naturally occurring variations in isotopic
abundance, thus eliminating costly taggants.
[0011] It is also an object of the invention to provide a new and
improved stable isotopic identification which can be used in the
pharmaceutical industry for APIs, drug products, excipients of drug
products, and/or impurities of drug products, and a new and
improved method of identifying and using such products.
[0012] It is also an object of the invention to provide a new and
improved stable isotopic identification utilizing the intrinsic or
ambient variability and the stable isotopic composition or ratios
of the product (not artificially altered or "tagged") thereby
eliminating the need for relatively expensive taggants and the
resultant dilution or impurity of the product, and a method
utilizing such isotopic concentrations or ratios in a machine
readable form for identifying batched products and tracking batched
products through manufacturing, marketing and use of a product, and
readily indexing product information to the product.
[0013] It is also an object of the invention to provide a new and
improved stable isotopic identification derived from stable
isotopic compositions or ratio of the common light elements in
batched products, and a method of identifying batched products and
indexing product information to the product utilizing the same.
[0014] It is also an object of the invention to provide a new and
improved stable isotopic identification for APIs, drug products,
excipients of drug products and/or impurities of drug products
which can be readily determined by either on-line or off-line
analysis of the intrinsic, ambient or naturally occurring stable
isotopic compositions or ratios of common light elements in such
products and a method for identifying and tracing such products
throughout the manufacturing process, the marketplace and use.
[0015] It is finally an object of the invention to provide a new
and improved stable isotopic identification and method for
utilizing the same including all of the above features throughout
the chemical, petroleum, pharmaceutical, biomedical, food,
environmental, paint, explosive-ammunition and combustible fuel
industries.
[0016] In the broader aspects of the invention there is provided a
stable isotopic identification comprising a mathematical or
numerical array of concentrations of isotopes found in a batched
product, said mathematical or numerical array being presented in a
machine readable form and comparable to analytical results whereby
the product can be distinguished from other similar products, said
machine readable form also being indexed through stored product
information. The stored product information may be displayed when
desired. By the stable isotopic identification of the invention, a
product may be securely traced through manufacturing of a product,
marketing of a product and the use of a product.
[0017] A method of identifying batched products is also provided
utilizing the stable isotopic identification including the steps of
analyzing a product for the concentration of isotopes, arranging
the concentrations of the isotopes in a mathematical or numerical
array, formulating the mathematical or numerical array in a machine
readable form, assembling product information, and indexing the
product information to the machine readable form of the
mathematical or numerical array, maintaining both the indexing and
the product information, and when desired measuring the isotopic
concentration of a comparable substance, comparing the mathematical
or numerical arrays, and accessing stored product information
through the indexing of the same to product information, whereby a
product may be traced through manufacturing, the marketplace and
use, identified, and indexed to product information.
DESCRIPTION OF A SPECIFIC EMBODIMENT
[0018] The present invention provides a stable isotopic
identification of batched products and a method for utilizing such
isotopic concentrations (which in a specific embodiment may be
expressed in isotopic ratios) in a machine readable form for
identifying batched products and tracking batched products through
manufacturing, marketing and use of a batched product, and readily
indexing product information to the batched product, especially
with pharmaceutical phases, such as active pharmaceutical
ingredients (APIs), drug products, the excipients of drug products
and/or impurities of drug products utilizing concentrations of
naturally occurring stable isotopes, and formulating a stable
isotopic identifications therefrom. The present invention also
provides a unique method for utilizing the stable isotopic
identification of the invention and identifying batched products
later in the manufacturing or the marketing or the use or misuse of
the product and referencing the same to detail product information,
serial numbers, or the like for identifying fraudulent products or
"knock-offs" throughout the chemical, petroleum, pharmaceutical,
biomedical, foodstuff, environmental, paint, explosive-ammunition
and combustible fuel industries.
[0019] The term "batched product" is used herein to include
products manufactured in the batch mode, in contrast to
continuously manufactured products. The term "batched product"
includes pharmaceutical ingredients, excipients of drug products,
impurities in drug products, raw materials in drug products,
additives to combustible fuels, batched combustible fuels, batched
natural occurring products, explosive products, ammunition, gun
powder, batched crude oil, batched petroleum distillates, hazardous
waste, paper, ink, tire materials, paints and other coatings and
other batched manufactured products including continuously
manufactured products or naturally occurring products which are
subsequently batched. All "batched products" within this definition
are homogenous to the extent that multiple samples from the batched
products will have the same composition as determined within the
error of analysis and sampling. Thus, while the term "batched
product" as that term is used in this application may refer to a
homogenous sample of a continuously produced product or a naturally
occurring product, the "batched product" will only relate to the
continuously manufactured product or the naturally occurring
product from which it came within the error of sampling. Thus, the
sample of a batched product which is traced by the method of the
invention to the batched product can only be traced to its origins
within the error in the sampling.
[0020] The term "error" is used herein generically to refer to the
deviation between a measured value and the true value of the
measurement no matter how expressed. The term "precision" is used
herein with regard to any group of multiple measurements to refer
to the 1-sigma standard deviation of those measurements divided by
the square root of the number of observations in the group of
measurements.
[0021] Stable isotopes can be routinely measured by combustion and
mass spectrometric analysis of either bulk phases or of specific
compounds, by spectroscopic means. Bulk phases are analyzed by
either off-line combustion followed by dual-inlet isotope ratio
mass spectrometry (irMS) or by on-line combustion coupled with high
resolution isotope ratio monitoring/mass spectrometry (irmMS).
Specific compounds are analyzed by either gas chromatography
coupled with irmMS (irmGCMS including CRIMS (Chemical Reaction
Interface MS)) as disclosed in U.S. Pat. No. 5,012,052 issued to
John M. Hayes on Apr. 30, 1991 or by liquid chromatography coupled
with irmMS (irmLCMS), depending upon the chromatographic properties
of the analytes. IrmGCMS including CRIMS allows for a continuous
uninterrupted automated analysis whereas off-line methods require
the samples to be purified into separate components and collected
in batches (e.g., glass ampoules) prior to analysis. The
concentrations monitored are generally recorded as isotopic ratios
which are expressed as the concentration of the heavy isotope A
divided by the concentration of lighter isotope B, e.g.,
.sup.13C/.sup.12C, D/H, .sup.15N/.sup.14N, .sup.18O/.sup.16O,
.sup.35S/.sup.32S, etc. Each of these ratios will include the error
of the concentration.
[0022] Ratios of isotopic concentrations are preferred as they
present two distinct advantages over individual concentrations.
First, isotopic ratios can be more reproducibly measured than
compositions. Second, isotopic ratios may not be modified by
non-nuclear physical or chemical processes or explosions such that
ratios will remain intact through subsequent chemical reactions,
including tire wear and explosions.
[0023] Further, isotopic concentrations provide stable isotopic
identifications which are highly specific. Elements which have more
than one stable isotope are numerous. Of the 83 known
non-radioactive elements known to exist on earth, 62 have more than
one stable isotope, and 40 have more than two stable isotopes. The
element tin (Sn) has the largest number of stable isotopes for any
single element. Among the 40 elements having more than two stable
isotopes, there are a total of 224 stable isotopes. Although a few
of the 220 stable isotopes are slightly radioactive, they have very
long lives and are present in many naturally occurring elements.
Thus, as will be seen, the stable isotopic identifications of the
invention are numerous and provide a ready and available means by
which any product (including all pharmaceutical phases APIs, drug
products, excipients of drug products and/or impurities of drug
products) may be readily identified.
[0024] If only the common light elements of carbon, hydrogen,
oxygen, nitrogen and sulfur were used, there are 13 different
stable isotopes. These 13 stable isotopes will provide ample means
for providing a highly specific stable isotopic identification for
any product desirably traced or desirably identified as will be
explained as a specific embodiment hereinafter.
The Stable Isotopic Identification
[0025] The new and improved stable isotopic identification of the
invention provides a highly specifics readable numerical array
which can be used to identify each product desirably identified.
The stable isotopic identification of different products or phases
(such as APIs, drug products, excipients of drug products and/or
impurities of drug products) or other isotopic compositions of a
given phase or isotopic compositions of a combination of different
phases provide a means by which any batched product and each of its
precursors or raw materials or intermediates in a manufacturing
process can be identified and traced through the manufacturing
process, marketing of the product and the use and misuse of the
product. The compositions used are usually stable isotope ratios
measured by combustion and mass spectrometry analysis of either
bulk phases or specific compounds.
[0026] The chemical analysis required to determine the stable
isotopic ratios are classified as bulk stable isotopic composition
(BSIA) or compound-specific isotopic composition (CSIA). These
analyses are performed by high resolution irmMS or by nuclear
magnetic resonance (NMR). Bulk phases are typically analyzed by
either off-line combustion followed by dual inlet mass spectrometry
or by on-line combustion coupled with irmMS. Specific compounds are
analyzed by either irmGCMS including CRIMS or irmLCMS, depending
upon the chromatographic properties of the analytes. NMR can be
applied to either homogeneous bulk phases or to purified specific
compounds.
[0027] Of course stable isotopic concentrations, not ratios, can
also be measured by combustion and mass spectrometric analysis of
either bulk phases or specific compounds by the same techniques in
other specific embodiments. These concentrations instead of being
expressed in ratios, i.e., .sup.13C/.sup.12C, D/H,
.sup.15N/.sup.14N, .sup.18O/.sup.16O, .sup.34S/.sup.32S etc., could
merely be expressed in concentrations, e.g., 12 parts per million
or 0.001 percent or parts per thousand or 0.001 weight percent,
0.001 mole percent, etc. or expressed with the measurement error,
e.g., two parts per thousand plus or minus two parts per million or
0.001 mole percent plus or minus 0.0001 percent. Similarly,
isotopic ratios can be presented in the same fashion as
concentrations.
[0028] The new and improved stable isotopic identification of the
invention is formulated from the concentrations or isotopic ratios
of a selected group of one or more naturally occurring isotopes
found in the product to be identified. Prior to formulating the
isotopic identification of each product, one needs to determine
what error in identifying the product is tolerable. The stable
isotopic identification of the invention may include a simple list
of a plurality of concentrations, a simple list of a plurality of
isotopic ratios, a simple list of a plurality of mathematical
products of isotopic concentrations, a simple list of a plurality
of mathematical products of isotopic ratios, groups of any such
lists, groups of any such mathematical products, groups of any such
ratios, groups of any such concentrations, mathematical products of
any such concentrations plus or minus their error added,
mathematical products of any such ratios plus or minus their errors
added, any of such concentrations, ratios, lists, groups and
mathematical products in quadrature, isotopic ratios of any of such
mathematical products, ratios of said concentrations plus or minus
their errors added, any of said concentrations plus or minus their
errors added, factor analysis of any such concentrations, ratios,
lists, groups, and mathematical products and determinants and
combinations thereof.
[0029] Thus, for example, if the tolerable error in identification
of the product is the same or greater than the error in the
concentration (stable isotope ratio), then simply a listing of the
concentration of a stable isotope may serve as the stable isotopic
identification of the invention. However, if in identification less
error (or greater specificity) is desired, the probability of the
two isotopic compositions of two separate batches from independent
sources being the same is inversely proportional to the product of
the dynamic ranges of each isotopic analysis undertaken; and thus,
the acceptable or tolerable error of identification desired can be
chosen by choosing any one of the above identified mathematical or
numerical arrays involving more than one isotopic
concentration.
[0030] Additionally, the "error of identification" can be reduced
or, the "precision of identification" can be increased by choosing
more than one isotopic concentration. There are a total of 13 if
one limits the stable isotopic identification of the invention to
the common light elements. Reduced error can be accomplished by
using any number of the total of 224 available stable isotopes.
[0031] Further, inasmuch as the specificity is inversely
proportional to the product of the concentrations (statistically,
the product of the dynamic ranges of each analysis), by use of a
mathematical or numerical array including one or more of the
above-identified mathematical products, the error of identification
can even be further reduced or, "the specificity of identification
can even be further increased". Still further, smaller errors of
identification can be obtained by using concentrations and their
error in quadrature, or in factor analysis, or in combinations
thereof.
[0032] By the new and improved stable isotopic identification of
the invention, the error of identification can be significantly
reduced beyond most recognizable error (smaller than one part per
million possibilities of incidental reproduction) such that
identifications can be nearly guaranteed with use of the stable
isotopic identification of the invention, and certainly within the
error of the more publicized DNA identifications from organic
tissue.
[0033] Even with the limitation to common light elements (e.g.,
carbon, hydrogen, nitrogen and sulfur), identification of most
products, pharmaceutical products, drug products, excipients and
impurities can be identified with very little error (high
precision), for example, by using a sample matrix of five isotopic
ratios as shown in Table 1. TABLE-US-00001 TABLE 1 Istopic Drug
Excipient Impurity Ratio Product API #1 #1 Delta .sup.13C C.sub.dp
C.sub.api C.sub.el C.sub.il Delta D D.sub.dp D.sub.api D.sub.el
D.sub.il Delta .sup.18O O.sub.dp O.sub.api O.sub.el O.sub.il Delta
.sup.15N N.sub.dp N.sub.api N.sub.el N.sub.i Delta .sup.34S
S.sub.dp S.sub.api S.sub.el S.sub.il
[0034] The error is reduced, by compounding the precision of five
analytical measurements. Table 1 records the isotopic ratios of
five common light elements occurring in the four phases of a given
pharmaceutical product. In fact, there may be more or fewer than 20
isotopic values indicated in any specific example. For example, the
elements N and S may not occur in a given API or there may be more
than one excipient or impurity. In all events, error in
identification is very small and quantitatively constrained.
[0035] In the other specific examples including the mathematical or
numerical arrays listed above, a variety of lists of
concentrations, lists of concentration ratios, lists of
mathematical products of concentrations or groups of lists or
concentrations, or ratios or mathematical products or mathematical
products of concentrations and errors may be placed in a matrix
such as shown in Table 1 to provide a stable isotopic
identification of the invention for any product known with a degree
of specificity that can be predicted (the probability that the
isotopic compositions of two batches or phases from independent
production sources are the same) that is inversely proportional to
the product of the dynamic ranges for each isotopic analysis
undertaken whether they are bulk or compound specific analyses.
[0036] The "dynamic range" is defined herein as the range of values
expected for a given type of measurement divided by the 1-sigma
standard deviation of that measurement.
[0037] For example, for one bulk isotopic measurement performed on
a subsample of a number of homogenized drug products from a given
batch, the random probability of another manufacturer producing the
same bulk isotopic value is estimated at about one in one hundred,
or 0.01. In fact, the probability may be less than that depending
upon the isotopic ranges of the production phases. A simple
calculation is based upon a conservative one-sigma value for the
standard deviation in the bulk isotopic measurement of
0.1.Salinity., with a 10.Salinity. range in the isotopic range in
the bulk materials (viz., the Dynamic
Range=10.Salinity./0.1.Salinity.=100, the probability=0.01).
[0038] In the second example, where two or more isotopic
compositions are measured for example, one bulk analysis and one
compound-specific analysis, the random probabilities of another
manufacturer producing two similar isotopic values decreases
multiplicatively by orders of magnitude, for example,
0.01.times.0.01=0.0001, or 1 in 10,000. Recalling that both types
of compound-specific analyses typically generate a number of
isotopic analyses of whatever is chromatographable in the sample
(often approximately 100 individual compounds), whether an API or
excipient or a drug product or an impurity or another product, the
probability of another manufacturer producing a product with a
similar isotopic composition is vanishingly small. Thus, such a
stable isotopic identification of the invention for any given batch
may be virtually unique or highly specific (significantly smaller
than 1 part per million).
[0039] For purposes of comparison, results of BSIA and/or CSIA
analyses can be expressed in three ways: a simple column, a table
like Table 1, or in mathematical determinants. The salient point is
to uniquely connect stable isotopic identifications of a product to
measured isotopic values for later retrieval and comparison to
sample or suspect pharmaceutical phases. In accordance with the
invention, these may be indexed in the form of serial numbers or a
machine readable bar code display on a container for the product or
both.
[0040] In specific embodiments, the mathematical or numerical array
of the stable isotopic identification of the invention may be in
tabular or matrix form as above described. When using a tabular or
matrix or mathematical or numerical array, computerized sorting of
the tabular rows and columns of isotopic values by increasing or
decreasing values of individual isotopic concentrations will reveal
whether or not a sample or suspect isotopic value would fit into
the table or matrix as an initial test of specificity. Overlap of
the sample isotopic value (e.g., within error limits) indicates a
possible match with a pre-existing possible match with the stable
isotopic identification of the invention which can be addressed
through standard statistical techniques of comparison. Further
comparison of the isotopic values of the stable isotopic
identification allows a stepwise comparison of the other isotopic
values of the stable isotopic identification. The lack of a match
with any previously tabulated isotopic value indicates a different
and distinguishable product or pharmaceutical phase, perhaps a
counterfeit product.
[0041] By contrast, a match with a previously identified isotopic
value indicates one of three possibilities: (1) a new and unique
isotopically defined pharmaceutical phase isotopic value that
exists within the statistical limits defined by the ranges of the
isotopic value considered, (2) the highly unlikely possibility of a
coincidental match (within limits defined by the isotopic range of
the product considered), or (3) the extremely unlikely possibility
of a fraudulent synthesized isotopic match. If the isotopic value
does not overlap with any previous stable isotopic identification,
then it shall be considered a new and different and distinguishable
composition. If it does not match a firm's list of stable isotopic
identifications for that firm's batches or products, then the
observed stable isotopic identification indicates a product not
produced by the firm.
[0042] In other specific embodiments, combination by multiplication
of isotopic values within a stable isotopic identification of the
invention (plus or minus the error of the measurements added in
quadrature) will result in a highly specific stable isotopic
identification which can be used as a batch's serial number or
added to a serial number. For example, the identification may be
stated as:
(.delta..sup.13C*.delta..sup.15N)*[1+/-([1.sigma.-.delta..sup.13C/.DELTA.-
.delta..sup.13C].sup.2+[1.sigma.-.delta..sup.15N/.DELTA..delta..sup.15N].s-
up.2).sup.0.5]
[0043] As with the tabular method above, the lack of matching with
previously recorded values indicates a distinctly different
product. But this method requires only that the investigator sort
the isotopic data by one column (as opposed to sorting by each
isotopic value). This method also hides the individual isotopic
values of the sample from all but those who have the original
isotopic values of each component.
[0044] Finally, factor analysis with specific intervals around data
clusters may be used to delineate specific sets of isotopically
defined products. Samples that have stable isotopic identifications
which fall within the confidence intervals of data clusters shall
be considered statistically from the same batch of products. Those
falling without the confidence intervals shall be considered to be
distinctly different products.
The Method of the Invention
[0045] The method of identifying products of the invention
utilizing stable isotopic identifications takes the advantage of
the natural variability in the product of isotopic compositions
based on the product and their raw materials. Two classes of
analytes are analyzed for their isotopic composition include bulk
properties (bulk solids, liquids, or gases) and molecular
properties (i.e., in pharmaceuticals, specific compounds such as
APIs, excipients, and impurities).
[0046] These analytes are typically analyzed by one of two methods:
Bulk properties are either measured in a stepwise
combustion-analysis mode by either dual inlet mass spectrometry
(off-line) or in a continuous combustion-analysis mode by irMS
(on-line). In the off-line method, bulk analytes are typically
prepared by combustion for analysis in sealed ampoules from which
carbon dioxide (CO.sub.2) or other combustion gases are
cryogenically distilled. In the on-line method (also known as
BSIA), an automated, on-line combustion device (e.g., an elemental
analyzer) combusts bulk organic matter into gases (for example,
CO.sub.2, N.sub.2). Those gases may either be directly or
indirectly isotopically analyzed, depending on the necessity for
chemical reduction. The combustion and reduction steps are followed
by isothermal packed-column chromatography that resolves the
gaseous products prior to isotopic analysis. The stable isotopic
analysis of specific compounds (CSIA) is typically performed either
by irmGCMS including CRIMS or irmLCMS. The selection of the method
depends on the chromatographic characteristics of the analyte. In
the CSIA methods, organic analytes are separated by either gas
chromatography or by liquid chromatography. The organic effluent is
then combusted in an on-line combustion oven, and the effluent
gases (typically, CO.sub.2 or N.sub.2) are isotopically analyzed by
an on-line high-resolution mass spectrometer. Carbon isotopic
results are typically expressed in either atom percent of the less
abundant isotope or delta values (parts per thousand differences
from a standard defined as:
.delta..sup.13C(.Salinity.)=[(R.sub.sample/R.sub.standard)-1]*(1000)
where: R.sub.smpl=the .sup.13C/.sup.12C ratio of the sample
material and the R.sub.std is the .sup.13C/.sup.12C ratio of an
International Atomic Energy Authority standard (known as "VPDB"
whose .sup.13C/.sup.12 C ratio has been defined as the official
zero point of the carbon-isotopic scale). Other stable isotope
ratios are similarly expressed.
[0047] In another specific embodiment, isotopic analyses of either
bulk drug products, APIs, excipients, or impurities can also be
performed using NMR spectroscopy.
[0048] In another specific embodiment, the use of bulk stable
isotopic analysis (BSIA) for drug products, for example, pills,
salves, evaporated liquids, etc., via either off-line (ampoulated)
or on-line high resolution mass spectrometry or the use of NMR
spectroscopy can also be achieved.
[0049] In another specific embodiment, the use of compound-specific
analysis (CSIA) for the analysis of Active Pharmaceutical
Ingredients (APIs) via either irmGCMS including CRIMS, irmLCMS, or
by NMR spectroscopy, depending on the nature of the analyte can
also be achieved.
[0050] In another specific embodiment, the use of CSIA for the
analysis of excipients in drug products via either irmGCMS
including CRIMS, irmLCMS or by NMR spectroscopy, depending on the
nature of the analyte can also be achieved.
[0051] In another specific embodiment, the use of CSIA for the
analysis of impurities in drug products via either irmGCMS
including CRIMS, irmLCMS or by NMR spectroscopy, depending on the
nature of the analyte can also be achieved.
[0052] The same analytical procedures can be used to identify other
products, such as organic products, such as gunpowder and other
explosives, crude oil, foodstuffs, petroleum distillates, hazardous
waste, paper and/or ink, and tire materials.
[0053] Once the product is analyzed with the concentration of
isotopes and the concentration of each of the stable isotopes of
the total of 224 stable isotopes available, which will form a part
of the stable isotopic identification of the invention have been
analyzed, the concentrations are arranged in a mathematical or
numerical array and the array is formulated into a readable form
and placed on the product or its container. This mathematical or
numerical array could be part of the serial number, or it could be
separately identified, or it could be a bar code on the product.
The mathematical or numerical array may be in the form as above
described, and in a specific embodiment, may be chosen from the
group of mathematical or numerical arrays consisting of a list of a
plurality of concentrations, a list of a plurality of isotope
ratios, a list of a plurality of products, or a list of a plurality
of products of concentrations and errors.
[0054] The array could also be a matrix as shown in Table 1 or
connected to serial numbers or formulated in tabular form or ratio
form or mathematical product form or in quadrature or in factor
analysis or any combinations thereof. Each of these forms are
described hereinabove with regard to the stable isotopic
identification of the invention.
[0055] The mathematical or numerical array is then formulated into
a readable form. This could be a set of numbers in a machine
readable language or in a bar code or in such other machine
readable form. The machine readable form could be part of a serial
number or part of a product identification.
[0056] The product information, such as ingredient identifications,
formulations, etc., is then assembled. With regard to
pharmaceutical products, physician directed information could all
be assembled as a part of the product information.
[0057] The product information is then indexed to the
aforementioned readable form. A machine readable form could be read
by a machine by which one would then view the product information
on a screen, scroll through the product information and/or print
out the sought for information, as required. Both the index and the
product information would be maintained such that the product
information could be accessed by machine from the machine readable
form of the stable isotopic identification of the invention.
[0058] The method of the invention further comprises the steps of
measuring the concentrations of the chosen isotopes of an unknown
product in the same manner as the product identified by the stable
isotopic identification of the invention was analyzed as above
described, and comparing the stable isotopic identification of the
known product with the isotopic analyses of the unknown product.
This can be achieved in a number of ways. Whenever the stable
isotopic identification is an array of more than concentration,
ratio or product, the comparison may involve any of the
statistically step by step comparisons of each ratio, concentration
or product to an identification of product and the error desired.
Once a product has been identified through its stable isotopic
identification number, all of the product information that has been
assembled can be found through the index.
[0059] While a specific embodiment of the invention has been shown
and described herein for purposes of illustration, the protection
afforded by any patent which may issue upon this application is not
strictly limited to the disclosed embodiment; but rather extends to
all structures and arrangements which fall fairly within the scope
of the claims which are appended hereto:
* * * * *