U.S. patent application number 15/165866 was filed with the patent office on 2016-09-15 for spectroscopic analysis.
The applicant listed for this patent is KLEIN MEDICAL LIMITED. Invention is credited to Donal Paul Krouse, Raymond Andrew Simpkin, Bryan James Smith.
Application Number | 20160265972 15/165866 |
Document ID | / |
Family ID | 49769066 |
Filed Date | 2016-09-15 |
United States Patent
Application |
20160265972 |
Kind Code |
A1 |
Simpkin; Raymond Andrew ; et
al. |
September 15, 2016 |
SPECTROSCOPIC ANALYSIS
Abstract
A method and analyser for identifying or verifying or otherwise
characterising a sample comprising: using or having an
electromagnetic radiation source for emitting electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, using or
having a sample detector that detects affected electromagnetic
radiation resulting from the emitted electromagnetic radiation
affected by the sample and provides output representing the
detected affected radiation, and using or having a processor for
determining sample coefficients from the output, and identifying or
verifying or otherwise characterising the sample using the sample
coefficients and training coefficients determined from training
samples, wherein the coefficients reduce sensitivity to a sample
retainer variation and/or are independent of concentration.
Inventors: |
Simpkin; Raymond Andrew;
(Auckland, NZ) ; Krouse; Donal Paul; (Wellington,
NZ) ; Smith; Bryan James; (Auckland, NZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KLEIN MEDICAL LIMITED |
Auckland |
|
NZ |
|
|
Family ID: |
49769066 |
Appl. No.: |
15/165866 |
Filed: |
May 26, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14409450 |
Dec 18, 2014 |
9354165 |
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PCT/NZ2013/000107 |
Jun 19, 2013 |
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15165866 |
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61661573 |
Jun 19, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 21/274 20130101;
G01N 2201/0691 20130101; G01N 21/3577 20130101; G01N 21/359
20130101; G01J 3/28 20130101; G01J 3/108 20130101; G01J 3/0297
20130101 |
International
Class: |
G01J 3/10 20060101
G01J003/10; G01J 3/02 20060101 G01J003/02 |
Claims
1. An analyser for identifying or verifying or otherwise
characterising a sample comprising: an electromagnetic radiation
source for emitting electromagnetic radiation in at least one beam
at a sample, the electromagnetic radiation comprising at least two
different wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected radiation, and a
processor for determining sample coefficients from the output, and
identifying or verifying or otherwise characterising the sample
using the sample coefficients and training coefficients determined
from training samples.
2. An analyser according to claim 1, wherein the sample detector
output represents intensities detected by the detector at the at
least two wavelengths, and wherein determining the sample
coefficients comprises determining and using a fractional spectral
intensity at each wavelength.
3. An analyser according to claim 2, further comprising a reference
detector for detecting reference electromagnetic radiation at the
at least two wavelengths that provides output representing
intensities detected at the at least two wavelengths, and the
fractional spectral intensity at each wavelength is a normalised
fractional spectral intensity using the output from the reference
detector.
4. A analyser according to claim 3, wherein the analyser is used on
a plurality of training samples to obtain from the sample detector
training output for a plurality of training samples representing
intensities detected by the detector at the at least two
wavelengths, and wherein the processor is configured to determine
the training coefficients by determining and using a fractional
spectral intensity at each wavelength of the training output.
5. An analyser according to claim 4, wherein the fractional
spectral intensity is a normalised fractional spectral intensity
using output from a reference detector.
6. An analyser according to claim 5, wherein the fractional
intensity is defined as the proportion of transmitted light
measured at a wavelength referenced to the sum of intensities over
all the at least two wavelengths.
7. A method for identifying or verifying or otherwise
characterising a sample comprising: emitting electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, detecting
affected electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and providing
detected output representing the detected affected radiation,
determining sample coefficients from the output, and identifying or
verifying or otherwise characterising the sample using the sample
coefficients and training coefficients determined from training
samples.
8. A method according to claim 7, wherein the detected output
represents intensities detected at the at least two wavelengths,
and wherein determining the sample coefficients comprises
determining and using a fractional spectral intensity at each
wavelength.
9. A method according to claim 8, further comprising detecting
reference electromagnetic radiation at the at least two wavelengths
and providing output representing intensities detected at the at
least two wavelengths, and the fractional spectral intensity at
each wavelength is a normalised fractional spectral intensity using
the output from the reference detector.
10. A method according to claim 9, further comprising: for a
plurality of training samples, emitting electromagnetic radiation
in at least one beam at each training sample, the electromagnetic
radiation comprising at least two different wavelengths, for each
training sample, detecting affected electromagnetic radiation
resulting from the emitted electromagnetic radiation affected by
the sample and providing detected output representing the detected
affected radiation, for each sample, determining training
coefficients from the output by determining and using a fractional
spectral intensity at each wavelength of the training output.
11. A method according to claim 10, wherein the fractional spectral
intensity is a normalised fractional spectral intensity using
output from a reference detector.
12. A method according to claim 11, wherein the fractional
intensity is defined as the proportion of transmitted light
measured at a wavelength referenced to the sum of intensities over
all the at least two wavelengths.
13. A method for identifying or verifying or otherwise
characterising a sample comprising: emitting electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, detecting
the emitted electromagnetic radiation at each wavelength and
providing detected output representing the emitted electromagnetic
radiation being reference intensity detected at each wavelength,
detecting affected electromagnetic radiation resulting from the
emitted electromagnetic radiation affected by the sample and
providing detected output representing the detected affected
radiation being output intensity detected at each wavelength,
measuring the temperature of the sample determining sample
coefficients from the output, and identifying or verifying or
otherwise characterising the sample using the sample coefficients
and training coefficients determined from training samples, wherein
determining the sample coefficients comprises: eliminating dark
current from the output of the reference and output intensities,
determining fractional spectral intensities from the reference and
output intensities, determining a concentration independent
coefficient from the fractional spectral intensities, wherein the
training coefficients have be determined from data temperature
corrected to the temperature of the sample.
Description
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic
priority claim is identified in the Application Data Sheet as filed
with the present application are hereby incorporated by reference
in their entireties and made a part of the present application.
FIELD OF THE INVENTION
[0002] The present invention relates to a spectroscopic analyser,
such as a spectrophotometer, for verifying and/or identifying or
otherwise analysing drugs, blood or other substances.
BACKGROUND OF THE INVENTION
[0003] Spectroscopy, for example through the use of a spectroscopic
analyser such as a spectrophotometer, can be used to analyse
substances. For example, by directing incident radiation towards a
sample, and analysing the spectral nature of the affected
radiation, it can be possible to gain an indication of the nature
of the sample.
[0004] However, such analysers often provide inaccurate analysis.
Accurately discriminating between different substances can be
difficult.
SUMMARY OF INVENTION
[0005] It is an object of the present invention to provide an
analyser and/or method for verifying or identifying or otherwise
characterising a drug or other substances using spectroscopy.
[0006] The embodiments described in the present specification are
directed towards drug characterisation but the invention is not
limited to just characterising drugs. Those skilled in the art will
appreciate that the disclosure herein can be applied to
characterisation of other substances also.
[0007] In one aspect the present invention may be said to consist
in an analyser for identifying or verifying or otherwise
characterising a sample comprising: an electromagnetic radiation
source for emitting electromagnetic radiation in at least one beam
at a sample, the electromagnetic radiation comprising at least two
different wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected radiation, and a
processor for determining sample coefficients from the output, and
identifying or verifying or otherwise characterising the sample
using the sample coefficients and training coefficients determined
from training samples.
[0008] Preferably the sample detector output represents intensities
detected by the detector at the at least two wavelengths, and
wherein determining the sample coefficients comprises determining
and using a fractional spectral intensity at each wavelength.
[0009] Preferably the analyser further comprises a reference
detector for detecting reference electromagnetic radiation at the
at least two wavelengths that provides output representing
intensities detected at the at least two wavelengths, and the
fractional spectral intensity at each wavelength is a normalised
fractional spectral intensity using the output from the reference
detector.
[0010] Preferably the analyser is used on a plurality of training
samples to obtain from the sample detector training output for a
plurality of training samples representing intensities detected by
the detector at the at least two wavelengths, and wherein the
processor is configured to determine the training coefficients by
determining and using a fractional spectral intensity at each
wavelength of the training output.
[0011] Preferably the fractional spectral intensity is a normalised
fractional spectral intensity using output from a reference
detector.
[0012] Preferably the fractional intensity is defined as the
proportion of transmitted light measured at a wavelength referenced
to the sum of intensities over all the at least two
wavelengths.
[0013] Preferably the normalised spectral intensity at each
wavelength is determined in the processor using:
g m = f m .SIGMA. f m ##EQU00001##
[0014] Where: f.sub.m is an electromagnetic radiation intensity (or
some parameter related to it--processed or unprocessed) detected at
the m.sup.th wavelength, and preferably the intensity f.sub.m is a
ratio of (optionally an average of) sample intensity(ies) to
(optionally an average of) reference intensity(ies) or of
(optionally an average of) training intensity(ies) to (optionally
an average of) reference intensity(ies) as appropriate, and
[0015] .SIGMA.f.sub.m is the sum of intensities over all of the at
least two wavelengths.
[0016] Preferably the sample and/or training samples comprise a
substance in a dilutant with a concentration and the sample
coefficients and/or training coefficients are independent of the
concentration.
[0017] Preferably each sample coefficient is determined by:
y m B = s m B .SIGMA. m ( s m B ) 2 .ident. g m B ( x ) - g m 0 _
.SIGMA. m ( g m B ( x ) - g m 0 _ ) 2 ##EQU00002##
[0018] where g.sub.m.sup.B(x)-g.sub.m.sup.0=s.sub.m.sup.Bx
(preferably being a slope or difference between the undiluted
substance and a dilutant)
[0019] X is the concentration of the substance in the dilutant
[0020] B denoting blind test sample
[0021] g.sub.m.sup.B(x), is the fractional spectral intensity of
the sample with unknown concentration, and
[0022] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0023] Preferably each training coefficient is determined by:
y m = s m .SIGMA. m s m 2 ##EQU00003##
[0024] where s.sub.m=g.sub.m-g.sub.m.sup.0 (preferably being a
slope or difference between the undiluted substance and a
dilutant)
[0025] g.sub.m is the fractional spectral intensity of the
undiluted sample (being the undiluted substance), and
[0026] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0027] Preferably the analyser further comprises a modulator such
that the emitted electromagnetic radiation at the sample is
modulated electromagnetic radiation and prior to determining the
sample coefficients the processor extracts the desired spectral
component from the intensity at each of the at least two
wavelengths to eliminate the dark current.
[0028] Preferably prior to determining the training coefficients
the desired spectral components are extracted by the processor from
the intensity at each of the at least two wavelengths to eliminate
the dark current.
[0029] Preferably the processor extracts the desired spectral
component by multiplying the output representing the detected
affected modulated electromagnetic radiation by sine and cosine
functions and integrating over the period of modulation oscillation
to remove the dark current component.
[0030] Preferably the processor extracts the desired spectral
component by conducting a Fourier Transform on the output
representing the modulated detected affected radiation and removing
the dark current component from the transformed output.
[0031] Preferably the analyser further comprises a temperature
sensor to measure the temperature of the sample and provide
temperature output to the processor, wherein the processor corrects
the desired spectral components of the training coefficients at the
at least two wavelengths to the temperate of the sample.
[0032] Preferably the temperature is corrected according to:
I ( T c ) = ! ( T b ) + I T .DELTA. T ( 1 ) ##EQU00004##
[0033] Where,
[0034] I is the intensity of affected electromagnetic radiation
detected by a detector at a particular wavelength for a sample,
[0035] T.sub.c is the temperature of the training sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0036] T.sub.b is the temperature of the unknown sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0037] .DELTA.T=T.sub.c-T.sub.b is the sample temperature
difference between the training sample temperature and unknown
sample temperature, and
[0038] dI/dT is the slope of the linear relationship of between
measure intensity and temperature for a sample at a given
wavelength.
[0039] Preferably to identify or verify or otherwise characterise
the sample using the coefficients and training coefficients
determined from training samples, the processor: determines or
obtains a training value for each training sample based on a
combination of weights for each training coefficient for each of
the training samples, determines or obtains a sample value for the
sample based on a combination of weights for each sample
coefficient, indentifies or verifies or otherwise characterises the
sample based on the relationship between the training and sample
values.
[0040] Preferably further comprising the processor determining the
concentration of the sample.
[0041] Preferably to determine the concentration of the sample the
processor uses:
x = g m B ( x ) - g m 0 _ s m ##EQU00005##
[0042] Where x is the concentration, and
g.sub.m.sup.B(x)-g.sub.m.sup.0=s.sub.m.sup.Bx
[0043] X is the concentration of the substance in the dilutant
[0044] B denoting blind test sample
[0045] g.sub.m.sup.B(x), is the fractional spectral intensity of
the sample with unknown concentration, and
[0046] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant
s.sub.m=g.sub.m-g.sub.m.sup.0
[0047] g.sub.m is the fractional spectral intensity of the
undiluted sample (being the undiluted substance), and
[0048] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0049] Preferably each wavelength or at least two of the
wavelengths is between substantially 1300 nm and 2000 nm, and each
wavelength or at least two of the wavelengths is in the vicinity of
the wavelength(s) of (or within a region spanning) a spectral
characteristic in the liquid spectrum between substantially 1300 nm
and 2000 nm.
[0050] Preferably the electromagnetic radiation comprises a
plurality of electromagnetic radiation beams, each beam having a
different wavelength.
[0051] Preferably the source is a laser comprising a photodetector,
wherein the photodetector is the reference detector.
[0052] Preferably the liquid is water, there are six
electromagnetic radiation beams and the wavelengths are
substantially 1350 nm, 1450 nm, 1550, nm, 1650, nm, 1750 nm and
1850 nm, and optionally wherein 1450 nm is the anchor
wavelength.
[0053] Preferably the sample is in an intravenous delivery device
such as an IV infusions set or syringe, or other receptacle such as
a test-cell, test-tube, flow cell or the like.
[0054] In another aspect the present invention may be said to
consist in a method for identifying or verifying or otherwise
characterising a sample comprising: emitting electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, detecting
affected electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and providing
detected output representing the detected affected radiation,
determining sample coefficients from the output, and identifying or
verifying or otherwise characterising the sample using the sample
coefficients and training coefficients determined from training
samples.
[0055] Preferably the detected output represents intensities
detected at the at least two wavelengths, and wherein determining
the sample coefficients comprises determining and using a
fractional spectral intensity at each wavelength.
[0056] Preferably the method further comprises detecting reference
electromagnetic radiation at the at least two wavelengths and
providing output representing intensities detected at the at least
two wavelengths, and the fractional spectral intensity at each
wavelength is a normalised fractional spectral intensity using the
output from the reference detector.
[0057] Preferably the method further comprises: for a plurality of
training samples, emitting electromagnetic radiation in at least
one beam at each training sample, the electromagnetic radiation
comprising at least two different wavelengths, for each training
sample, detecting affected electromagnetic radiation resulting from
the emitted electromagnetic radiation affected by the sample and
providing detected output representing the detected affected
radiation, for each sample, determining training coefficients from
the output by determining and using a fractional spectral intensity
at each wavelength of the training output.
[0058] Preferably the fractional spectral intensity is a normalised
fractional spectral intensity using output from a reference
detector.
[0059] Preferably the fractional intensity is defined as the
proportion of transmitted light measured at a wavelength referenced
to the sum of intensities over all the at least two
wavelengths.
[0060] Preferably the normalised spectral intensity at each
wavelength is determined by:
g m = f m .SIGMA. f m ##EQU00006##
[0061] Where: f.sub.m is an electromagnetic radiation intensity (or
some parameter related to it--processed or unprocessed) detected at
the m.sup.th wavelength, and preferably the intensity f.sub.m is a
ratio of (optionally an average of) sample intensity(ies) to
(optionally an average of) reference intensity(ies) or of
(optionally an average of) training intensity(ies) to (optionally
an average of) reference intensity(ies) as appropriate, and
[0062] .SIGMA.f.sub.m is the sum of intensities over all of the at
least two wavelengths.
[0063] Preferably the sample and/or training samples comprise a
substance in a dilutant with a concentration and the sample
coefficients and/or training coefficients are independent of the
concentration.
[0064] Preferably each sample coefficient is determined by:
y m B = s m B .SIGMA. m ( s m B ) 2 .ident. g m B ( x ) - g m 0 _
.SIGMA. m ( g m B ( x ) - g m 0 _ ) 2 ##EQU00007##
[0065] Where g.sub.m.sup.B(x)-g.sub.m.sup.0=s.sub.m.sup.Bx
(preferably being a slope or difference between the undiluted
substance and a dilutant)
[0066] X is the concentration of the substance in the dilutant
[0067] B denoting blind test sample
[0068] g.sub.m.sup.B(x), is the fractional spectral intensity of
the sample with unknown concentration, and
[0069] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0070] Preferably each training coefficient is determined by:
y m = s m .SIGMA. m s m 2 ##EQU00008##
[0071] where s.sub.m=g.sub.m-g.sub.m.sup.0 (preferably being a
slope or difference between the undiluted substance and a
dilutant)
[0072] g.sub.m is the fractional spectral intensity of the
undiluted sample (being the undiluted substance), and
[0073] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0074] Preferably the emitted electromagnetic radiation at the
sample is modulated electromagnetic radiation and prior to
determining the sample coefficients the desired spectral component
is extracted from the intensity at each of the at least two
wavelengths to eliminate the dark current.
[0075] Preferably prior to determining the training coefficients
the desired spectral components are extracted from the intensity at
each of the at least two wavelengths to eliminate the dark
current.
[0076] Preferably the desired spectral component is extracted by
multiplying the output representing the detected affected modulated
electromagnetic radiation by sine and cosine functions and
integrating over the period of modulation oscillation to remove the
dark current component.
[0077] Preferably the desired spectral component is extracted by
conducting a Fourier Transform on the output representing the
modulated detected affected radiation and removing the dark current
component from the transformed output.
[0078] Preferably the method further comprises measuring the
temperature of the sample and provide temperature output to the
processor, and correcting the desired spectral components of the
training coefficients at the at least two wavelengths to the
temperate of the sample.
[0079] Preferably the temperature is corrected according to:
I ( T c ) = ! ( T b ) + I T .DELTA. T ( 1 ) ##EQU00009##
[0080] Where,
[0081] I is the intensity of affected electromagnetic radiation
detected by a detector at a particular wavelength for a sample,
[0082] T.sub.c is the temperature of the training sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0083] T.sub.b is the temperature of the unknown sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0084] .DELTA.T=T.sub.c-T.sub.b is the sample temperature
difference between the training sample temperature and unknown
sample temperature, and
[0085] dI/dT is the slope of the linear relationship of between
measure intensity and temperature for a sample at a given
wavelength.
[0086] Preferably to identify or verify or otherwise characterise
the sample using the coefficients and training coefficients
determined from training samples, comprises: determining or
obtaining a training value for each training sample based on a
combination of weights for each training coefficient for each of
the training samples, determining or obtaining a sample value for
the sample based on a combination of weights for each sample
coefficient, indentifying or verifying or otherwise characterising
the sample based on the relationship between the training and
sample values.
[0087] Preferably the method further comprises determining the
concentration of the sample.
[0088] Preferably determining the concentration of the sample the
processor uses:
x = g m B ( x ) - g m 0 _ s m ( 7 ) ##EQU00010##
[0089] Where x is the concentration, and
[0090] Where g.sub.m.sup.B(x)-g.sub.m.sup.0=s.sub.m.sup.Bx
[0091] X is the concentration of the substance in the dilutant
[0092] B denoting blind test sample
[0093] g.sub.m.sup.B(x), is the fractional spectral intensity of
the sample with unknown concentration, and
[0094] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant
s.sub.m=g.sub.m-g.sub.m.sup.0
[0095] g.sub.m is the fractional spectral intensity of the
undiluted sample (being the undiluted substance), and
[0096] g.sub.m.sup.0 is the fractional spectral intensity of the
dilutant.
[0097] Preferably each wavelength or at least two of the
wavelengths is between substantially 1300 nm and 2000 nm, and each
wavelength or at least two of the wavelengths is in the vicinity of
the wavelength(s) of (or within a region spanning) a spectral
characteristic in the liquid spectrum between substantially 1300 nm
and 2000 nm.
[0098] Preferably the electromagnetic radiation comprises a
plurality of electromagnetic radiation beams, each beam having a
different wavelength.
[0099] Preferably the liquid is water, there are six
electromagnetic radiation beams and the wavelengths are
substantially 1350 nm, 1450 nm, 1550, nm, 1650, nm, 1750 nm and
1850 nm, and optionally wherein 1450 nm is the anchor
wavelength.
[0100] Preferably the sample is in an intravenous delivery device
such as an IV infusions set or syringe, or other receptacle such as
a test-cell, test-tube, flow cell or the like.
[0101] In another aspect the present invention may be said to
consist in a method for identifying or verifying or otherwise
characterising a sample comprising: emitting electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, detecting
the emitted electromagnetic radiation at each wavelength and
providing detected output representing the emitted electromagnetic
radiation being reference intensity detected at each wavelength,
detecting affected electromagnetic radiation resulting from the
emitted electromagnetic radiation affected by the sample and
providing detected output representing the detected affected
radiation being output intensity detected at each wavelength,
measuring the temperature of the sample determining sample
coefficients from the output, and identifying or verifying or
otherwise characterising the sample using the sample coefficients
and training coefficients determined from training samples, wherein
determining the sample coefficients comprises: eliminating dark
current from the output of the reference and output intensities,
determining fractional spectral intensities from the reference and
output intensities, determining a concentration independent
coefficient from the fractional spectral intensities, wherein the
training coefficients have be determined from data temperature
corrected to the temperature of the sample.
[0102] In another aspect the present invention may be said to
consist in an analyser for identifying or verifying or otherwise
characterising a sample comprising: an electromagnetic radiation
source for emitting electromagnetic radiation in at least one beam
at a sample, the electromagnetic radiation comprising at least two
different wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected radiation, and a
processor for determining sample coefficients from the output, and
identifying or verifying or otherwise characterising the sample
using the sample coefficients and training coefficients determined
from training samples, wherein the sample coefficients are found
from the slope/difference of normalised spectral intensity at a
particular wavelength normalised with respect to the
root-sum-of-squares slope/difference of normalised spectral
intensity taken over all wavelengths, each slope/difference of
normalised spectral intensity being obtained from detector output
for the sample in undiluted form and a dilutant for a particular
wavelength, and each normalised spectral intensity being found from
the detected intensity at a particular wavelength over the sum of
detected intensities for all wavelengths for a sample.
[0103] The wavelengths relate to the test wavelengths.
[0104] In another aspect the present invention may be said to
consist in an analyser for identifying or verifying a liquid based
drug sample comprising: an electromagnetic radiation source for
emitting electromagnetic radiation in at least one beam at a
sample, the electromagnetic radiation comprising at least two
different wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected radiation, and a
processor for identifying or verifying the sample from the detector
output representing the detected affected electromagnetic
radiation, wherein each wavelength or at least two of the
wavelengths is between substantially 1300 nm and 2000 nm, and each
wavelength or at least two of the wavelengths is in the vicinity of
the wavelength(s) of (or within a region spanning) a spectral
characteristic in the liquid spectrum between substantially 1300 nm
and 2000 nm.
[0105] Preferably the electromagnetic radiation comprises a
plurality of electromagnetic radiation beams, each beam having a
different wavelength.
[0106] Preferably verifying or identifying the drug sample is
against comparison data for one of a set of n drugs, and wherein
the electromagnetic radiation comprises at least log.sub.2 n
different wavelengths in one or more beams.
[0107] Preferably the different wavelengths span or capture a
plurality of at least some of the spectral characteristics in the
liquid spectrum between 1300 nm and 2000 nm.
[0108] Preferably the liquid spectrum comprises two or more
spectral characteristics, and wherein: each spectral characteristic
falls in or spans a region of the liquid spectrum, each wavelength
falls within one of the regions.
[0109] Preferably each region is defined by a wavelength range.
[0110] Preferably the spectral characteristics comprise peaks,
troughs, inflections, stable points or regions plateaus, knees
and/or slopes of the liquid spectrum.
[0111] Preferably the liquid is water and comprises spectral
characteristics falling in the following regions of the water
spectrum: a first region between 1300 nm and 1400 nm, a second
region between 1400 nm and 1500 nm, a third region between 1500 nm
and 1600 nm, a fourth region between 1600 nm and 1700 nm, a fifth
region between 1700 nm and 1800 nm, and a sixth region between 1800
nm and 200 nm.
[0112] Preferably the electromagnetic radiation has an anchor
wavelength in the vicinity of the wavelength(s) of (or within a
region spanning) a stable region in the liquid spectrum.
[0113] Preferably the each wavelength further corresponds to a
wavelength produced by a source that is readily/cheaply
obtainable.
[0114] Preferably the source is a plurality of lasers, each laser
configured to emit an electromagnetic radiation beam at a fixed or
tuneable wavelength.
[0115] Preferably comprises a modulator for modulating the
electromagnetic radiation beam(s) emitted at the sample resulting
in detected affected radiation detected by the sample detector that
is modulated wherein the processor as part of identifying or
verifying the sample from the output from the detector removes the
dark current component from the output representing the detected
affected modulated electromagnetic radiation
[0116] Optionally the processor removes the dark current component
by multiplying the output representing the detected affected
modulated electromagnetic radiation by sine and cosine functions
and integrating over the period of modulation oscillation to remove
the dark current component.
[0117] Optionally the processor removes the dark current component
by conducting a Fourier Transform on the output representing the
modulated detected affected radiation and removing the dark current
component from the transformed.
[0118] Preferably the processor identifies or verifies the drug
sample using reference information. Preferably the affected
electromagnetic radiation at or the electromagnetic radiation beam
comprising the anchor wavelength provides the reference
information.
[0119] Preferably the analyser further comprises: an optical device
for directing the plurality of electromagnetic radiation beams to a
reference sample, a reference detector that detects affected
electromagnetic radiation beams affected by the reference sample to
obtain the reference information and that passes the reference
information to the processor.
[0120] Preferably the detector and/or source are temperature
compensated to provide temperature stability, preferably using
thermistors and peltier devices in a closed loop system.
[0121] Preferably each electromagnetic radiation beam is a high
intensity narrowband light beam.
[0122] Preferably the detector is a broadband photodiode that is
biased to have a response corresponding to the wavelength/s of the
affected radiation.
[0123] Preferably the emitted electromagnetic radiation beams from
the plurality of lasers are directed to a sample path by one or
more of: a carousel or carriage device to position the laser beams
in the sample path, or a prism, diffraction grating, beam splitter
or other optical device to redirect a radiation beam along the
sample path.
[0124] Preferably the processor receives: output representing the
affected electromagnetic radiation from the drug sample which
provides drug sample information, and optionally reference
information for each wavelength, and the processor: determines a
representative value of the drug sample information using that
information and optionally reference information for each
wavelength.
[0125] Preferably the sample information and reference information
correlate intensity and wavelength for each electromagnetic
radiation beam.
[0126] Preferably the representative value corresponds to a best
fit between the sample information and optionally the reference
information.
[0127] Preferably the representative value for the electromagnetic
radiation beam for each wavelength is compared to stored values to
verify or identify the drug sample.
[0128] Preferably the liquid is water, there are six
electromagnetic radiation beams and the wavelengths are
substantially 1350 nm, 1450 nm, 1550, nm, 1650, nm, 1750 nm and
1850 nm, and optionally wherein 1450 nm is the anchor
wavelength.
[0129] Preferably the sample is in an intravenous delivery device
such as an IV infusions set or syringe, or other receptacle such as
a test-cell, test-tube, flow cell or the like.
[0130] Preferably the source is a laser comprising a photodetector,
wherein the photodetector detects electromagnetic radiation from
the laser and outputs the reference information.
[0131] In another aspect the present invention may be said to
consist in a method for identifying or verifying or otherwise
characterising a liquid based drug sample comprising: emitting
electromagnetic radiation in at least one beam at a sample, the
electromagnetic radiation comprising at least two different
wavelengths, detecting affected electromagnetic radiation resulting
from the emitted electromagnetic radiation affected by the sample
and providing output representing the detected affected radiation,
and identifying or verifying the sample from the output
representing detected affected electromagnetic radiation, wherein
each wavelength or at least two of the wavelengths is between
substantially 1300 nm and 2000 nm, and each wavelength or at least
two of the wavelengths is in the vicinity of the wavelength(s) of
(or within a region spanning) a spectral characteristic in the
liquid spectrum between substantially 1300 nm and 2000 nm.
[0132] Preferably the electromagnetic radiation comprises a
plurality of electromagnetic radiation beams, each beam having a
different wavelength.
[0133] Preferably verifying or identifying the drug sample is
against comparison data for one of a set of n drugs, and wherein
the electromagnetic radiation comprises at least log.sub.2 n
different wavelengths in one or more beams.
[0134] Preferably the different wavelengths span or capture a
plurality of at least some of the spectral characteristics in the
liquid spectrum between 1300 nm and 2000 nm.
[0135] Preferably the liquid spectrum comprises two or more
spectral characteristics, and wherein: each spectral characteristic
falls in or spans a region of the liquid spectrum, each wavelength
falls within one of the regions.
[0136] Preferably each region is defined by a wavelength range.
[0137] Preferably the spectral characteristics comprise peaks,
troughs, inflections, stable points or regions, plateaus, knees
and/or slopes of the liquid spectrum.
[0138] Preferably the liquid is water and comprises spectral
characteristics falling in the following regions of the water
spectrum: a first region between 1300 nm and 1400 nm, a second
region between 1400 nm and 1500 nm, a third region between 1500 nm
and 1600 nm, a fourth region between 1600 nm and 1700 nm, a fifth
region between 1700 nm and 1800 nm, and a sixth region between 1800
nm and 200 nm.
[0139] Preferably the electromagnetic radiation has an anchor
wavelength in the vicinity of the wavelength(s) of (or within a
region spanning) a stable region in the liquid spectrum.
[0140] Preferably each wavelength further corresponds to a
wavelength produced by a source that is readily/cheaply
obtainable.
[0141] Preferably the electromagnetic radiation is generated using
a source comprising a plurality of lasers, each laser configured to
emit an electromagnetic radiation beam at a fixed or tuneable
wavelength.
[0142] Preferably wherein a modulator is used for modulating the
electromagnetic radiation beams emitted at the sample resulting in
detected affected radiation that is modulated, and wherein
identifying or verifying the sample from the output from the output
comprises removing the dark current component from the output
representing the detected affected modulated electromagnetic
radiation.
[0143] Optionally removing the dark current component comprises
multiplying the output representing the detected affected modulated
electromagnetic radiation by sine and cosine functions and
integrating over the period of modulation oscillation to remove the
dark current component.
[0144] Optionally removing the dark current component comprises
conducting a Fourier Transform on the output representing the
modulated detected affected radiation and removing the dark current
component from the transformed.
[0145] Preferably the indentifying or verifying is carried out by a
processor that identifies or verifies the drug sample using
reference information.
[0146] Preferably the affected electromagnetic radiation at or the
electromagnetic radiation beam comprising the anchor wavelength
provides the reference information.
[0147] Preferably the method further comprises: directing the
plurality of electromagnetic radiation beams to a reference sample
using an optical device, detecting using a reference detector
affected electromagnetic radiation beams affected by the reference
sample to obtain the reference information and that passes the
reference information to the processor.
[0148] Preferably the method further comprises temperature
compensating the detector and/or source provide temperature
stability, preferably using thermistors and peltier devices in a
closed loop system.
[0149] Preferably each electromagnetic radiation beam is a high
intensity narrowband light beam.
[0150] Preferably the detector is a broadband photodiode that is
biased to have a response corresponding to the wavelength/s of the
affected radiation.
[0151] Preferably the emitted electromagnetic radiation beams from
the plurality of lasers are directed to a sample path by one or
more of: a carousel or carriage device to position the laser beams
in the sample path, or a prism, diffraction grating, beam splitter
or other optical device to redirect a radiation beam along the
sample path.
[0152] Preferably the processor receives: affected electromagnetic
radiation from the drug sample which provides drug sample
information, and optionally reference information for each
wavelength, and the processor: determines a representative value of
the drug sample information and optionally reference information
for each wavelength.
[0153] Preferably the sample information and reference information
correlate intensity and wavelength for each electromagnetic
radiation beam.
[0154] Preferably the representative value corresponds to a best
fit between the sample information and optionally the reference
information.
[0155] Preferably the representative value for the electromagnetic
radiation beam for each wavelength is compared to stored values to
verify or identify the drug sample.
[0156] Preferably the liquid is water, there are six
electromagnetic radiation beams and the wavelengths are
substantially 1350 nm, 1450 nm, 1550, nm, 1650, nm, 1750 nm and
1850 nm, wherein 1450 nm is the anchor wavelength.
[0157] Preferably the sample is in an intravenous delivery device
such as an IV infusions set or syringe, or other receptacle such as
a test-cell, test-tube, flow cell or the like.
[0158] Preferably each laser comprises a photodetector, wherein the
photodetector detects electromagnetic radiation from the laser and
outputs the reference information.
[0159] In another aspect the present invention may be said to
consist in an analyser for identifying or verifying or otherwise
characterising a drug sample (or other substance) in a liquid
carrier comprising: an electromagnetic radiation source for
emitting electromagnetic radiation in at least one beam at a
sample, the electromagnetic radiation comprising at least two
different selected wavelengths, a sample detector that detects
affected electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample, and a processor
for identifying or verifying the sample from the detected affected
electromagnetic radiation, wherein each wavelength is selected to
be in the vicinity of the wavelength(s) of (or within a region
spanning) a spectral characteristic in the spectrum of the liquid
carrier, each wavelength falling within an analysis range suitable
for the liquid carrier.
[0160] In another aspect the present invention may be said to
consist in a method for identifying or verifying or otherwise
characterising a drug sample (or other substance) in a liquid
carrier comprising: emitting electromagnetic radiation in at least
one beam at a sample, the electromagnetic radiation comprising at
least two different selected wavelengths, detecting affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample, and identifying
or verifying the sample from the detected affected electromagnetic
radiation, wherein each wavelength is selected to be in the
vicinity of the wavelength(s) of (or within a region spanning) a
spectral characteristic in the spectrum of the liquid carrier, each
wavelength falling within an analysis range suitable for the liquid
carrier.
[0161] In another aspect the present invention may be said to
consist in an analyser for identifying or verifying or otherwise
characterising a liquid based drug sample (or other substance)
comprising:
[0162] an electromagnetic radiation source for emitting
electromagnetic radiation in at least one beam at a sample, the
electromagnetic radiation comprising at least two different
wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample, and a processor
for identifying or verifying the sample from the detected affected
electromagnetic radiation, wherein each wavelength is falls in an
analysis range that provides improved identification/verification
for drugs in the liquid carrier, and each wavelength is in the
vicinity of the wavelength(s) of (or within a region spanning) a
spectral characteristic in the liquid spectrum in the analysis
range.
[0163] In another aspect the present invention may be said to
consist in a method for identifying or verifying or otherwise
characterising a liquid based drug sample (or other substance)
comprising: emitting electromagnetic radiation in at least one beam
at a sample, the electromagnetic radiation comprising at least two
different wavelengths, detecting affected electromagnetic radiation
resulting from the emitted electromagnetic radiation affected by
the sample, and identifying or verifying the sample from the
detected affected electromagnetic radiation, wherein each
wavelength is falls in an analysis range that provides improved
identification/verification for drugs in the liquid carrier, and
each wavelength is in the vicinity of the wavelength(s) of (or
within a region spanning) a spectral characteristic in the liquid
spectrum in the analysis range.
[0164] In another aspect the present invention an analyser for
identifying or verifying or otherwise characterising a liquid based
drug sample comprising: an electromagnetic radiation source for
emitting modulated electromagnetic radiation in at least one beam
at a sample, the electromagnetic radiation comprising at least two
different wavelengths, a sample detector that detects affected
modulated electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected modulated radiation, and
a processor for identifying or verifying the sample from the output
representing detected affected modulated electromagnetic radiation
including removing dark current from the output,
[0165] wherein each wavelength or at least two of the wavelengths
is between substantially 1300 nm and 2000 nm.
[0166] In another aspect the present invention a method for
identifying or verifying or otherwise characterising a liquid based
drug sample comprising: emitting modulated electromagnetic
radiation in at least one beam at a sample, the electromagnetic
radiation comprising at least two different wavelengths, detecting
affected modulated electromagnetic radiation resulting from the
emitted electromagnetic radiation affected by the sample and
providing output representing the detected affected radiation, and
identifying or verifying the sample from the output representing
detected affected modulated electromagnetic radiation including
removing dart current from the output, wherein each wavelength or
at least two of the wavelengths is between substantially 1300 nm
and 2000 nm.
[0167] In another aspect the present invention an analyser for
identifying or verifying or otherwise characterising a liquid based
drug sample comprising: an electromagnetic radiation source for
emitting electromagnetic radiation in at least one beam at a
sample, the electromagnetic radiation comprising at least two
different wavelengths and for measuring the power of the emitted
electromagnetic radiation, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and provides
output representing the detected affected radiation, and a
processor for identifying or verifying the sample from the detector
output representing the detected affected electromagnetic radiation
including using the measured power of the emitted electromagnetic
radiation, wherein each wavelength or at least two of the
wavelengths is between substantially 1300 nm and 2000 nm, and each
wavelength or at least two of the wavelengths is in the vicinity of
the wavelength(s) of (or within a region spanning) a spectral
characteristic in the liquid spectrum between substantially 1300 nm
and 2000 nm.
[0168] In another aspect the present invention a method for
identifying or verifying or otherwise characterising a liquid based
drug sample comprising: emitting electromagnetic radiation in at
least one beam at a sample, the electromagnetic radiation
comprising at least two different wavelengths and measuring the
power of the emitted electromagnetic radiation, detecting affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample and providing
output representing the detected affected radiation, and
identifying or verifying the sample from the output representing
detected affected electromagnetic radiation including using the
measured power of the emitted electromagnetic radiation, wherein
each wavelength or at least two of the wavelengths is between
substantially 1300 nm and 2000 nm.
[0169] In another aspect the present invention a analyser for
identifying or verifying or otherwise characterising a sample
comprising: an electromagnetic radiation source for emitting
electromagnetic radiation in at least one beam at a sample, the
electromagnetic radiation comprising at least two different
wavelengths, a sample detector that detects affected
electromagnetic radiation resulting from the emitted
electromagnetic radiation affected by the sample, and a processor
for identifying or verifying the sample from the detected affected
electromagnetic radiation, wherein each wavelength or at least two
of the wavelengths is between substantially 1300 nm and 2000
nm.
[0170] Preferably the source is a plurality of lasers in a single
package, each laser configured to emit an electromagnetic radiation
beam at a fixed or tuneable wavelength.
[0171] It is intended that reference to a range of numbers
disclosed herein (for example, 1 to 10) also incorporates reference
to all rational numbers within that range (for example, 1, 1.1, 2,
3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of
rational numbers within that range (for example, 2 to 8, 1.5 to 5.5
and 3.1 to 4.7).
[0172] The term "comprising" as used in this specification means
"consisting at least in part of". Related terms such as "comprise"
and "comprised" are to be interpreted in the same manner.
[0173] This invention may also be said broadly to consist in the
parts, elements and features referred to or indicated in the
specification of the application, individually or collectively, and
any or all combinations of any two or more of said parts, elements
or features, and where specific integers are mentioned herein which
have known equivalents in the art to which this invention relates,
such known equivalents are deemed to be incorporated herein as if
individually set forth.
BRIEF DESCRIPTION OF THE DRAWINGS
[0174] Preferred embodiments of the invention will be described
with reference to the following drawings, of which:
[0175] FIG. 1 shows in schematic form a spectroscopic analyser
according to the present invention,
[0176] FIG. 2 shows in schematic form the hypothetical spectrum of
a hypothetical liquid base/carrier,
[0177] FIG. 3 is a graph showing the error vs. number of
wavelengths used in the spectroscopic analyser,
[0178] FIG. 4 is a flow diagram showing operation of the
spectroscopic analyser,
[0179] FIG. 5 shows the spectrum of a drug (gelofusine succinated
gelatine solution 4%) overlaid the spectrum of a liquid based,
being water,
[0180] FIG. 6 shows spectral characteristics of water between 1300
and 2000 nm,
[0181] FIG. 7 shows a schematic diagram of a second embodiment of
the spectroscopic analyser in which the sources are lasers on a
rotating carousel,
[0182] FIG. 8 shows a method of processing the output from the
detectors, including a pre-processing and a
verification/identification stage,
[0183] FIG. 9 shows a method of processing the output from the
detectors, including a pre-processing and comparison data
generation stage,
[0184] FIG. 10 shows a best fit line through data points obtained
from outputs from the sample and reference detectors,
[0185] FIG. 11 shows a separation line between pre-processed data
points for a training sample and a comparison sample,
[0186] FIG. 12 shows a third embodiment in which the source
comprises six lasers that are directed along the sample path 14a
using a diffraction grating,
[0187] FIG. 13 shows a fourth embodiment comprising a source of six
lasers the outputs of which are directed along a sample path using
beam splitters,
[0188] FIG. 14 shows in schematic form a fifth embodiment for the
source comprising six lasers the outputs of which are converged
onto a sample path using a prism,
[0189] FIG. 15 shows a matrix indicating verification for a set of
sample drugs,
[0190] FIG. 16 shows an analyser using source modulation to
eliminate a reference channel,
[0191] FIG. 17 shows laser output power where the source is
modulated,
[0192] FIG. 18 shows a schematic diagram of an analyser with a
modulator,
[0193] FIG. 19 shows a flow diagram for extracting dark current
[0194] FIG. 20 shows in schematic form a sixth embodiment for the
source comprising six lasers the outputs of which are converged
onto a sample path using a planar lightwave circuit,
[0195] FIG. 21 shows in schematic form a seventh embodiment for the
source comprising a single package source and collimated lens.
[0196] FIG. 22 shows a schematic diagram of a first embodiment of
the spectroscopic analyser in which the sources are lasers in a
single package,
[0197] FIG. 23 is a flow diagram showing operation of the
spectroscopic analyser according to the first embodiment,
[0198] FIGS. 24 and 25 are flow diagrams showing the
verification/identification process in more detail.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Overview
[0199] FIG. 1 shows an overview of a spectroscopic analyser 10 (for
example, a spectrophotometer) according to the present invention
for verifying or identifying (that is, analyse/characterise) drugs
or other samples (e.g. blood, biological samples, etc.). The term
"drug" should be interpreted broadly to cover any pharmaceutical or
other medicament or substance for treating patients, which is
clinician controlled 9 (e.g. through a hospital, prescription or
pharmacy) or freely available. The analyser can be used for blind
tests, wherein an unknown sample is analysed to be
verified/identified or otherwise characterised. The analyser can
also be used to obtain training data from test samples during a
training process to assist in the later analysis of an unknown
sample in a blind test.
[0200] The analyser (apparatus) 10 comprises a controller 12 that
controls both physical control and processing aspects of operation.
The analyser 10 comprises an electromagnetic radiation source 11
for generating and emitting electromagnetic radiation 22 with/at a
plurality of wavelengths within a wavelength range. The source
might also have a photodetector 4 or similar for control purposes.
The electromagnetic radiation could take the form of a plurality of
electromagnetic radiation beams at different wavelengths, or a
single electromagnetic radiation beam comprising a plurality of
wavelength components. The term "wavelength" used for
electromagnetic radiation output refers to a particular wavelength,
such as 1300 nm. As will be appreciated, in practice, a source will
not provide electromagnetic radiation output with a pure single
wavelength--the output could contain components either side of the
centre wavelength/peak. In this case, the term "wavelength" refers
to the centre wavelength/peak of the electromagnetic radiation
output, where the radiation output might also have a wavelength
components either side of the centre wavelength, e.g. +/-30 nm, or
+/-12 nm or even just a few nm (e.g. 2 nm for lasers) either side.
Each such wavelength could be termed a "discrete" wavelength, as
for practical purposes it is discrete, even if other components
exist.
[0201] The electromagnetic radiation beams 22 could be visible
light beams emitted from one or more lasers, for example. In one
example, the electromagnetic radiation source ("source") 11 could
be a single device that can be configured to generate and emit a
plurality of electromagnetic radiation beams with different
wavelengths in sequence or simultaneously, or that emits a single
electromagnetic radiation beam with multiple wavelength components.
In another example, the source 11 could be a set of individual
sources, each configured to generate and emit electromagnetic
radiation beams 22 with a desired wavelength. The term "source" can
refer to a single source or multiple sources making up a source. In
each case, the source 11 might generate a fixed wavelength
electromagnetic radiation beam(s), or it might be tuneable to emit
an electromagnetic radiation beam(s) at one of a range of
wavelengths. The source electromagnetic radiation might optionally
be modulated as described later. Other examples could be envisaged
by those skilled in the art also. The source can have an inbuilt or
separate temperature sensor 2a (which may form part of the
photodiode 4), such as a thermistor for detecting the operating
temperature. The output can be passed to the processor 18.
[0202] Preferably, the source 11 is configured so that each
electromagnetic radiation beam 22 with a corresponding
wavelength(s) can be independently emitted in sequence. This might
be achieved through using a single source that is tuned to emit
electromagnetic radiation beams that sweep through a range of
wavelengths. Alternatively, where a source comprises multiple
electromagnetic radiation sources, each of which can be operated in
turn, it might be achieved by each source becoming the "active"
source--such as a single package comprising multiple lasers. So
that the electromagnetic radiation beam of the active source is
directed along the desired sample path 14a, each electromagnetic
radiation beam output from the source can be arranged to hit a
grating, mirror, prism or other optical apparatus 13 that redirects
the beam from that source along the desired sample path 14a. In
such arrangement, each electromagnetic radiation beam can be
directed in sequence along the desired path as it is
generated/activated. Alternatively, multiple electromagnetic
radiation beams could be simultaneously directed along a beam path
14a, resulting in a single beam of electromagnetic radiation
comprising a plurality of wavelength components. Alternatively, the
sources could be arranged on a carousel or linear carriage (also
represented by 13) that can be mechanically controlled to
physically position each source to emit a radiation beam along the
path 14a. These alternatives will be described further later. Other
arrangements for redirecting a plurality of electromagnetic
radiation beams from a source 11 along a desired path 14a could
also be envisaged. The electromagnetic radiation beam directed
along the path 14a can be termed the sample electromagnetic
radiation beam.
[0203] The apparatus 10 comprises a sample/sample retainer 16 for
holding a sample in the path 14a of the sample electromagnetic
radiation beam. A non-contact infrared or other temperature sensor
71 is incorporated into or disposed near the sample retainer 16 to
enable a measurement to be made of the temperature of the sample
under test and the retainer. This could be the same or separate to
the retainer temperature sensor 2b, 2c.
[0204] The sample retainer 16 could be a test-tube/test-tube
holder, other type of test cell, part of an infusion pump/IV set,
flow-cell, syringe or any other type of device for holding any of
these or for holding a sample/substance in any manner. The sample
could alternatively simply be placed in the path 14a. Any sample
retainer allows for transmission of the electromagnetic radiation
22 to and through the sample. The sample is preferably (although
not limited to) a liquid based drug. The liquid based sample could,
for example be a water based drug, but it could also be another
type of sample/substance in water or other liquid carrier. The use
of "drug" in the embodiments below is for illustrative purposes
only and it will be appreciated that the embodiments could be used
for other types of samples. The term "sample" is used generally to
indicate a substance for analysis (e.g.
verification/identification) and is not necessarily restricted to a
test sample/small portion of a larger amount of substance. For
example, the sample could be an actual drug to be administered--not
simply a (sample) portion of that drug to be administered. The
apparatus 10 can be used in a clinical or other environment to
verify/identify a drug prior to admission. In this case, the sample
put in the apparatus 10 will be the actual drug being administered.
The sample can be a training sample, or an unknown sample under
test. The retainer in the sample and reference channels can have an
inbuilt or separate temperature sensor, such as a thermistor, for
detecting the retainer temperature, 2a, 2c and/or the sample. The
output can be passed to the processor 18.
[0205] An electromagnetic radiation beam emitted along the path 14a
provides incident electromagnetic radiation on a sample (substance)
16 placed in the path (e.g. in the sample retainer.) Any incident
electromagnetic radiation beam 14a that reaches the sample 16 is
affected by the sample (e.g. either by transmission through and/or
reflection by the sample.) The affected (sample) electromagnetic
radiation 14b that exits the sample 16 is affected electromagnetic
radiation and contains spectral information regarding the sample.
Spectral information broadly means any information contained in
affected electromagnetic radiation. For example, the affected
electromagnetic radiation 14b comprises information about the
intensity of the affected electromagnetic radiation at one
wavelength of the incident radiation.
[0206] A sample detector 17 is placed in the affected
electromagnetic radiation path 14b such that affected
electromagnetic radiation 14b exiting the sample can be detected.
The detector 17 can comprise, for example, one or more
photodetectors. The detector 17 outputs information 14c in the form
of data/a signal that represents or indicates spectral information
of the sample 16--that is, the output represents the detected
affected electromagnetic radiation. The detector output 14c could,
for example represent or provide an indication of the
electromagnetic intensity of the affected electromagnetic radiation
incident on the detector--typically in the form of a voltage that
is proportional to the intensity. It will be appreciated that while
the output might not actually be the electromagnetic radiation
intensity, it will have some relationship to it, such as being a
signal with a voltage being proportional to the actual intensity.
Use of the term "intensity" throughout this specification when
referring to the detector output will be understood to not be
limiting and could relate to any parameter relating to intensity.
The detector 17 output 14c is passed through to a processor 18 that
carries out a verification/identification algorithm in order to
verify or identify or otherwise analyse the sample in the retainer.
Pre-processing can optionally occur, although this is not
essential; for example if a stable source is used such as a laser.
The processor 18 can form part of the controller 12, or can be
separate thereto. The processor 18 comprises or has access to a
database 23 with reference/training/comparison data for verifying
or identifying or otherwise analysing the sample. The database 23
is a datastore and can take any suitable form and use any suitable
hardware (such as memory in the processor or an external or even
remote hardware). It is not necessarily part of the processor 18,
but is shown as such for simplicity. The path 14a, 14b, emitted and
affected radiation and/or the sample/sample holder 16 can be termed
the "sample channel." The sample detector 16 and inputs to the
processor 18 (and optionally the processor itself) can also form
part of the sample channel.
[0207] Optionally there might also be a reference channel, in which
the emitted electromagnetic radiation beam 14a incident on the
sample 16 is split 21 or otherwise redirected along a reference
path 15a towards another retainer 19 containing a reference
sample/substance (or simply "reference") 19. A beam splitter 21
could be used to achieve this. The reference could be saline, for
example. The reference sample retainer 19 could be any one of those
retainers 16 mentioned with respect to the sample channel.
Alternatively, the reference may have no retainer and/or sample and
be for the purposes of measuring uninterrupted electromagnetic
radiation. The reference channel, while shown as a separate
channel, could in fact be the same as the sample channel, but
reconfigured to remove the sample and/or retainer and place the
appropriate reference sample (if any) in the electromagnetic
radiation path. The reference electromagnetic radiation beam along
the reference path 15a is incident on and affected by the reference
sample 19 (if any) to produce affected (reference) electromagnetic
radiation 15b which is incident on and detected by a reference
detector 20. The reference detector 20 could be the same or
different detector to that of the sample channel. In FIG. 1, the
reference detector 20 is shown as an independent detector by way of
example.
[0208] The reference detector 20 outputs information 15c in the
form of data/a signal that represents or indicates spectral
information 15c of the reference--that is, the output represents
the detected affected electromagnetic radiation. The detector
output 15c could, for example, represent the electromagnetic
intensity of the affected electromagnetic radiation such as
described earlier for the sample channel. The detector output 15c
is passed through to the processor 18 that carries out a
verification/identification algorithm in order to verify or
identify the sample 16 in the retainer. Pre-processing can be
carried out, although this is not essential if a stable source is
used, such as a laser. The detector output 15c from the reference
channel provides data from which to normalise and/or correct the
sample channel data 14c. The reference channel might also comprise
a neutral density filter prior to the sample. This attenuates the
incident electromagnetic radiation in a manner to normalise the
detected affected electromagnetic radiation, or otherwise modify it
so that the output of the detector is at a suitable level to enable
processing/comparison with the output of the detector on the sample
channel.
[0209] In an alternative to the reference channel, optionally the
output from a monitor diode 4 on the source could be used to
provide reference data/output/signal/information from which to
normalise and/or correct the sample channel data 14c. The output
can be provided to the controller 12 and/or processor 18 The
monitor diode could be a pre-existing detector on the source that
measures power of the output electromagnetic radiation. In this
case, the monitor diode could be considered a "reference detector"
and in effect provide a reference channel.
[0210] Each electromagnetic radiation beam 22 has a wavelength (or
has a plurality of wavelength components) that falls in the
analysis range ("analysis region"), preferably of 1300-2000
nanometres (nm). This region can nominally be termed "near
infrared" or "NIR". This region provides useful spectral
information for verifying or identifying drugs. The wavelength of
each electromagnetic radiation beam 22 (or the wavelengths making
up an electromagnetic beam) is preferably selected based on
spectral characteristics (features) of the base liquid of the drug
sample that fall within the analysis range. Such characteristics
could be, for example, peaks, troughs, points of inflection, stable
point or regions, plateaus, knees and/or slopes of that base liquid
spectrum. Each wavelength selected is in the vicinity of (or within
a region spanning) such a spectral characteristic. The position of
a spectral characteristic could be defined by a nominal wavelength
(of for example the centre wavelength of the characteristic) or a
range of wavelengths defining a region spanning the
characteristic.
[0211] Selection of each wavelength can be demonstrated with
reference to the spectrum of a hypothetical base liquid as shown in
FIG. 2. The hypothetical spectrum comprises the following spectral
characteristics A-E in the analysis range. [0212] A peak between
1300 nm and 1400 nm (centre wavelength of 1350 nm of actual peak)
(A). [0213] A trough between 1400 nm and 1500 nm (centre wavelength
of 1450 nm of actual trough) (B). [0214] An inflection between 1500
nm and 1600 nm (centre wavelength of 1550 of actual inflection)
(C). [0215] A slope between 1600 nm and 1800 nm (D). [0216] A
plateau between 1800 nm and 2000 nm (E). [0217] A knee is also
shown around 1800 nm between characteristics D and E.
[0218] For analysis of drugs with this hypothetical liquid as a
base, wavelengths could be chosen that are within the vicinity of
the wavelength ranges (or centre wavelength) for one or more of the
spectral features A-E above, or that fall within in a region
spanning (defining/delimiting) the wavelength ranges for one or
more of the spectral features A-E above. A wavelength in the
"vicinity" of a spectral characteristic also can mean a wavelength
at the spectral characteristic centre wavelength. For example,
three different wavelengths could be chosen as follows. [0219]
Wavelength #1 1310 nm--within the region 1300-1400 nm for feature
A. [0220] Wavelength #2 1450 nm, roughly at or within the vicinity
of the centre wavelength of feature B. [0221] Wavelength #3 1800
nm, at the edge/knee (i.e. within the region) of feature E.
[0222] The chosen discrete wavelengths that relate to spectral
characteristics of the liquid spectrum can be termed "selected
wavelengths" or "chosen wavelengths". In general terms, the
selected or chosen wavelengths "correspond" to or "capture" a
spectral characteristic.
[0223] It will be appreciated that FIG. 2 shows just some
hypothetical examples of spectral characteristics (features)--many
more are possible for a spectrum. Further, the wavelength ranges
for spectral characteristics could overlap or even coincide.
Further, a separate wavelength need not be chosen for each spectral
characteristic in the analysis range--just a selection of
wavelengths relating to a selection of spectral characteristics
might be chosen. It might not be possible to define a spectral
characteristic by a wavelength range, or any such range might vary
depending on interpretation. A wavelength in the vicinity of a
spectral characteristic might instead be chosen. This could be a
wavelength that is near or within a certain tolerance (e.g. +/-30
nm) of the centre point wavelength of a spectral characteristic,
for example.
[0224] In addition, the selected wavelength might be influenced by
sources 11 that are readily obtainable or configurable to a
wavelength that is in the vicinity of or falls within in a region
spanning such a spectral characteristic. The selection of suitable
wavelengths for the emitted radiation will provide better
information for accurate verification or identification by the
processor.
[0225] In addition, preferably, the selected wavelengths can be
selected independently from the drug(s) being tested.
[0226] It will be appreciated that the wavelengths could be
selected in any other suitable manner, such as by randomly or
evenly spacing them across the region, or using some other
selection criteria.
[0227] Any suitable number of wavelengths can be used. Optionally,
although not essentially, the number of different wavelengths
constituting the electromagnetic radiation (either in one or
multiple beams 22) provided by the source 11 is at least log.sub.2
n, where n is the number of samples that are tested for. The more
wavelengths that are used, the better the accuracy, but this is
optimised against costs and convenience. As seen in FIG. 3, as the
number of electromagnetic radiation beams/wavelengths increases,
the error of detection decreases. A selection of two wavelengths
provides an error of 0.14 for a set of 30 drugs, whereas five
wavelengths provide an error of just 0.02.
[0228] One of the electromagnetic radiation wavelengths 22 can
optionally be selected to have a wavelength at an anchor point,
which can be used to eliminate the need for a reference channel.
The anchor point is chosen to have a wavelength in a stable or
other suitable portion of the spectrum of the underlying base
liquid. The anchor wavelength is described further later.
[0229] Upon receiving output from a sample detector 17 and
optionally a reference detector 20 (or alternatively output from a
monitor diode that measures power of output electromagnetic
radiation), the processor 18 executes an algorithm that accesses a
database 23 comprising training/comparison data (possibly in the
form of a look up table), and uses that output to verify or
identify ("characterise") the sample 16 based on the affected
electromagnetic radiation 14b detected from the sample 16, and
optionally:
[0230] a) where a reference channel is used, the output of the
detected affected radiation 15b from that reference sample, or
[0231] b) where a source monitor diode is used, measured power of
the output source electromagnetic radiation,
[0232] using the training/comparison data. The training/comparison
data can be obtained in a previous analysis of training samples
using the analyser. In one option, the raw training/comparison data
obtained from the detector(s) is processed to obtain
training/comparison coefficients that can be used for
characterisation of an actual unknown sample in a blind test.
[0233] The processor 18 can operate with or independently from the
controller 12. Processing will be described further later.
[0234] In addition to or as part of the verification/identification
process one or more of the following can be undertaken. [0235]
Measurement of the sample (including where appropriate the
retainer) temperature and correction of the training/comparison
data based on the sample temperature. [0236] Determining parameters
(coefficients) representative of the sample or training data/sample
that are independent of sample concentration that can be referenced
against parameters representative of the comparison data/comparison
sample for identification/verification. [0237] Determining
concentration of the sample. [0238] Processing raw
training/comparison data and actual sample data to reduce
inaccuracies caused by dimension tolerances in the system including
the sample retainer (e.g. a test-tube/test-tube holder, other type
of test cell, part of an infusion pump/IV set, flow-cell, syringe
or any other type of device for holding any of these or holding a
sample/substance in any manner.) [0239] Determine and/or eliminate
the dark current of the photodetectors using either a technique
involving a modulated source or dark current measured using a
chopper wheel arrangement.
[0240] A user interface 24 allows a user to operate the apparatus
10, including setting parameters, inputting anticipated drugs (e.g.
for verification) or other sample identification and receiving the
results of analysis (via a screen, display, audio alarm, indicator
or similar). The results might indicate whether the drug is as
anticipated (verification/confirmation), or might advise of the
drug (identification) and/or might indicate concentration of the
sample under blind test.
[0241] The controller 12 and/or processor 18 might also control an
external device (such as an infusion pump) to allow or prevent
delivery of a drug based on the test result.
[0242] Preferably, the apparatus 10 also comprises a feedback
system to stabilise the temperature of the electromagnetic
radiation source 11 and/or the detectors(s) 17, 20. In one example,
thermistors detect the temperature of the electromagnetic radiation
source and/or detector(s) and/or also optionally the sample
retainer 2a, 2b, 2c, 5a, 5b. Peltier cooling devices can be
operated to cool and stabilise the temperate of the source 11 and
detectors 17, 20. The output of the thermistor(s) is sent to the
controller 12, which controls the peltier cooling devices to cool
the source and/or detectors. Preferably the thermistor is the
built-in photodetector/source thermistor 2a, 2b, 2c, 5a, 5b, and
the peltier thermo-electric cooler is built-in to the
photodetector/source 2a, 2b, 2c, 5a, 5b.
[0243] The apparatus 10 works generally as follows, with reference
to the flow diagram in FIG. 4. The controller 12 is used to operate
the source 11 to emit one or more electromagnetic radiation beams
22 (preferably--although not essentially--individually and in
sequence) with/at the selected wavelengths towards the sample 16,
step 40. The electromagnetic radiation incident 14a on a sample 16
is transmitted or reflected through the sample and becomes affected
electromagnetic radiation 14b which is detected by the detector 17,
step 41. Optionally, the emitted radiation maybe diverted by a beam
splitter 21 also to a reference sample 19 (of free-space path),
which is detected by the same or a different detector 20, step 42.
The outputs 14c, 15c from the sample detector 17 and optionally the
reference detector 20 are passed to the processor 18, step 42. Here
pre-processing takes place to normalise and/or correct the detector
output 14c, 15c, step 42 if required. Then the
identification/verification algorithm is executed, step 43, which
includes querying the database 23 of reference drugs, the
information from which (e.g. training/comparison data) being
utilised to identify or verify the sample from the normalised
detector output. The result of the verification or identification
of the sample is communicated by the user interface 24, step
44.
[0244] Other options will become apparent as a more detailed
description of the invention is provided.
First Embodiment
[0245] One embodiment of the invention will now be described in
detail by way of example. This should not be considered limiting
but illustrative. The embodiment is described in relation to an
apparatus for providing verification or identification of water or
other liquid based drugs from e.g. a set of 15 drugs set out in the
table below. While in this embodiment the sample is referred to as
a drug, more generally the embodiment could be applied to any other
sample type.
[0246] Six wavelengths of electromagnetic radiation are chosen for
this example, six being greater than log.sub.2 n of 30. The
wavelengths are chosen in the analysis range and are based on the
spectral characteristics of water, being the base liquid, falling
in that range. The spectrum of a water based drug (or other liquid
based drug or aqueous solution) will be heavily dominated by the
base liquid spectrum. For example referring to FIG. 5, the spectrum
(dotted line) of drug W (gelofusine succinated gelatine solution
4%) is very similar to the spectrum of water (solid line). This is
because the spectrum of water dominates. However, the differences
in transmission coefficient between different water based drugs can
be measured. Focussing on areas/wavelengths of spectral
characteristics of the water spectrum, by using electromagnetic
radiation beams at those wavelengths, the difference between the
water spectrum and the water based drug spectrum at those
wavelengths can be utilised to provide drug discrimination for drug
identification or verification.
[0247] FIG. 6 shows a spectrum of water with some possible spectral
characteristics (features) in the analysis range indentified, and
explained further below. [0248] Spectral characteristic A
(slope)--in a first region between 1300 nm and 1400 nm. [0249]
Spectral characteristic B (plateau/trough)--in a second region
between 1400 nm and 1500 nm. [0250] Spectral characteristic C
(slope)--in a third region between 1500 nm and 1600 nm. [0251]
Spectral characteristic D (peak)--in a fourth region between 1600
nm and 1700 nm. [0252] Spectral characteristic E (inflection)--in a
fifth region between 1700 nm and 1800 nm. [0253] Spectral
characteristic F (knee) a sixth region between 1800 nm and 2000
nm.
[0254] This is not an exhaustive list of possible spectral
features.
[0255] The selection of a wavelength for an electromagnetic
radiation beam is not strictly fixed, and not necessarily solely
based on spectral characteristics of the base liquid. It is
influenced by the wavelength of spectral characteristics in
spectrum of the base water of the drug sample, but in addition the
selected wavelength can be based on other factors also. For
example, in interest of cost effectiveness and a regularly
obtainable supply chain, it might be preferable to use or select an
alternative wavelength that is close to the spectral characteristic
but not quite the same, if that alternative wavelength is easily
obtainable by an off-the-shelf laser or other optical
component.
[0256] For example, it is possible to use 1310 and 1550 nm as
selected wavelengths for water based drugs as there are many
devices configured for these wavelengths as they have wide spread
use within the communications industry. Laser diodes nominally have
centred wavelengths at 1650 nanometres, 1750 nanometres and 1850
nanometres, although these can be varied by up to plus or minus 30
nanometres. So wavelengths in these ranges can also be selected.
Therefore by looking at the availability of these components, and
the spectral characteristics of the base liquid, suitable
wavelengths for the emitted radiation can be determined.
[0257] Therefore, based on the above explanation, each of the six
wavelengths can be chosen to be within the vicinity or within the
region spanning one of each of the spectral features, but also
influenced by the availability of hardware. The six wavelengths for
water could therefore be (by way of example): 1350 nanometres
corresponding to feature A, 1450 nanometres corresponding to
feature B, 1550 nanometres corresponding to feature C, 1650
nanometres corresponding to feature D, 1750 nanometres
corresponding to feature E and 1850 nanometres corresponding to
feature F, all which fall within the 1300-2000 nanometres. As can
be seen the 1350 nm to 1850 nm wavelength selections do not match
exactly to peaks and troughs and other spectral characteristics in
the water spectrum, although are close. The selections also relate
to operating wavelengths of available hardware. These are of course
nominal wavelengths and the actual wavelength might vary in
practice due to source 11 characteristics. It should also be noted
that arbitrary wavelengths could be chosen spread across the
region, rather than selected at specific spectral features.
[0258] FIG. 22 shows in schematic form one possible form of the
apparatus 10 as generally described in FIG. 1. The spectroscopic
analyser 10 has a controller 12 and a single laser package (more
generally "laser") that contains six laser modules 51a-51f, which
together form the source 11 to output electromagnetic radiation 22
at a plurality of wavelengths in the form of light. The single
package 211 comprises 6 lasers forming the source 11 that are
arranged to emit their electromagnetic radiation beam 22 (which
could be any one of wavelengths 201a-201f) towards an integrated
collimating lens 210. The package is operable to emit a tuned or
tuneable wavelength at each of six wavelengths 201a-201f towards
the lens 210. The package comprises one or more laser diodes
providing a stable, high intensity, narrow band collimated
electromagnetic radiation output that is controlled electronically
via controller 12. The controller can have a user interface 24 for
user input and output. The source can have an inbuilt or separate
temperature sensor 2a, such as a thermistor for detecting the
operating temperature. The output can be passed to the processor
18.
[0259] The controller 12 activates the laser package to
sequentially or otherwise to emit a beam 201a-201f of a single
wavelength towards the sample. Alternatively, multiple beams
201a-201f could be operated at once such that an electromagnetic
beam 22 comprising multiple wavelength components (e.g. 201a-201f
or a subset thereof) could be emitted towards 14a the sample 16 via
the lens 210.
[0260] The apparatus comprises a modulator 70, which can be a
separate device coupled to the laser package 211 or incorporated
into the controller 12, or it can be incorporated into the laser
package itself. The modulator 70 controls the laser package 211 to
modulate the output electromagnetic radiation 22. Modulating the
electromagnetic radiation allows for processing to account for dark
current as will be described below.
[0261] The package 211 comprises one or more monitor photodiodes 4a
for detecting output electromagnetic radiation 22 (e.g. for
measuring output power of the electromagnetic radiation) for
feedback control of that radiation. This can be combined with the
temperature sensor 2a. The output is provided to the processor 18
either directly or via the controller 12. Lasers have fewer heat
emission problems than other sources, thus reducing the detrimental
effects of heat on the measurements. The output power of each laser
preferably is nominally the same (typically 2-3 mW although could
be more) in the interests of having a balanced apparatus.
Preferably, this also enables a common diode driver circuit to be
used for the laser diodes.
[0262] There is also a temperature sensor 71 (e.g. non-contact
infrared sensor) for measuring the sample 16 under test and its
retainer. There may be a combined or separate temperature sensor
for measuring the retainer temperature as well. The outputs are
provided to the processor 18, either directly or via the controller
12.
[0263] Once activated, the laser 211 emits (preferably modulated)
electromagnetic radiation 22 towards the sample along the path 14a
via the lens 210. The path 14a from the source to the detector is a
combination of free-space with optical fibre components. This
reduces optical attenuation and hardware. The apparatus also
comprises a sample retainer 16a, which is aligned with the beam
path 14a. The emitted electromagnetic radiation from an active
laser 51a-51f is incident on and transmits or reflects through the
sample 16 in the sample retainer.
[0264] The detector 17 is placed in the affected radiation path 14b
that exits the sample 16. Preferably the detector 17 is a single
photodetector (such as a photodiode) biased to have a suitable
response to detect electromagnetic radiation of wavelengths that
will be in the affected radiation. A single detector reduces the
errors due to variability introduced by components--it removes the
relative differences between multiple photodetectors enabling a
more stable response to the output of the emitted electromagnetic
radiation thus enhancing sensitivity. An InGaAs photodiode could be
used, for example. The detector 17 detects the affected radiation
14b and the output 14c of the detector 17 is passed to a processor
18 that using previously obtained training/comparison data in a
database 23 verifies or identifies or otherwise characterises the
sample as described herein. In addition to or as part of that
process the processor 18 also undertakes the following. [0265]
Measurement of the sample (including where appropriate the
retainer) temperature and correction of the training/comparison
data based on the sample temperature. [0266] Determining parameters
(coefficients) representative of the sample or training data/sample
that are independent of sample concentration that can be referenced
against parameters representative of the comparison data/comparison
sample for identification/verification. [0267] Determining
concentration of the sample. [0268] Processing raw
training/comparison data and actual sample data to reduce
inaccuracies caused by dimension tolerances in the system including
the sample retainer (e.g. a test-tube/test-tube holder, other type
of test cell, part of an infusion pump/IV set, flow-cell, syringe
or any other type of device for holding any of these or holding a
sample/substance in any manner.) [0269] Determine and/or eliminate
the dark current of the photodetectors using either a technique
involving a modulated source or dark current measured using a
chopper wheel arrangement.
[0270] Preferably, the apparatus also comprises a feedback system
to stabilise the temperature of the electromagnetic radiation
source 11 and the detectors(s). In one example, thermistors 2a, 71,
5a detect the temperature of the electromagnetic radiation source
and/or detector(s) and/or retainer. Peltier cooling devices can be
operated to cool and stabilise the temperate of the source and
detectors. The output of the thermistor(s) is sent to the
controller, which controls the Peltier cooling devices to cool the
source and/or detectors. Preferably the thermistor is the built-in
photodetector/source thermistor 2a, 71, 5a, and the peltier
thermo-electric cooler is built-in to the photodetector 2a, 5a.
[0271] The apparatus/analyser 10 is used to obtain raw
training/comparison data from training samples carried out during a
training process/test. It also obtains raw data of an actual
unknown sample under test during a blind test. It can process the
raw training/comparison data and/or the raw data of the sample
under test to obtain coefficients (comparison data) that can be
utilised in a process to characterise the unknown sample in the
blind test.
[0272] Referring to FIG. 23 (which is based on but provides more
detail than Figure), operation of the apparatus 10 will now be
described for a blind test. A blind test is where an actual unknown
sample for verification or identification or other characterisation
is tested. An unknown sample 16 to be tested is placed in the
retainer or otherwise placed in or introduced to the analyser 10.
The controller 12 operates the laser 211 to emit an electromagnetic
radiation beam 22 at one of the selected wavelengths 201a-201f to
the sample 16, step 230 As part of this, preferably the modulator
70/controller 12 operates the laser 211 to modulate the
electromagnetic source radiation beam 20, step 230, in a manner to
be described below with respect to the processor 18. In this
manner, six modulated electromagnetic source radiation beams
201a-201f with different selected wavelengths can be emitted, step
230, in sequence from the laser 211, each tuned to a different
selected wavelength. The temperature of the sample is measured and
recorded for each test at any suitable time in the process, e.g. at
the same time as emitting the radiation, step 230.
[0273] Each electromagnetic beam 22 is emitted via the integrated
collimating lens 210 along the path 14a towards the sample 16. The
affected radiation coming from the sample is detected by the
photodetector 17, step 231, for each electromagnetic radiation beam
emitted 14a towards the sample 16.
[0274] Optionally, the monitor diode 4a in the laser 211 measures
the power of the output electromagnetic radiation beam 22 to obtain
reference information. Alternative, reference information can be
obtained using a reference channel such as shown in FIG. 1 or FIG.
18.
[0275] The output (electromagnetic radiation intensity
measurements) from the sample detector 17 and optionally the
monitor diode 4 in the source laser 211 are passed to the processor
18 and/or database 23 where it is stored as data, step 232, for
identification/verification of the sample 16 under test. The
temperature measurement is also passed to the processor 18 and/or
database 23. The output 14c received at the processor 18 from the
sample detector 17 or from the monitor diode 4 indicates the
intensity of the affected electromagnetic radiation 14b for each
emitted electromagnetic radiation beam at the sample 16. It may,
for example, comprise data which directly or indirectly indicates
photocurrent of the detector (such as a voltage proportional to
intensity) and/or intensity of the detected electromagnetic
radiation. In this case of modulated source (as discussed below) a
modulated waveform output is received which is digitised. The steps
230-232 are preferably repeated several times for each wavelength
to obtain multiple intensity measurements that can be processed to
obtain an average or other representative intensity for each
wavelength, step 233. For example, at each wavelength, the analyser
detects affected electromagnetic radiation affected by the sample
at 25 different times and passes this output to the processor 18
and/or database 23, step 230-233. Once the process has been
completed for one wavelength, the process, steps 230-233, is
repeated for the remaining wavelengths, step 234. The temperature
measurement can be taken during each iteration also and stored in
the processor/database as appropriate, step 230. The intensity and
temperature data in the processor/database can be termed "blind
test raw data".
[0276] Once all the intensity, temperature and any other
measurements have been received by the processor 18, verification
or identification can take place, step 235. Identification or
verification of a sample is based on training data (also termed
"comparison data") that has previously been generated or otherwise
obtained. In this embodiment, sample coefficients or other data
representing the sample under blind test are obtained/determined
from the blind test raw data during the identification/verification
process and these are compared to corresponding training
coefficients or other comparison data obtained from test samples
during a training process. If the coefficients or other data of the
sample under test match to the required similarity to those of a
test sample, then a verification or identification can be made.
[0277] It will be appreciated that in general terms, the raw
training data and/or blind test raw data can be used as is or
processed in any suitable way to undertake characterisation of the
unknown sample under test. The coefficients described in this
embodiment demonstrate one way in which to use the raw data.
"Training data" can refer to raw training data in its unprocessed
form, or processed raw training data. Furthermore, "comparison
data" can refer to processed or unprocessed raw training data
and/or processed or unprocessed raw blind test data. Comparison
data refers to any data that can be used to characterise an unknown
sample under blind test.
[0278] Verification involves confirming that a sample drug is the
drug that is expected. For example, a clinician can specify what
they think the drug is (e.g. from the set of n drugs) through the
user interface 24 step 85, then use the apparatus to confirm
whether the drug in the retainer is actually that drug which is
specified by the clinician. Identification involves determining
what a drug actually is, without any suggestion from the clinician
as to what the drug is. For verification/identification, the blind
test raw data are processed and are compared against the processed
raw training data in the database 23, step 85, to identify the
drug, or verify whether it is the anticipated drug as specified by
the clinician. Output is then provided to the user interface, step
87.
[0279] The verification/identification processing will now be
described in more detail. However, as the
verification/identification processing utilises training data, the
acquisition and (optional) processing of training data will be
described first with reference to FIG. 23.
Acquisition of Training Data
[0280] In overview, training data is obtained during a training
process at some point prior to verification/identification of an
actual unknown sample taking place in a blind test. It can be
obtained once, or periodically updated. It is stored in the
processor 18 and/or the database 23, either integrated with or
accessible by the processor 18 for use during
verification/identification. As mentioned above, the terms
"training data" and "comparision data" in general can refer to raw
data obtained during a training process, or raw data that has
subsequently been post-processed for utilisation in the
identification/verification process. The training data is obtained
from known samples against which data from blind test samples will
be analysed. Preferably, any unknown sample type (e.g. a particular
drug) that may be tested for in a blind test will have
corresponding training data previously obtained from the same
sample type (e.g. drug). A set of training samples (e.g. a set of
drugs) corresponding to those that may be tested for, are obtained,
analysed in the training process and raw training data obtained for
them and stored. The raw training data is obtained in the same way
as actual the blind test data is obtain as described herein, e.g.
as shown in FIG. 23 using e.g. the apparatus in FIG. 22 or any of
the other embodiments described.
[0281] As an example, with reference to FIG. 23, a set of test
(training) samples (e.g. different training drugs/dilutants such as
those in the table below) are obtained, step 237. The samples
comprise a range of undiluted drugs of known concentration and
dilutants of interest (e.g. 0.9% saline, 5% glucose) being the
dilutants in which a drug may be diluted in for an actual blind
test. Each one is analysed in turn, using e.g. the analyser of FIG.
22. As described previously for the actual blind test, the training
drug is placed in a retainer, and (optionally modulated)
electromagnetic radiation of different wavelengths is emitted at
the drug in the retainer in sequence, step 238. The intensity of
the affected electromagnetic radiation from the drug at each
wavelength is detected by a detector, step 239 and is passed to the
processor 18, and/or database 23, step 240. Preferably, each
wavelength of electromagnetic radiation can be emitted multiple
times, step 241, and the detector intensity output/measurement from
each is averaged or otherwise processed in the processor to obtain
the raw training data. Once one wavelength is complete, the sample
is tested at the next wavelength 242. Each drug can also be tested
multiple times at each wavelength in a different retainer (e.g.
different test tubes) to average out variations in each retainer,
step 243. The temperature at each measurement at each wavelength
for the lasers, detectors and sample/retainer can also be taken and
passed to the processor/database for storing along with the
intensity measurement, steps 238, 240. This is repeated for each
sample drug, step 244. Note, while the FIG. 23 shows that each
wavelength is tested multiple times, then the retainer is changed,
alternative orders could occur--such as the retainer changed for
each wavelength before changing the wavelength. Various orders are
possible and the description and FIG. 8 should not be considered
limiting.
[0282] If a reference channel is used, the same process is carried
out for the reference channel--that is (optionally modulated)
electromagnetic radiation of different wavelengths is emitted at
detector without a sample or retainer in the path, step 238. The
intensity of the received electromagnetic radiation at each
wavelength is detected by a detector, step 239, and is passed to
the processor 18, and/or database 23, step 240. Preferably, each
wavelength of electromagnetic radiation can be emitted multiple
times, step 241, and the detector intensity output/measurement from
each is averaged or otherwise processed in the processor to obtain
the raw training data. Once one wavelength is complete, the next
wavelength is emitted, step 242. The temperature at each
measurement at each wavelength for the lasers and detectors can
also be taken and passed to the processor/database for storing
along with the intensity measurement. This is repeated for each
sample drug, step 244.
[0283] Alternatively, if a monitor diode 4 is used instead of a
reference channel, the same process is undertaken. Optionally
modulated electromagnetic radiation of different wavelengths is
emitted at detector without a sample or retainer in the path, step
238. The intensity of the received electromagnetic radiation at
each wavelength is detected by the monitor diode 4, step 239, and
is passed to the processor 18, and/or database 23, step 240.
Preferably, each wavelength of electromagnetic radiation can be
emitted multiple times, step 241, and the monitor diode intensity
output/measurement from each is averaged or otherwise processed in
the processor to obtain the raw training data. Once one wavelength
is complete, the next wavelength is emitted, step 242. Each drug
can also be tested multiple times at each wavelength in a different
retainer (e.g. different test tubes) to average out variations in
each retainer, step 243--the monitor diode output is obtained for
each one. The temperature at each measurement at each wavelength
for the lasers and detectors can also be taken and passed to the
processor/database for storing along with the intensity
measurement. This is repeated for each sample drug, step 244.
[0284] The result is a store of raw training data of (spectral)
intensities and temperatures for each measurement at each
wavelength for each sample drug and for each monitor diode 4 or
reference channel measurement. The data comprises spectral
transmission intensities (in the form described previously) at the
wavelengths of interest (e.g. 6 wavelengths) along with respective
temperature readings for each training drug. Where a monitor diode
is used, the data also comprises spectral transmission intensities
at the wavelengths of interest (e.g. 6 wavelengths) for each
training drug. Where a reference channel is used, the data also
comprises spectral transmission intensities at the wavelengths of
interest (e.g. 6 wavelengths) along with respective temperature
readings for each reference channel measurement. The raw training
data will consist of multiple scans at each wavelength (typically
25 scans are used although any suitable number can be) using
different retainers (for example, 5 different test tube retainers).
The (spectral) intensities can take the form of a voltage or
similar output from the detector that is digitised for the
processor. In the case of the modulated source (which will be
described further below) the digitised intensity may take the form
of a wave form, or the amplitudes of components of the wave
form.
[0285] The training data is obtained at a measured temperature. For
later temperature compensation, the slope of the intensity versus
temperature for a sample at a particular wavelength is obtained,
step 240. This happens by placing the sample under test (preferably
in the same retainer) into a laboratory spectrometer known in the
art. The intensity for each sample is measured at several
temperatures for each wavelength, and a straight line slope di/dt
of the intensity versus temperature determined and passed to the
processor 18/database 23 for later use.
[0286] The raw training data is later processed during the
verification/identification process to obtain comparison (also
termed "training") coefficients (comparison data) that can be used
to verify/identify unknown samples in an actual blind test. In a
preferred embodiment, the raw training data has dark current
eliminated and is temperature corrected to match the blind sample
test temperature. The data is converted into a set of coefficients,
each of which reduces sensitivity to variations in the retainer
path length and that is concentration independent and compensates
for variations in the retainer path length. In a preferred
embodiment, this processing occurs at the time of carrying out the
blind test or shortly thereafter, but this is not essential. The
processing could alternatively be carried out in advance of the
actual blind test or after the blind test. The processing of the
raw training data is described in detail further below.
Acquisition of Blind Test Data and Verification/Identification
[0287] In overview, the blind test data for an unknown sample drug
is acquired as described previously resulting in raw blind test
data comprising intensities and sample temperatures (T.sub.b) at
various wavelengths as measured during the blind test of the actual
drug, and also (where used) reference intensities and temperatures
at various wavelengths from the monitor diode (or alternatively the
reference channel). The blind test raw data is processed to
generate blind test (sample) coefficient(s). Mathematical analysis
can be carried out between training coefficients based on
previously determined training/comparison data and blind test
coefficients to identify/verify the unknown sample under test.
[0288] In summary, the following occurs to each value of the raw
data (each being data representing the detected intensity for a
particular wavelength for a particular sample), which initially
represents a modulated output from the detector. [0289] First, the
DC component of the output (for the blind test data and the
training data) is removed/eliminated (e.g. utilising a modulation
technique) and the magnitude of the signal is obtained (see
heading--eliminating dark current using modulation). This DC
component elimination occurs on the raw training data, either at
the time of collection, or during the verification/identification
process. This results in: [0290] a set of dark current eliminated
data (N.sub.1 to N.sub.n) (for the unknown sample under test)
comprising a data point for each wavelength of the blind test data;
[0291] a set of dark current eliminated data (N.sub.1 to N.sub.n)
for each drug in the training set comprising a data point for each
wavelength of the raw training data. [0292] Second, the magnitude
of the set of dark current eliminated data (N.sub.1 to N.sub.n) for
each drug in the training set comprising a data point for each
wavelength of the raw training data then undergoes temperature
correction/adjustment (see heading--temperature correction). This
results in a set of temperature corrected data (I(T.sub.b).sub.1 to
I(T.sub.b).sub.n) for each drug in the training set that matches
the temperature of the blind test sample. [0293] Third, a
fractional intensity ratio (fractional spectral intensity) is
obtained for: [0294] each dark current eliminated data point
(N.sub.1 to N.sub.n) for the unknown sample under test; [0295] each
dark current eliminated data point (N.sub.1 to N.sub.n) for each
drug in the training set [0296] wherein the fractional intensity
ratio is a parameter that reduces retainer tolerance sensitivity in
verifying/identifying a substance (see heading--retainer tolerance
sensitivity reduction.
[0297] This results in: [0298] a set of fractional spectral
intensity data (g.sub.mt to g.sub.mn) (for the unknown sample under
test) comprising a data point for each wavelength of the blind test
data; [0299] a set of fractional spectral intensity data (g.sub.m1
to g.sub.mn) for each drug in the training set comprising a data
point for each wavelength of the raw training data. [0300] Fourth,
a coefficient is derived from using the fractional intensity ratio
that is independent of sample concentration (see
heading--concentration independent coefficients).
[0301] This results in: [0302] a set of concentration independent
data (y.sub.m1 to y.sub.mn) (for the unknown sample under test)
comprising a data point for each wavelength of the blind test data;
[0303] a set of concentration independent data (y.sub.m1 to
y.sub.mn) for each drug in the training set comprising a data point
for each wavelength of the raw training data.
[0304] The set of data (y.sub.m1 to y.sub.mn) for the unknown
sample under test can then be compared to set of data
(y.sup.B.sub.m1 to y.sup.B.sub.mn) for each drug in the training
set to verify or identify the uknown sample under test.
[0305] The verification/identification processing will now be
described in more detail, with reference to FIG. 24 that shows step
235 of FIG. 23 in more detail.
Eliminating Dark Current Using Modulation
[0306] First, the dark current of the photodetectors 17/4 is
compensated for, step 235a. This is done for the reference and
sample data for both the raw training data and the blind test data.
Photodectors have a baseline output (termed "dark current") even
when there is no incident radiation. In this embodiment, rather
than using a traditional chopper wheel arrangement to find dark
current, laser driver current modulation is used to eliminate the
need for dark current readings. Referring to the analyser in FIG.
22, the laser is output is modulated as previously described, step
230, FIG. 23. The affected detected radiation is received by the
sample and reference detectors 17 (for both the training process
and the blind test) and passed to the processor 18, steps 231, 232
for processing as previously described. The received output at the
processor contains DC components corresponding to dark current as
demonstrated in the derivation below. This output can be processed
by the processor step 235a to remove the dark current (DC)
component A.sub.0S and A.sub.0R of the received output (as per the
equations below) and any other unwanted components. The desired
components sin(.omega.t) and cos(.omega.t) are obtained and
represent the intensity measurement without dark current. This
processing can be done using any suitable signal processing know to
those in the art.
[0307] For example, in one possibility, Fourier analysis of the
output currents could be performed by multiplying the outputs by
sin(.omega.t) and cos(.omega.t) respectively, and integrating over
a period of the oscillation. This can be used where the modulation
is a single frequency, e.g. sine wave modulation at a single
frequency. This procedure provides a form of averaging which is
beneficial in reducing measurement noise.
[0308] Alternatively, a Fast Fourier Transform (FFT) algorithm can
be applied to a digitised output waveform and the relevant Fourier
components extracted. From the Fourier coefficients we therefore
obtain:
[0309] S.DELTA.P= {square root over
(A.sub.1S.sup.2+B.sub.1S.sup.2)} for the sample channel and
R.DELTA.P= {square root over (A.sub.1R.sup.2+B.sub.1R.sup.2)} for
the reference channel.
[0310] Taking the ratio of these Fourier amplitudes eliminates the
dependence on the modulation depth .DELTA.P to give a normalised
(intensity) output, N, given by:
N = S R ##EQU00011##
[0311] Where: [0312] S is a constant representing the attenuation
in the optical path including the sample cell. [0313] R is a
constant representing the fraction of incident power delivered to
the reference.
[0314] A value of N (compensated intensity component) is determined
at each wavelength of interest for the liquid/drug under analysis
(be it a training sample or unknown sample under blind test) The
set of values for each wavelength for a drug form a set of dark
current eliminated data (N.sub.1 to N.sub.n). For example, where 8
wavelengths are used for testing, the set will comprise 8 N
values--one for each wavelength
[0315] The procedure results in dark current eliminated training
data (comprising intensity components with the dark current
removed) for the samples/drugs in the training process/set and dark
current compensated blind test data (comprising intensity
components with the dark current removed) for the sample under
blind test. The intensity components with the dark current
eliminated (N.sub.1 to N.sub.n) for each drug (in the training set
and under actual blind test) are stored in the processor 18 and/or
database 23.
Derivation of Dark Current Elimination Using Modulation
[0316] The modulated affected radiation leaving the sample 16 is
detected by the photodetector 17, which provides a resulting output
current. The output current is the sum of two components--a dark
current term that is present even in the absence of any
illumination, and a term proportional to the intensity of light
incident on the detector. Therefore, we can write the sample
channel output current, I.sub.S as follows:
I.sub.S=I.sub.S.sup.Dark+SP (1)
[0317] where in (1):
[0318] I.sub.S.sup.Dark is the dark current signal of the sample
channel detector
[0319] S is a constant representing the attenuation in the optical
path including the sample cell.
[0320] P is the incident power illuminating the sample cell.
[0321] A similar expression can be written for the reference
channel output current, I.sub.R, generated from the built-in
photo-detector of the laser diode source, namely:
I.sub.R=I.sub.R.sup.Dark+RP (2)
[0322] where in (2):
[0323] I.sub.R.sup.Dark is the dark current signal of the reference
photo-detector in the laser diode package.
[0324] R is a constant representing the fraction of incident power
delivered to the reference.
[0325] The laser 211 output is modulated by modulating the driver
current with a known waveform. Typically, a sinusoidal modulation
with angular frequency .omega. is used to vary the current about a
mean value. This has the effect of modulating the output power of
the laser diode source in a similar sinusoidal manner illustrated
in FIG. 17:
[0326] Mathematically, the time-dependent laser output power, P(t),
can be written as follows:
P(t)=P.sub.0+.DELTA.Psin(.omega.t+.phi.) (3)
[0327] where in (3):
[0328] P.sub.0 is the mean output power from the laser
[0329] .DELTA.P is the modulation amplitude in the output power
waveform (depth of modulation)
[0330] .phi. is the phase of the modulation waveform at tine,
t=0.
[0331] Substituting for the incident power in equations (1) and (2)
using (3), the following expressions for the output currents from
sample and reference channels are obtained:
I.sub.S=I.sub.S.sup.Dark+SP.sub.0+S.DELTA.Psin(.omega.t+.phi.)
I.sub.R=I.sub.R.sup.Dark+RP.sub.0+R.DELTA.Psin(.omega.t+.phi.)
[0332] The parameters of interest with respect to characterising
the sample under test are the constants S and R. The ratio of these
two constants represents a normalised coefficient characteristic of
the liquid in the sample cell.
[0333] Expanding the sinusoidal term in the above equations,
gives:
sin(.omega.t+.phi.)=sin(.omega.t)cos .phi.+cos(.omega.t)sin
.phi.
[0334] which gives the following:
I S = I S Dark + S . P 0 + S . .DELTA. P . sin ( .omega. t ) cos
.phi. + S . .DELTA. P . cos ( .omega. t ) sin .phi. .ident. A 0 S +
A 1 S cos ( .omega. t ) + B 1 S sin ( .omega. t ) ( 4 ) I R = I R
Dark + R . P 0 + R . .DELTA. P . sin ( .omega. t ) cos .phi. + R .
.DELTA. P . cos ( .omega. t ) sin .phi. .ident. A 0 R + A 1 R cos (
.omega. t ) + B 1 R sin ( .omega. t ) ( 5 ) ##EQU00012##
[0335] So that:
[0336] A.sub.0S=I.sub.S.sup.Dark+SP.sub.0
[0337] A.sub.0R=I.sub.R.sup.Dark+RP.sub.0
[0338] A.sub.1S=S.DELTA.Psin .phi.
[0339] B.sub.1S=S.DELTA.Pcos .phi.
[0340] A.sub.1R=R.DELTA.Psin .phi.
[0341] B.sub.1R=R.DELTA.Pcos .phi.
[0342] Inspection of equations (4) and (5) shows the output
currents have the form of a simple Fourier series consisting of
constant DC terms, A.sub.0S and A.sub.0R, plus sine and cosine
terms that oscillate with the modulation frequency, .omega., with
amplitudes A.sub.1S, A.sub.1R, B.sub.1S and B.sub.1R.
[0343] The dark current terms contribute only to the DC term of the
Fourier series in (4) and (5). The dark current terms are contained
within the DC components of equations (4) and (5). Therefore, a
simple Fourier analysis of the modulated output waveform gives the
Fourier coefficients of the sin(.omega.t) and cos(.omega.t)
terms--which are independent of the dark current.
[0344] By measuring the sinusoidally varying component of each
output current, the constants, S and R, can be determined without
the need to measure the dark current of each detector diode. These
latter terms can be eliminated from the measurement by DC blocking
components or by performing a Fourier analysis of the output
currents and discarding all but the sinusoidal terms.
[0345] In conventional spectrometer systems, the dark current would
be measured by blocking off the illumination to the detector diode
using a rotating mechanical chopper that periodically blocks then
re-instates the optical illumination. Using the laser-current
modulation described above eliminates the need for mechanical
components such as rotating choppers which simplifies the
spectrometer design, reduces cost and improves reliability by not
using any moving parts. Electrical interference from the electric
motors used to drive mechanical choppers is also eliminated.
Temperature Correction
[0346] In overview, next temperature correction processing can be
done to compensate for changes in intensity measurements from the
detector due to temperature fluctuations of the retainer/sample
step 235b of FIG. 24.
[0347] It can be shown that the temperature dependence is linear
with respect to changes in sample temperature--see further the
explanation below. Therefore, for each wavelength, the gradient of
the intensity value with respect to temperature provides
information to characterise the change in transmission intensity
with changes in temperature. This gradient data is obtained as
described earlier and stored in the drug/dilutant data base along
with the spectral training data.
[0348] Using the temperature dependence data in the training set
data base (the gradient of intensity with respect to temperature;
one gradient for each wavelength for each undiluted drug), the
processor generates a new training data set for all undiluted drugs
and dilutants at the same temperature as the blind test sample was
measured at, namely, T.sub.b. This temperature correction is
applied to data for all retainers (e.g. test tubes) in the original
reference training data set (which has had dark current eliminated
as above). This results in a set of temperature corrected training
data that are the next step in obtaining the comparison
coefficients for verifying/identifying the unknown sample under
test.
[0349] Temperature correction applied to the training data set in
this manner allows a direct comparison to be made with data
acquired for the blind test since all data is now converted
to/valid at the blind test sample temperature, T.sub.b.
[0350] As previously described, when performing a blind test on an
unknown drug sample, intensity data is measured at different
wavelengths and the temperature is taken of the sample and also
stored in the database 23. With the temperature of the fluid known,
a set of temperature-corrected training data coefficients is
generated for all drugs in the data base corresponding to the
temperature of the unknown drug measured in the blind test.
Therefore, both the blind test concentration-independent
coefficients and those of the training data set have a common
temperature.
[0351] Referring to FIG. 24, step 235b, temperature compensation
occurs as follows. For each drug in the training set, the set of
training data is taken and for each training data value (with dark
current eliminated) N.sub.1 to N.sub.n at each wavelength, the dark
current corrected intensity value is then corrected for temperature
using the following equation in the processor 18:
I ( T t ) = ! ( T b ) + I T .DELTA. T ( 6 ) ##EQU00013##
[0352] Where in (6),
[0353] I is the intensity of affected electromagnetic radiation
detected by a detector at a particular wavelength for a sample
(with dark current eliminated e.g. N),
[0354] T.sub.t is the temperature of the training sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0355] T.sub.b is the temperature of the unknown sample when the
affected electromagnetic radiation was detected at that
wavelength,
[0356] .DELTA.T=T.sub.t-T.sub.b, is the sample temperature
difference between the training sample temperature and unknown
sample temperature, and
[0357] dI/dT is the slope of the linear relationship of between
measure intensity and temperature for a sample at a given
wavelength.
[0358] All parameters are known from the training data and blind
test data.
[0359] In particular, the equation is rearranged to solve for
I(T.sub.b):I(T.sub.b)=I(T.sub.t)-(dI/dT).DELTA.T. Each intensity I
(T.sub.t) is obtained (being the intensity of the training sample
obtained during training) along with dI/dT and .DELTA. T. For each
intensity I (T.sub.t) from the training data, a corresponding a
temperature corrected I(T.sub.b) is obtained using the rearranged
equation (6) and stored--this correlating to an "expected"
intensity for the unknown drug at the blind test temperature if the
unknown drug were the training drug. I(T.sub.b) is the temperature
corrected intensity. This corrected I(T.sub.b) is what is used to
calculate the training coefficients below.
[0360] The temperature correction is not applied to the reference
data if it comes from the monitor diode 4. However, if it comes
from a reference channel with components and/or a sample the
temperature correction does take place as described above.
[0361] After this step, the processor 18/database 23 now has a set
of training data (I(T.sub.b).sub.1 to I(T.sub.b).sub.n) for each
drug in the training set that represents intensities that have had
dark current eliminated and have been temperature corrected to
match the temperature of the unknown sample under test.
Derivation of Temperature Correction
[0362] When performing a blind test on an unknown drug sample,
intensity data is measured at different wavelengths and the
temperature of the sample are stored. With the temperature of the
fluid known, a set of temperature-corrected training data
coefficients is generated for all drugs in the data base
corresponding to the temperature of the unknown drug measured in
the blind test. Therefore, both the blind test
concentration-independent coefficients and those of the training
data set have a common temperature.
[0363] The temperature correction is implemented by exploiting the
experimentally observed linear relationship between measured
intensity and temperature for a given drug at a particular
wavelength as set out below. Thus, the temperature dependence of a
given drug can be measured and characterised by a single
coefficient at each wavelength of interest which corresponds to the
slope of the measured intensity with respect to temperature
change.
[0364] For a given drug in the training data set, at a given
wavelength, we can express the intensity at temperature
T.sub.0+.DELTA.T in terms of that at temperature, T.sub.0 as
follows:
I ( T 0 + .DELTA. T ) = I ( T 0 ) + I T .DELTA. T ( A6 )
##EQU00014##
[0365] Equation (A6) is equivalent to equation (6)
[0366] In (A6), the slope dI/dT is a constant coefficient that is
known for each drug in the data base. These coefficients are
determined by measurement on each dilutant and undiluted drug of
interest. There is a separate coefficient for each wavelength.
These temperature coefficients form part of the training data
set.
[0367] The temperature T.sub.0 in (A6) is defined as the
temperature at which the original training data measurements were
performed (as determined from the temperature sensor in the fluid
test cell holder). This need not be the same for each entry in the
data base, and can be different for each wavelength.
[0368] The temperature deviation from T.sub.0 is denoted by
.DELTA.T. This is determined by measuring the fluid temperature of
the unknown drug under test (the blind test) and subtracting the
known value of T.sub.0. Thus, a temperature-corrected set of
concentration-independent training coefficients can be generated at
the same temperature as the blind test measurement using the linear
correction formula of (A6).
Retainer Tolerance Sensitivity Reduction
[0369] The sample retainer 16 could be a test tube, cell, IV line,
syringe or other suitable retainer having a transparent wall.
Inaccuracies due to tolerances in the sample retainer wall and path
length and any other geometric and/or material parameters can be
reduced. For example, during blind or training tests, the fluid
(sample) thickness is controlled by having a fixed cavity bounded
by two optically transparent walls typically made of a plastic. In
the present invention, such plastic retainers are designed to be a
consumable product that is used just once prior to disposal.
Although well-controlled during the manufacturing process,
inevitably there are minor deviations from the intended nominal
fluid thickness from tube to tube due to manufacturing tolerances.
Typically, for a nominal fluid thickness of e.g. several mm there
will be a dimensional tolerance of +/-15 microns. This dimensional
uncertainty from tube to tube translates into a spread in measured
intensity values for a given fluid around the mean value associated
with a retainer of nominal thickness.
[0370] In overview, in order to reduce the sensitivity of the
intensity data to variations in the retainer (e.g. test tube)
geometry (due to manufacturing tolerances) the following `retainer
correction` algorithm has been found to work well which generates
normalised ratios of the intensity values for the training data and
blind test data, step 235c. This algorithm is applied to both
training data and blind test data after dark current and
temperature correction has been applied. Details of the derivation
of this algorithm are set out below. While not necessarily a
correction as such, the algorithm produces coefficients that render
the verification/identification process less sensitive to retainer
tolerance/variations. The process will now be described in more
detail with reference to FIG. 8, step 235c. The ratio of the sample
intensity to the reference intensity for each wavelength (from the
compensated training data or blind test data as appropriate) is
then evaluated by the processor, for each retainer (in the case
where multiple tests are carried out on the same sample in multiple
retainers). Second, the ratio data is normalised by the processor
for each retainer with respect to the sum-over-wavelengths.
Mathematically, this is described below.
[0371] Firstly, for each undiluted drug and dilutant in the
training set, for each wavelength, the average is found over the
number of scans for the set of reference raw data intensities
(however obtained, e.g. by monitor diode or via a reference
channel) and the set of training data raw intensities
((I(T.sub.b).sub.1 to I(T.sub.b).sub.n) in the case where both the
reference and training data set have been processed for dark
current and temperature correction as described earlier). The ratio
f.sub.m of these averages (being training raw data average
intensities divided by the reference raw data average intensities)
is found for each wavelength, for each retainer. Secondly, the
ratio data is normalised for each tube with respect to the
sum-over-wavelengths. Mathematically, this is described below.
[0372] Denoting the ratio at the m.sup.th wavelength by f.sub.m,
the normalised ratios are given by the parameter g.sub.m as
follows:
g m - f m .SIGMA. f m ( 7 ) ##EQU00015##
[0373] The same is also carried out for the sample data as
required. That is, for the sample drug and dilutant, for each test
wavelength, the average is found over the number of scans for the
reference raw data intensities (however obtained, e.g. by monitor
diode or via a reference channel) and the unknown sample data raw
intensities (both of which may have been processed for dark current
and temperature correction). The ratio f.sub.m of these averages
(unknown sample raw data average intensities divided by the
reference raw data average intensities) is found for each (test)
wavelength. Secondly, the ratio data is normalised for each tube
with respect to the sum-over-wavelengths. Mathematically, this is
described in equation (7) above.
[0374] The g.sub.m values represent the fractional (spectral)
intensity (also termed "fractional ratio") defined as the
proportion of transmitted light measured at the m.sup.th wavelength
referenced to the sum of intensities over all test wavelengths
measured for a given retainer. The values of g.sub.m always lie
between 0 and 1 since they represent fractions of the total amount
of energy received over all test wavelengths measured.
[0375] For the temperature corrected and dark current eliminated
training data, a set of g.sub.m values (g.sub.mt to g.sub.mn) for
each retainer used is obtained as per equation (7). The same
procedure is applied to the dark current corrected blind test data
to obtain a set of g.sub.m values (g.sub.m1 to g.sub.mn) for the
retainer used.
[0376] This results in a set of g.sub.m coefficients (g.sub.m1 to
g.sub.mn) for each drug, that are stored in the processor
18/database 23 and that form the basis of training and blind test
coefficients that can be calculated (as set out further below) that
can be used for verification/identification purposes with reduced
sensitivity to retainer geometry.
Derviation for Retainer Tolerance Sensitivity Reduction
[0377] Measurements of intensity for the fluid under test are
carried out using a purpose-made test tube (vial) which contains
the fluid sample. The fluid thickness is controlled by having a
fixed cavity bounded by two optically transparent walls typically
made of a plastic. A typical fluid thickness is several mm with the
plastic walls having a comparable total thickness. In the present
invention, such plastic test tubes are designed to be a consumable
product that is used just once prior to disposal.
[0378] Although well-controlled during the manufacturing process,
inevitably there are minor deviations from the intended nominal
fluid thickness from tube to tube due to manufacturing tolerances.
Typically, for a nominal fluid thickness of several mm there will
be a dimensional tolerance of +/-15 microns for an
injection-moulded component. This dimensional uncertainty from tube
to tube translates into a spread in measured intensity values for a
given fluid around the mean value associated with a tube of nominal
thickness. This error can be expressed mathematically for the
m.sup.th wavelength in the measurement set using the Beer-Lambert
law as a starting point, namely:
f m = ( I I 0 ) m = T m 2 .alpha. _ m w 2 .alpha. m d ( B1 )
##EQU00016##
[0379] where in (B1):
[0380] I=Measured transmitted intensity through the fluid in its
test tube (in this case temperature corrected I(T.sub.b)).
[0381] I.sub.0=Incident intensity on the test tube (proportional to
the reference channel reading).
[0382] T.sub.m=Transmission factor involving the refractive indices
of the test tube wall and fluid that accounts for reflections at
the material interfaces.
[0383] .alpha..sub.m=Attenuation coefficient of test tube wall
material with total thickness, w, at m.sup.th wavelength.
[0384] .alpha..sub.m=Attenuation coefficient of fluid with
thickness, d, at m.sup.th wavelength.
[0385] By way of example, consider the sensitivity of the measured
transmission coefficient f.sub.m with respect to changes in the
fluid thickness, d. Differentiating (B1) with respect to d while
keeping all other variables constant gives:
.differential. f m .differential. d = - 2 .alpha. m f m ( B2 )
##EQU00017##
[0386] Defining the nominal fluid thickness as d.sub.0 and the
deviation from this value as .DELTA.d, the resulting effect on the
measured intensity can be expressed as:
f m ( d 0 + .DELTA. d ) = f m ( d 0 ) + .differential. f m
.differential. d .DELTA. d ( B3 ) ##EQU00018##
[0387] Combining (B2) and (B3) gives the error term .DELTA.f.sub.m
as:
.DELTA.f.sub.m=f.sub.m(d.sub.0+.DELTA.d)-f.sub.m(d.sub.0)=2.alpha..sub.m-
f.sub.m.DELTA.d (B4)
[0388] Measurements carried out on fluids using numerous test tubes
of the same nominal design have shown that errors of the form given
in (B4) are consistent with the typical dimensional tolerance
associated with the fluid space, d. It has also been found that
these tube-to-tube variations can be comparable or larger in
magnitude than the difference between mean intensity values between
some drugs. This makes drug discrimination for certain drugs very
difficult or even impossible.
[0389] To remedy this, an alternative measurement parameter is
considered which is less sensitive to the dimensional tolerances
associated with the test tubes. This parameter is the fractional
intensity, denoted by g.sub.m, which is defined as the proportion
of transmitted light measured at the m.sup.th wavelength referenced
to the sum of intensities over all wavelengths measured for a given
test tube. That is we define:
g m = f m .SIGMA. f m ( B5 ) ##EQU00019##
[0390] The values of g.sub.m always lie between 0 and 1 since they
represent fractions of the total amount of energy received over all
wavelengths measured. To estimate the sensitivity of g.sub.m to
dimensional tolerances in the fluid thickness, we follow a similar
procedure to before using partial differentiation with respect to
the fluid thickness, d. Denoting .SIGMA.f.sub.m by .SIGMA., this
gives:
.differential. g m .differential. d = 1 .SIGMA. .differential. f m
.differential. d - f m .SIGMA. 2 .differential. .SIGMA.
.differential. d ( B6 ) ##EQU00020##
[0391] Using (B6) and noting that, using (B2),
.differential. .SIGMA. .differential. d = - 2 .SIGMA..alpha. m f m
##EQU00021##
[0392] we can express the error term .DELTA.g.sub.m associated with
g.sub.m in the following form:
.DELTA. g m = g m ( d 0 + .DELTA. d ) - g m ( d 0 ) = .DELTA. f m
.SIGMA. - f m .SIGMA. 2 .SIGMA. m .DELTA. f m ( B7 )
##EQU00022##
[0393] Inspection of (B7) indicates that the spread in values,
.DELTA.g.sub.m, associated with dimensional tolerances in the fluid
thickness in the test tube are reduced in magnitude when we use the
fractional intensity g.sub.m instead of the transmission
coefficient f.sub.m. This is by virtue of the denominator terms in
(B7) which involve the factors .SIGMA. and .SIGMA..sup.2 which are
larger than unity.
[0394] We now consider the case of the fractional intensity
parameter for a test tube of nominal fluid thickness d.sub.0 when
the fluid attenuation coefficient changes, as would occur when
performing measurement s on different drugs. If the fluid
attenuation coefficient changes from .alpha..sub.m to
.alpha..sub.m+.DELTA..alpha..sub.m then the effect on the
fractional intensity is as follows:
g m ( .alpha. m + .DELTA..alpha. m ) = f m ( .alpha. m +
.DELTA..alpha. m ) .SIGMA. f m ( .alpha. m + .DELTA..alpha. m ) = f
m ( .alpha. m ) ( 1 - 2 d 0 .DELTA..alpha. m ) .SIGMA. f m (
.alpha. m ) ( 1 - 2 d 0 .DELTA..alpha. m ) ( B8 ) ##EQU00023##
[0395] In (B8), variations in attenuation coefficient in the
denominator will be negligible compared to those in the numerator.
Therefore, we can write (B8) as:
g m ( .alpha. m + .DELTA..alpha. m ) .apprxeq. f m ( .alpha. m ) (
1 - 2 d 0 .DELTA..alpha. m ) .SIGMA. f m ( .alpha. m ) = g m (
.alpha. m ) ( 1 - 2 d 0 .DELTA..alpha. m ) ( B9 ) ##EQU00024##
[0396] Therefore, from (B9), the fractional change in the parameter
g.sub.m with respect to changes in the fluid attenuation
coefficient is given by:
g m ( .alpha. m + .DELTA..alpha. m ) - g m ( .alpha. m ) g m (
.alpha. m ) .apprxeq. - 2 d 0 .DELTA..alpha. m ( B10 )
##EQU00025##
[0397] Equation (B10) establishes that the fractional intensity
parameter g.sub.m remains sensitive to changes in fluid attenuation
coefficient and so is suitable as a drug discrimination
parameter.
[0398] The use of the fractional intensity parameter g.sub.m has
been tested with measured data obtained using multiple test tubes
containing the same fluid. The resulting spread in values across
different tubes was found to be greatly reduced compared to values
obtained using just the measured transmission coefficients, thereby
verifying the theoretical result of (B7).
[0399] It was also found that the inherent differences in the
attenuation coefficients of different drugs were still maintained
when using the fractional intensity parameter, which verified the
result of (B10).
[0400] The reduction in sensitivity to fluid thickness variations
from test tube to test tube proved to be a key factor in
discriminating between drugs which had previously proven impossible
to tell apart from just the transmission coefficient data
alone.
Concentration Independent Coefficients
[0401] Having applied dark current, temperature correction and path
length correction as described above resulting in the g.sub.m
coefficients from the training data and blind test data, the next
step is from that to generate a set of spectral (comparison)
coefficients at each wavelength for a given drug-dilutant
combination that are independent of concentration, step 235d, for
both the training sample drugs and unknown sample drug under blind
test.
[0402] It has been shown experimentally and theoretically that the
intensity for a given drug-dilutant combination is linearly
dependent on the concentration. Consequently, it is possible to
characterise this dependence using the slope of the resulting
straight line with respect to the volume fraction of undiluted
drug, denoted by x. Here, x=0 corresponds to the case of pure
dilutant, and x=1, the case for the pure undiluted drug. Details of
the derivation of the concentration-independent coefficients are
set out below.
[0403] Referring to FIG. 24, step 235d, the steps involved in
calculating in the processor the concentration-independent
coefficients are given below: First choose a dilutant--for example,
0.9% saline. Next, from the compensated training data set
obtain/evaluate, as set out previously, the average-over-test-tubes
for the g.sub.m values for the chosen dilutant and for each
undiluted drug. There will be one such average value for each drug
and the chosen dilutant for each wavelength (suffix m). Denote the
undiluted drug tube averages by g.sub.m and those of the dilutant
as g.sub.m.sup.0. For the blind test data, (for which there is only
a single retainer), also obtain/evaluate g.sub.m value denoted by
g.sub.m.sup.0(x) where x is the unknown concentration (superscript
B for blind test). Next, for each drug, subtract the dilutant tube
average from each undiluted drug tube average, to give the slope,
s.sub.m, of the intensity versus concentration curve for each
drug-dilutant combination, that is:
s.sub.m=g.sub.m-g.sub.m.sup.0 (8)
[0404] Next, the processor carries out the same steps for each
further dilutant. Next, the processor evaluates the training-set
coefficients y.sub.m as follows:
y m = s m .SIGMA. m s m 2 ( 9 ) ##EQU00026##
[0405] These coefficients are the slopes of equation (8) normalised
with respect to the root-sum-of-squares taken over all wavelengths.
These coefficients are independent of the concentration x and are
defined at each wavelength for a given undiluted drug and its
chosen dilutant.
[0406] Next, we now turn our attention to the blind data for which
the drug identity and concentration are both unknown. For the case
of a mixture of drug and chosen dilutant with unknown
concentration, x, the linear dependence on concentration for the
spectral intensity, g.sub.m.sup.B(x), at the m.sup.th wavelength
can be defined by the following:
g.sub.m.sup.B(x)-g.sub.m.sup.0-s.sub.m.sup.Bx (10) [0407] Where in
equation (10) the concentration slope for the blind test drug is
denoted by s.sub.m.sup.B which, along with the concentration, x, is
unknown.
[0408] Using equation (10) and the equation given in (9), a set of
concentration-independent coefficients for the blind test drug,
y.sub.m.sup.B, can be evaluated by the processor as follows:
y m B = s m B .SIGMA. m ( x m B ) 2 .ident. g m B ( x ) - g m 0 _
.SIGMA. m ( g `m B ( x ) - g m 0 _ ) 2 ( 11 ) ##EQU00027##
[0409] Equation (11) shows that the above coefficients
y.sub.m.sup.B can be determined from the measured values of
g.sub.m.sup.B(x) and the known dilutant values g.sub.m.sup.0
obtained from the training data set.
[0410] Since there will be several possible dilutants used, if the
identity of the dilutant is not known or in doubt, the above
procedure can be repeated for each different dilutant giving rise
to a different set of concentration-independent coefficients for
both training data and blind test data. The full set of y.sub.m and
y.sub.m.sup.B would therefore, in general, consist of coefficients
for all dilutants of interest.
[0411] Using the equations 9 and 11, the processor obtains y.sub.m
resulting in a set (y.sub.m1 to y.sub.mn) of training data
coefficients for each drug, and y.sub.m.sup.B resulting in a set
(y.sup.B.sub.m1 to y.sup.B.sub.mn) of blind test data coefficients
(together "comparison coefficients"), which are stored in the
processor 18/database and can be used for verification
identification.
Derivation of Concentration Independent Coefficients
[0412] The properties of each fluid of interest can be
characterised by its complex refractive index. We can write the
complex refractive index of the fluid under test, n, in terms of
its real and imaginary parts n' and n'' as:
n=n'-jn'' (C1)
[0413] where in (C1): j= {square root over (-1)}.
[0414] Physically, the real part of the refractive index, n',
determines the wavelength of electromagnetic radiation in the fluid
according to .lamda.=.lamda..sub.0/n where .lamda..sub.0 is the
wavelength in free space. More importantly for NIR transmission
through aqueous fluids, the imaginary part of the refractive index,
n'', determines the attenuation (via absorption) of incident
electromagnetic waves consistent with the Beer-Lambert law as
follows:
I I 0 = - 2 .alpha. d ( C2 ) ##EQU00028##
[0415] In (C2), the transmitted light intensity through the fluid
is denoted by I with I.sub.0 the intensity incident on the fluid
sample. The thickness of the fluid is denoted by d and .alpha. is
the attenuation coefficient which is given by:
.alpha. = 2 .pi. .lamda. m n m ( C3 ) ##EQU00029##
[0416] Therefore, the measured attenuation through a fluid under
test at a given free-space wavelength is determined by the
imaginary part of the complex refractive index of the fluid. A
common occurance in the preparation of intravenous drugs prior to
administration, is dilution of a drug with a dilutant such as
saline or water. Drug verification under these circumstances has
the additional complication of drug concentration which needs to be
accounted for in any subsequent verification analysis. The
following procedure is applied to obtain a set of coefficients for
each undiluted drug that is independent of the drug's concentration
when the identity of the dilutant is known.
[0417] Consider the diluted drug as a mixture of two fluids, each
denoted by subscripts `1` and `2`, with complex relative
permittivities e.sub.1 and e.sub.2, respectively. The complex
relative permittivity of the fluid under test is denoted by e and
is related to the complex refractive index, n, of the fluid by the
relation:
e=n.sup.2 (C4)
[0418] This complex relative permittivity can be expressed in terms
of the complex relative permittivities of the individual components
and the volume fraction of each component by invoking the
Lichtenecker mixture law [ref 1] which is given below:
? = ( ? ) x ? indicates text missing or illegible when filed ( C5 )
##EQU00030##
[0419] In (C5), x denotes the volume fraction of component `2`
which we can define as the undiluted drug, with component `1` the
dilutant. Thus, when x=0, the mixture consists of 100% dilutant,
and when x=1, the mixture is 100% undiluted drug.
[0420] Until recently, this formula was regarded as semi-empirical
in nature without any firm physical basis. However, in 2010, the
formula was derived from first principles by Simpkin [ref 2] using
Maxwell's equations and the conservation of charge.
[0421] Equation (C5) can now be expressed in terms of the complex
refractive indices of the relevant media by substituting (C4) into
(C5) and taking the square root of each side. This gives the
self-same formula for the complex refractive indices of the
mixture, namely:
? = ( ? ) x ? indicates text missing or illegible when filed ( C6 )
##EQU00031##
[0422] Where n.sub.1 is the complex refractive index of the
dilutant and n.sub.2 is the complex refractive index of the
undiluted drug with volume fraction x.
[0423] We now express the complex refractive index of the undiluted
drug in terms of the difference, .DELTA.n, with respect to that of
the dilutant, that is:
n.sub.2=n.sub.1+.DELTA.n (C7)
[0424] Substituting (C7) into (C6) gives:
n n 2 = ( 1 + .DELTA. n ? ) x ? indicates text missing or illegible
when filed ( C8 ) ##EQU00032##
[0425] For the case of intravenous drugs, the complex refractive
index is dominated by the properties of water and deviations in
complex refractive index from that of water are small in magnitude.
Therefore, in (C8), the fraction .DELTA.n/n.sub.1 is small compared
with unity so that to a very good approximation we can expand the
right hand side in a Binomial series and use only the first few
terms. Thus, (C8) becomes:
n ? .apprxeq. 1 + x .DELTA. n n 1 n .apprxeq. n 1 + x .DELTA. n = n
1 + x ( n 2 - n 1 ) ? indicates text missing or illegible when
filed ( C9 ) ##EQU00033##
[0426] Therefore, the mixture law for the two fluids is
well-approximated by a linear relationship with respect to the
volume fraction of the undiluted drug. Taking the imaginary part of
both sides of (C9) then gives:
n''=n'.sub.1+x(n''.sub.2-n''.sub.1) (C10)
[0427] If we now take the natural logarithm of the Beer-Lambert law
of equation (C2) and substitute for the attenuation coefficient
.alpha. using (C3), we obtain:
- ln ( I I 0 ) = 2 ad = 4 .pi. d .lamda. 0 ? ? indicates text
missing or illegible when filed ( C11 ) ##EQU00034##
[0428] If l represents the measured transmitted intensity of a
diluted drug, then we can substitute for n'' using equation (C10)
to obtain the following:
- ln ( I I 0 ) = 4 .pi. d .lamda. 0 { ? + x ( ? - ? ) }
##EQU00035## ? indicates text missing or illegible when filed
##EQU00035.2##
[0429] The above expression can be expressed as follows:
ln ( I I 0 ) = ( 1 - x ) ln ( ? I 0 ) + x ln ( I 2 I 0 ) ?
indicates text missing or illegible when filed ( C12 )
##EQU00036##
[0430] where in (C12):
ln ( ? I 0 ) = - 4 .pi. d .lamda. 0 ? ##EQU00037## ? indicates text
missing or illegible when filed ##EQU00037.2##
[0431] is the Beer-Lambert law applicable to the pure dilutant with
measured intensity I.sub.1, and
ln ( I 2 I 0 ) = - 4 .pi. d .lamda. 0 ? ##EQU00038## ? indicates
text missing or illegible when filed ##EQU00038.2##
[0432] is the Beer-Lambert law applicable to the undiluted drug
with measured intensity I.sub.2.
[0433] The above can be further simplified since the incident
intensity I.sub.0 cancels out in (C12) to give:
ln ( I ? ) = x ln ( I 2 ? ) ? indicates text missing or illegible
when filed ( C13 ) ##EQU00039##
[0434] Equation (C13) shows that the measured intensities obey a
logarithmic mixture law identical to the Lichtenecker formula.
Expressions like those in (C13) can be applied to a given
drug-dilutant mixture for each of several wavelengths measured.
[0435] In (C13), we can simplify the logarithmic expressions by
observing that the measured spectral intensities differ only
slightly for different drugs. That is, the ratios
( I I 2 ) ##EQU00040## and ( I 2 ? ) ##EQU00040.2## ? indicates
text missing or illegible when filed ##EQU00040.3##
[0436] are close to unity. Therefore, we can write the following
approximations:
ln ( I I 1 ) = ln ( 1 + ( I - I 1 ) I 1 ) .apprxeq. ( I - I 1 ) I 1
##EQU00041## and ##EQU00041.2## ln ( I 2 I 1 ) = ln ( 1 + ( I 2 - I
1 ) I 1 ) .apprxeq. ( I 2 - I 1 ) I 1 ##EQU00041.3##
[0437] which are valid since I-I.sub.1 and I.sub.2-I.sub.1 are
small in magnitude with respect to I.sub.1. Using these
approximations in (C13) results in the following linear
expression:
I(x)-I.sub.1=(I.sub.2-I.sub.1)x (C14)
[0438] Expressions of the form given in (C14) can be defined for
each wavelength. The important point to note is that the volume
fraction of the undiluted drug, x, which is a measure of the drug
concentration, is common to all wavelengths for a given mixture.
Therefore, by making measurements at a minimum of two wavelengths,
it is possible to eliminate the concentration, x, and obtain values
that are characteristic of the particular undiluted drug with
respect to a given dilutant. The optimum way to eliminate the
concentration, x, that utilises measured data at all wavelengths,
is proposed as follows. A normalisation procedure is used whereby
the normalising factor is the root-sum-of-squares over all
wavelengths. To illustrate this latter scheme, consider M
wavelengths so that we obtain a set of M equations like that in
(C14), one for each wavelength, .lamda..sub.m, where m=1, 2, 3 . .
. M, namely:
I(x,.lamda..sub.m)-I.sub.1(.lamda..sub.m)=(I.sub.2(.lamda..sub.m)-I.sub.-
1(.lamda..sub.m))x (C15)
[0439] In (C15) we now square both sides, sum over all wavelengths
(suffix m) and take the square root to give the following
expression for x:
x = m ( I ( x , .lamda. m ) - ? ( ? ) ) 2 m ( ? ( .lamda. m ) - ? (
? ) ) 2 ? indicates text missing or illegible when filed ( C16 )
##EQU00042##
[0440] Substituting for x in (C14) using (C16) then gives for each
wavelength a coefficient, y.sub.m, defined as follows:
y m = I ( ? ) - I 2 ( .lamda. m ) ? m ( I ( x , .lamda. m ) - ? ( ?
) ) 2 = ( ? ) - I 2 ( .lamda. m ) ? m ( ( .lamda. m ) - ? ( ? ) ) 2
? indicates text missing or illegible when filed ( C17 )
##EQU00043##
[0441] By virtue of the far right-hand side of (C17), the
coefficients y.sub.m are independent of the drug concentration and
are characteristic of the undiluted drug and its dilutant.
[0442] When performing a blind test on an unknown drug, the
coefficients are found by measuring the intensity
I(x,.lamda..sub.m) for the unknown drug mixture at M wavelengths.
For each wavelength, the difference between these measured
intensities and the dilutant is then normalised with respect to the
root-sum-over-squares over all wavelengths as per the first
expression on the right hand side of (C17). The identity of the
dilutant is assumed known and its intensity I.sub.1(.lamda..sub.m),
which will typically be contained within the set of training data.
Usually, the dilutant is saline, water, or glucose. If the dilutant
identity is not known, or is in doubt, concentration-independent
coefficients for all possible combinations of dilutants and
undiluted drugs can be determined for use in the drug verification
analysis.
[0443] The consequence of (C17) is that when generating a set of
training data, it is only necessary to measure the intensities of
the dilutants of interest (denoted by I.sub.1(.lamda..sub.m) in
(C17) and the intensities of the drugs of interest in their
undiluted form (denoted by I.sub.2(.lamda..sub.m) in (C17). It is
not necessary to generate training data for every possible
combination of dilutant and drug--just data for each dilutant and
each undiluted drug of interest. The set of training data for a
range of drugs and dilutants is then populated by
concentration-independent coefficients given by the far right-hand
side of (C17).
[0444] Once a drug's identity has been verified from the blind test
and training set coefficients so generated, it is possible to
determine the concentration of the drug by calculating the value of
x by back-substitution using (C15).
Drug Verification/Identification or Other Characterisation
[0445] Now that there exists a set of concentration-independent
coefficients for each of the drugs in the training data set with
its chosen dilutant--these are the training coefficients y.sub.m
obtained from equation (9). Now there also exists a set of
concentration-independent coefficients for the unknown blind test
drug--these are the sample coefficients y.sub.m.sup.B obtained from
equation (11).
[0446] The drug identity is now verified/identified or otherwise
characterised by the processor using, for example, Linear
Discriminant Analysis, with y.sub.m as training data and
y.sub.m.sup.B as test data, step 235e. In general terms, the
representative sample/training coefficients are found for the
sample at each selected wavelength and with respect to each other
comparison sample. The sample coefficients are analysed against the
training coefficients. Representative value(s) could be obtained
for each sample based on the coefficients. If there is sufficient
similarity between the representative value(s) found for the
unknown sample and the representative value(s) of a training sample
(corresponding to the same sample), then verification or
identification is made. Sufficient similarity can be determined
using any suitable statistical or other technique. For example,
sufficient similarity might occur when some or all of the
representative values match those in the verification matrix. In
another example, this might occur when the sample falls below the
threshold for each comparison sample. An alarm or output might be
made via a user interface to advise the user of the result of the
verification/identification.
[0447] In verification, the y.sub.m.sup.B values for the unknown
sample are analysed against the y.sub.m values for the drug
identified/entered by the clinician to see if there is a match. An
output answer such as "Yes" or "no" can be output on the interface
to advise the clinician if the blind test sample matches the
expected input drug, step 236 of FIG. 23. In identification, the
the y.sub.m.sup.B values for the unknown sample are analysed
against the y.sub.m values for all training samples. The processor
18 can provide an output on the user interface for example advising
the clinician what the sample drug is, step 236 of FIG. 23 and also
control external equipment where appropriate.
[0448] One possible embodiment of a verification/identification
method is described with reference to FIG. 25 (which shows step
235e of FIG. 24 in more detail)--the processor 18 undertakes the
steps. As previously described, each unknown sample and training
sample have a set of coefficients, one for each wavelength. In
overview, a linear score is defined for the set of coefficients for
each sample by 6 weights--one for each wavelength:
score=w.sub.1.times.normalised value at wavelength 1+ . . .
+w.sub.6.times.normalised value at wavelength 6. In addition, for
each score a threshold value is determined, .tau., such that an
alarm is raised when the score e.g. exceeds .tau..
[0449] First a sample coefficient is obtained by the processor 18
from the database 23, step 240. It is then multiplied by or
otherwise has a weighting applied to it, step 241. The weighting is
added to a previous weighting for that sample, step 242. This
provides a cumulative weighting which becomes a representative
sample value for the sample. If all coefficients for the sample
have been processed, step 243, the method moves to the next step.
If not, step 243, the next coefficient is obtained, step 240,
weighted, step 241, and added to the cumulative weighting, step 242
for that sample.
[0450] Next, the same process happens for the training sample
coefficients--the processor 18 undertakes the steps. If
verification takes place then following happens. The first
coefficient is obtained by the processor 18 for the sample/drug
that the clinician input previously as the predicted drug, step
244. It is then multiplied by or otherwise has a weighting applied
to it, step 245. The weighting is added to a previous weighting for
that training sample, step 246. This provides a cumulative
weighting which becomes a representative training value for the
training sample. If all coefficients for the sample have been
processed, step 247, the method moves to the next step. If not,
step 247, the next coefficient is obtained, step 244, for that
training sample weighted, step 245, and added to the cumulative
weighting, step 246 for that sample.
[0451] Next the cumulative representative training value and the
cumulative representative sample value are compared or compared
against a threshold(s) or some other relationship between them is
determined, step 248. For example, if the sample value is within
`X` of the training value or if the sample value is above or below
a threshold with some reference to the training value, then a
"match" is determined, and the unknown sample is deemed the same as
that of the training value. Otherwise it is deemed not to be a
match. Output as previously described can then take place
indicating the result, step 236. The process stops.
[0452] Where identification takes placed, steps 244 to 248 cycles
through for all training sample coefficients for all training
samples, step 249. That is, if the comparison step 248 results in
no match, step 249, then the processor 18 determines the
representative training sample value from the training coefficients
for the next training sample in the database 23, steps 244 to 247.
The training and sample representative values are compared, and it
is determined whether a match occurs, step 248, and the result
outputted step 236. If there is no match, step 249, steps 244 to
248 are repeated until all training sample coefficients have been
analysed, or a match occurs.
[0453] It will be appreciated that the above embodiment is
conceptual only and the actual steps taken and their order by a
processor could be different. For example, training samples
coefficients could be processed first. Many alternatives could be
envisaged.
Determining Weights and Thresholds
[0454] The drugs below were tested using and apparatus and method
as described in the first embodiment. The weights w.sub.1 . . .
w.sub.6 are chosen by solving a linear program that provides a
separation of 1 unit in the score. This is possible if the
`intended` drug is well-separated from the rest. However, even when
it is possible to get a solution, there is the issue of
`robustness`. Large weights are symptomatic of a lack of
`robustness`. To get a better idea of blind test performance we
will need to add +/-1% to the training data and consider the
resulting false and missed alarm rates. The threshold value .tau.
is chosen to give acceptable error rates (if possible).
Determination of Drug Concentration.
[0455] With the drug identity verified, the slope of the
concentration curve S.sub.m can now be found by the processor using
equation (8). Then, the concentration of the drug in its chosen
dilutant can be found by the processor from back-substitution into
equation (10) on setting S.sub.m.sup.B=S.sub.m. Thus, the
concentration, x, is given by:
x = g m B ( x ) - ? ? ? indicates text missing or illegible when
filed ( 12 ) ##EQU00044##
[0456] The processor can provide output on the user interface
advising the clinician what the concentration of the sample drug
is.
[0457] It will be appreciated that in this embodiment that not all
corrections or processing are essential. While the raw data is
described as having dark current eliminated, temperature corrected,
fractional intensities found, and concentration-independent
coefficients found, a subset of these could be used. Further, the
order in which they are described as occurring should not be
considered limiting. It will also be appreciated that while
temperature correction, fractional intensity and concentration
independent coefficients are found after the blind test, this is
not essential. Some or all of these might be found after the
training test. A database 23 (e.g. in the form of a look up table)
could be produced at training acquisition time or afterwards and
then used by the characterisation process after the blind test.
Training sample coefficients could be provided for e.g. all likely
temperatures and then used by the processor 18 during
characterisation.
[0458] It will also be appreciated that where verification takes
place, it may not be necessary to process and compare all training
data/coefficients. Rather, just the training data/coefficients for
the identified drug are processed and compared to those of the
unknown sample. In identification the training data/coefficients
for several or all of the training samples may need
processing/comparing with the unknown drug until a match is
found.
Second Embodiment
[0459] One possible embodiment of the invention will now be
described in detail by way of example. This should not be
considered limiting but illustrative. The embodiment is described
in relation to an apparatus for providing verification or
identification of water based drugs from e.g. a set of 30
drugs.
[0460] Six wavelengths of electromagnetic radiation are chosen for
this example, six being greater than log.sub.2 n of 30. The
wavelengths are chosen in the analysis range and are based on the
spectral characteristics of water, being the base liquid, falling
in that range. The spectrum of a water based drug (or other liquid
based drug or aqueous solution) will be heavily dominated by the
base liquid spectrum. For example referring to FIG. 5, the spectrum
(dotted line) of drug W (gelofusine succinated gelatine solution
4%) is very similar to the spectrum of water (solid line). This is
because the spectrum of water dominates. However, the differences
in transmission coefficient between different water based drugs can
be measured. Focussing on areas/wavelengths of spectral
characteristics of the water spectrum, by using electromagnetic
radiation beams at those wavelengths, the difference between the
water spectrum and the water based drug spectrum at those
wavelengths can be utilised to provide drug discrimination for drug
identification or verification.
[0461] FIG. 6 shows a spectrum of water with some possible spectral
characteristics (features) in the analysis range indentified, and
explained further below. [0462] Spectral characteristic A
(slope)--in a first region between 1300 nm and 1400 nm. [0463]
Spectral characteristic B (plateau/trough)--in a second region
between 1400 nm and 1500 nm. [0464] Spectral characteristic C
(slope)--in a third region between 1500 nm and 1600 nm. [0465]
Spectral characteristic D (peak)--in a fourth region between 1600
nm and 1700 nm. [0466] Spectral characteristic E (inflection)--in a
fifth region between 1700 nm and 1800 nm. [0467] Spectral
characteristic F (knee) a sixth region between 1800 nm and 2000
nm.
[0468] This is not an exhaustive list of possible spectral
features.
[0469] The selection of a wavelength for an electromagnetic
radiation beam is not strictly fixed, and not necessarily solely
based on spectral characteristics of the base liquid. It is
influenced by the wavelength of spectral characteristics in
spectrum of the base water of the drug sample, but in addition the
selected wavelength can be based on other factors also. For
example, in interest of cost effectiveness and a regularly
obtainable supply chain, it might be preferable to use or select an
alternative wavelength that is close to the spectral characteristic
but not quite the same, if that alternative wavelength is easily
obtainable by an off-the-shelf laser or other optical
component.
[0470] For example, it is possible to use 1310 and 1550 nm as
selected wavelengths for water based drugs as there are many
devices configured for these wavelengths as they have wide spread
use within the communications industry. Laser diodes nominally have
centred wavelengths at 1650 nanometres, 1750 nanometres and 1850
nanometres, although these can be varied by up to plus or minus 30
nanometres. So wavelengths in these ranges can also be selected.
Therefore by looking at the availability of these components, and
the spectral characteristics of the base liquid, suitable
wavelengths for the emitted radiation can be determined.
[0471] Therefore, based on the above explanation, each of the six
wavelengths can be chosen to be within the vicinity or within the
region spanning one of each of the spectral features, but also
influenced by the availability of hardware. The six wavelengths for
water could therefore be (by way of example): 1350 nanometres
corresponding to feature A, 1450 nanometres corresponding to
feature B, 1550 nanometres corresponding to feature C, 1650
nanometres corresponding to feature D, 1750 nanometres
corresponding to feature E and 1850 nanometres corresponding to
feature F, all which fall within the 1300-2000 nanometres. As can
be seen the 1350 nm to 1850 nm wavelength selections do not match
exactly to peaks and troughs and other spectral characteristics in
the water spectrum, although are close. The selections also relate
to operating wavelengths of available hardware. These are of course
nominal wavelengths and the actual wavelength might vary in
practice due to source 11 characteristics.
[0472] FIG. 7 shows in schematic form one possible form of the
apparatus 10 as generally described in FIG. 1. The spectroscopic
analyser 10 has a controller 12 and a carousel 50 that supports six
lasers 51a-51f, which together form the source 11 to output
electromagnetic radiation 22 at a plurality of wavelengths in the
form of light. Each laser is tuned or tuneable to emit
electromagnetic radiation 22 at one of the six wavelengths defined
above. Each laser can comprise or be formed from laser diodes
providing a stable, high intensity, narrow band collimated
electromagnetic radiation output that is readily controlled
electronically via driver circuitry. Each laser comprises a lens
that can collimate the emitted electromagnetic radiation 14a into a
beam using appropriate lenses. Each laser 51a-51f can have one or
more photodiodes 4a-4f for detecting output electromagnetic
radiation for feedback control of that radiation. Lasers have fewer
heat emission problems than other sources, thus reducing the
detrimental effects of heat on the measurements. The output power
of each laser preferably is nominally the same (typically 30 mW) in
the interests of having a balanced apparatus. Preferably, this also
enables a common diode driver circuit to be used for the laser
diodes.
[0473] The controller 12 can control the carousel 50 to rotate
about an axis to activate any one of the lasers 51a-51f in turn and
align the activated laser (e.g. 51f as shown) to emit a beam 22
along the sample path/beam path 14a. The lasers 51a-51f can also be
turned off completely to facilitate the measurement of dark current
signals if required. The use of mechanically activated optical
chopper can thereby be eliminated (although one can be included if
desired.) Once activated, the laser emits electromagnetic radiation
22 towards the sample along the path 14a. The path 14a from the
source to the detector is preferably predominantly via free-space
preferably with minimal if any optical fibre components. This
reduces optical attenuation and hardware. The apparatus also
comprises a sample retainer 16a, which is aligned with the beam
path 14a. The emitted electromagnetic radiation from an active
laser 51a-51f is incident on and transmits or reflects through the
sample 16 in the sample retainer.
[0474] The detector 16 is placed in the affected radiation path 14b
that exits the sample 16a. Preferably the detector 16 is a single
photodetector/photodiode biased to have a suitable response to
detect electromagnetic radiation of wavelengths that will be in the
affected radiation. A single detector reduces the errors due to
variability introduced by components--it removes the relative
differences between multiple photodetectors enabling a more stable
response to the output of the emitted electromagnetic radiation
thus enhancing sensitivity. An InGaAs photodiode could be used, for
example. The detector 17 detects the affected radiation 14b and the
output 14c of the detector 17 is passed to a processor 18 that
verifies or identifies the sample as described above.
[0475] The apparatus also has a beam splitter 21 to redirect the
incident electromagnetic radiation beam 22/14a towards a reference
sample retainer along a reference path 15a, which passes through to
a reference detector 20. The output of the reference detector 20 is
also passed to the processor 18. The reference could be saline, for
example.
[0476] Preferably, the apparatus also comprises a feedback system
to stabilise the temperature of the electromagnetic radiation
source 11 and the detectors(s). In one example, thermistors detect
the temperature of the electromagnetic radiation source and/or
detector(s). Peltier cooling devices can be operated to cool and
stabilise the temperate of the source and detectors. The output of
the thermistor(s) is sent to the controller, which controls the
peltier cooling devices to cool the source and/or detectors.
Preferably the thermistor is the built-in photodetector thermistor
5a, 5b. And the peltier thermo-electric cooler is built-in to the
photodetector 5a, 5b.
[0477] Referring to FIG. 4, operation of the apparatus 10 will now
be described. The controller 12 operates the carousel 50 to rotate
each laser 51a-51f in turn to the activate position. When in the
activate position, the laser 51a-51f is operated by the controller
12 to emit an electromagnetic radiation beam at one of the selected
wavelengths to the sample 16 (and optionally to reference sample
19.) In this manner, six electromagnetic radiation beams with
different selected wavelengths are emitted, step 40, in sequence
from each of the six lasers 51a-51f, each tuned to a different
selected wavelength. Each laser 51a-51f in turn emits an
electromagnetic beam 22 along the path 14a towards the sample. The
affected radiation coming from the sample is detected, step 41, for
each electromagnetic radiation beam emitted 14a towards the sample
16. The electromagnetic radiation beam could be switched on and off
to get a reading/measurement made by the detector during the off
phase also--this can give a dark signal/current for reference
purposes. The emitted electromagnetic radiation is also directed
along the reference path 15a, through the reference sample 19 using
the beam splitter 21, and detected by the reference detector 20.
The outputs from the sample detector 17 and the reference detector
20 are passed to the processor 18, step 42. The processor
(optionally) carries out pre-processing on the output from the
detectors, and then verifies or identifies the drug based on the
pre-processed outputs, step 43. It outputs the results via the user
interface 24, step 44.
[0478] In one possible embodiment, the processor 18 comprises or
implements a pre-processing method and then a
verification/identification method as shown in FIG. 8. In this
embodiment a reference channel is used and also dark current
readings. Dark current is the output provided by the detectors 17,
20 when no electromagnetic radiation (e.g. light) is incident on
them. This dark current reading from the detector can be subtracted
from the actual reading from the detectors for calibration
purposes. Having a dark reading is not essential for the invention
and is described here as one possible option--the remaining
description of the processing method would work also without dark
readings being taken or by.
[0479] Prior to carrying out the verification or identification in
FIG. 8, a training process is carried out to produce a comparison
data from which samples can be verified/identified as shown in
FIGS. 9-11. In the training process, an algorithm is used to
generate the comparison data, which determines the particular
linear combination of data values from each of the sample data that
optimises the separation between different drugs. The resulting
mathematical rule is then applied to the data acquired for the drug
under test to verify that it is the intended drug. In the
embodiment described, dark current readings are used. The training
process preferably comprises a pre-processing stage, and a
comparison data generation stage. Pre-processing is not essential,
but improves performance.
[0480] Referring to FIG. 9, for the training process, a number of
training samples are tested in the analyser in turn. Each training
sample relates to a sample that will be test for during actual use
of the analyser. For each training sample, output from both sample
and reference channels is received at the processor, step 90. If
dark current is being used, the output from each detector for the
dark reading is subtracted from the output of the actual reading.
The output 14c received at the processor 18 from the sample
detector 17 indicates the intensity of the affected electromagnetic
radiation 14b for each emitted electromagnetic radiation beam at
the sample 16. It may, for example, comprise data which directly or
indirectly indicates photocurrent of the detector and/or intensity
of the detected electromagnetic radiation. Likewise, the output 15c
received at the processor 18 from the reference detector 20
indicates the intensity of the affected electromagnetic radiation
15b for each emitted electromagnetic radiation beam at the
reference sample. Preferably, the apparatus carries out multiple
measurements for each wavelength. For example, at each wavelength,
the apparatus detects affected electromagnetic radiation affected
by the sample at 15 different times and passes this output to the
processor, step 94. Similarly, at each wavelength, the apparatus
detects affected electromagnetic radiation affected by the
reference at 15 different times and passes this output to the
processor, step 94.
[0481] Next, for each wavelength, the processor 18 generates from
the output of the reference and sample detectors a range of sample
data points for the sample that correlate an intensity of affected
electromagnetic radiation 14b affected by the sample at a
particular selected wavelength, step 91. These data points 100
could be plotted, as shown for example in FIG. 10--although it will
be appreciated that the processor does not necessarily actually
plot the data. The x axis shows intensity indicative values
corresponding to detector output for the sample detector 17, and
the y axis shows intensity indicative values correlating to
detector output for the reference detector 20. The values indicate
directly or indirectly the intensity of detected affected
electromagnetic radiation. Where a reference channel is used,
output on the reference detector is paired with output from the
sample detector taken at the same time. Each sample/reference
channel detector output value pair is plotted on the graph. Such
measurements can be taken for several times for each wavelength.
Therefore, the plot in FIG. 10 shows the values indicative of
intensity 103 measured at several times (e.g. 15) for a particular
selected wavelength (e.g. nominally 1350 nm) of electromagnetic
radiation incident 14a on the training sa 16 and on the reference
19.
[0482] For each training sample, the process is then repeated to
get similar data points for a second (comparison) sample 101 and a
control (e.g. saline) 102. The sample/reference channel detector
output value pairs for the second (comparison) 101 sample and
control sample 102 could also plotted on the graph, as shown in
FIG. 9, step 91.
[0483] A best fit straight line can then be calculated using a
suitable statistical technique, step 92, and the intercept value of
the x axis is found, step 92, for each of the: [0484] training
sample set, 103 [0485] second (comparison) sample 101, and the
[0486] control sample 102 set of data points for the particular
wavelength (1350 nm), as shown in FIG. 10.
[0487] From this a normalised pre-processed value is found. For
example, the x-axis intercept values (e.g. 842500 and 850500) for
the training sample 103 and control 102 respectively can be found,
and then can be subtracted from each other to obtain normalised
pre-processed values (e.g. 8000), step 93. Similarly, the x-axis
intercept values (e.g. 86000 and 850500) for the second
(comparison) sample 101 and control 102 respectively can be found
also, and then subtracted from each other to obtain normalised
pre-processed values (e.g. 95000), step 93. This process can be
carried out for each of the other selected wavelengths (e.g. five
others in this case), step 94 and steps 90-93, resulting in a set
of six normalised pre-processed values (--one for each wavelength)
for the training sample. The process can also be carried out for
each of the other selected wavelengths for the second (comparison)
sample, resulting in a set of six normalised pre-processed values
for the second (comparison) drug for each wavelength. These sets of
normalised pre-processed values for the training sample and second
(comparison) for each wavelength sample can be correlated/plotted
in a multidimensional space, each axis corresponding to a
wavelength and the pre-processed value for that wavelength being
plotted relative to that axis.
[0488] In practice, this process, steps 90-94, can then be carried
out numerous times for each wavelength, so that for each training
sample and second (comparison) sample, there are a plurality of
sets of six normalised pre-processed values. Each set can be
plotted/correlated as one point in a multidimensional (six
dimensions in this case) space. An example of such a plot is shown
in FIG. 11. Here, for simplicity, only a two dimensional space is
shown, each axis relating to the results from two wavelengths--in
reality it would need to be a six-dimensional graph to cover all
six wavelengths. For each set for each of the training sample and
second (comparison) sample, a pair of two normalised pre-processed
value (i.e. one value for each wavelength) is plotted as a single
point on the two dimensional graph, e.g. 110, resulting in a
normalised pre-processed value data set for the training sample 111
and the second (comparison) sample 112.
[0489] The pre-processing stage described above reduces the
detrimental effects of systematic errors in the system and drift in
the measured data. Note, the reference channel/value is optional.
In an alternative, x-axis intercept values are found for the sample
data only.
[0490] In an alternative embodiment, the pre-processing steps
previously described can be omitted on the grounds that system
drift and systematic errors can be virtually eliminated with the
use of highly stable laser diode sources and a reference signal
derived from the laser's own monitor diode output. This facilitates
the use of a single channel with a single photo-detector
eliminating the need for separate optical reference channel and/or
control sample to be used. To this end, the data base of measured
transmission spectra for a range of intravenous drugs can be built
up in a more straightforward manner by sequentially measuring
samples of each drug in a single channel using multiple test
tubes.
[0491] After the data has been pre-processed for the training
sample and second (comparison) sample and correlated as shown in
FIG. 11, a representative value can be obtained for the training
sample. If no pre-processing is carried out, the process proceeds
to finding the representative value on non-pre-processed (raw)
data. First a line 113 that separates the training sample data set
111 from the second (comparison) sample data set 112 is determined,
step 95. Then the normal direction of the line is used as a
weighting in a score to separate the training sample from the
comparison sample. Also, a threshold is determined below which the
training sample falls, step 96. The threshold and weighting score
provide a representative value for comparison data to assist in
verification/identification for that training sample. The
representative value is stored as comparison data in a database 23
for the training sample, step 98.
[0492] The entire process is the repeated (step 99, and steps
90-98) for the same training sample against a third (comparison)
sample to get a second representative value for storing as
comparison data in the database 23 for the training sample. Then
the process is repeated again (step 99, and steps 90-98) against a
fourth and subsequent comparison samples to generated a third and
subsequent representative values for storing as comparison data for
the training sample. Together these form the representative values
in the comparison database to identify/verify the training
sample.
[0493] The entire process (step 100, step 90-99) is the repeated
for each other training sample (in the set of n drugs) against
multiple comparison samples, in order to obtain representative
values for each additional training sample also.
[0494] It will be appreciated that in describing the training
process steps 90-100, there has been reference to graphs and
techniques. These are described for illustrative purposes. Any
processor carrying out the training process to determine
representative values might not actually produce such graphs or
utilise such techniques to obtain the end result, but rather use
other processing techniques that achieve the same result.
[0495] The above training process will generate comparison data for
each training sample (in the set of n drugs) that can stored in the
database 23 and can be used to identify or verify actual samples
from the set under test. The comparison database 23 can be
generated well in advance of actual sample testing, or can be
generated soon before or even on-the-fly. The comparison data can
be considered as a multidimensional verification/identification
matrix based on the acquired multidimensional spectral data from
the detectors. The comparison data can be used to verify or
identify any of the drugs from any of the other drugs in the set of
n drugs.
[0496] Referring back to FIG. 8, once a comparison database is
produced and stored in the database 23, verification/identification
of actual samples occurs as follows. Output from both sample and
reference channels is received at the processor, step 80. If dark
current is being used, the output from each detector for the dark
reading is subtracted from the output of the actual reading. The
output 14c received at the processor 18 from the sample detector 17
indicates the intensity of the affected electromagnetic radiation
14b for each emitted electromagnetic radiation beam at the sample
16. It may, for example, comprise data which directly or indirectly
indicates photocurrent of the detector and/or intensity of the
detected electromagnetic radiation. Likewise, the output 15c
received at the processor 18 from the reference detector 20
indicates the intensity of the affected electromagnetic radiation
15b for each emitted electromagnetic radiation beam at the
reference sample. Preferably, the apparatus carries out multiple
measurements for each wavelength. For example, at each wavelength,
the apparatus detects affected electromagnetic radiation affected
by the sample at 15 different times and passes this output to the
processor, step 80. Similarly, at each wavelength, the apparatus
detects affected electromagnetic radiation affected by the
reference at 15 different times and passes this output to the
processor, step 80.
[0497] This output is then preferably pre-processed, steps 81-84,
in the same manner as described above for the training process and
with reference to FIGS. 9 to 11. That description need not be
repeated here, but in summary, data points are generated, step 81,
best fit lines found, step 82, and x-axis values are obtained which
provide normalised pre-processed values, step 83. This is done for
all wavelengths, step 84. Pre-processing is not essential, but can
improve performance.
[0498] After this pre-processing is carried out for the affected
radiation of each wavelength, steps 81-84, the
identification/verification algorithm can then be invoked, step 85.
Verification involves confirming that a sample drug is the drug
that is expected. For example, a clinician can specify what they
think the drug is (e.g. from the set of n drugs) through the user
interface 24, e.g. step 80, then use the apparatus to confirm
whether the drug in the retainer is actually that drug which is
specified by the clinician. Identification involves determining
what a drug actually is, without any suggestion from the clinician
as to what the drug is. For verification/identification, the
spectral data (that is, the pre-processed values) are compared
against the comparison data in the database 23, step 85, to
identify the drug, or verify whether it is the anticipated drug as
specified by the clinician. Output is then provided to the user
interface, step 86.
[0499] In one possible identification/verification algorithm, once
the sample data is obtained and pre-processed, representative
values are found for the sample, in the same manner that they were
found during the training process as explained with reference to
FIGS. 9 to 11. The representative values are found for the sample
at each selected wavelength and with respect to each other
comparison sample. The representative values are compared to the
representative values in the comparison data. If there is
sufficient similarity between the representative values found for
the sample and the representative values in the comparison data
corresponding to the same sample, then verification or
identification is made. Sufficient similarity can be determined
using any suitable statistical or other technique. For example,
sufficient similarity might occur when some or all of the
representative values match those in the verification matrix. In
another example, this might occur when the sample falls below the
threshold for each comparison sample. An alarm or output might be
made via a user interface to advise the user of the result of the
verification/identification.
[0500] FIG. 15 shows test data for a set of 30 drugs verified using
the analyser. In the test, each drug was inserted in the analyser,
and then systematically the analyser was configured to check if it
was one of the 30 drugs. If an alarm was raised, this indicated the
drug was not the one that was anticipated, and the alarm noted.
Each drug was tested 15 times, in relation to each of the other
drugs. So, for example, Metaraminol was put into the analyser and
then the analyser was configured to check for Metaraminol. After 15
tests, the analyser did not once raise an alarm, indicating that
the analyser did not detect Metaraminol as another drug. Keeping
Metaraminol in the sample retainer, the analyser was then
configured to check for Heparin. For each of 15 independent tests,
the analyser raised an alarm, indicating it detected each time that
the drug in the analyser (Metaraminol) was not the drug it was
expecting (Heparin). The analyser was then reconfigured for each of
the other drugs, and the test done 15 times for each, while
Metaraminol was in the sample retainer. The same process was then
repeated for every other drug being used as a sample, with the
analyser systematically being re-configured to check for every
other drug. Each time an alarm was raised (indicating the analyser
did not consider the drug in the retainer was that being checked
form), the alarm was noted. The table in FIG. 15 reflects the
number of times an alarm was raised of each drug detection
combination. The error rates are shown. The low error rates
demonstrate a significant improvement in verification accuracy.
Third Embodiment
[0501] FIG. 12 shows an alternative embodiment of the apparatus 10.
In this embodiment rather than using a carousel 50, the six lasers
51a-51f forming the source 11 are arranged to emit their
electromagnetic radiation beam 22 towards a diffraction grating 120
of the reflection type. Each laser 51a-51f is operable to emit a
tuned or tuneable wavelength of a collimated electromagnetic beam
22 towards the diffraction grating. The angle of incidence X on the
grating surface for each laser 51a-51f is chosen that their first
order diffracted beam emerges at the same angle Y thereby producing
a common optical path 14a for each laser. The controller 12
activates each laser 51a-51f sequentially to emit a beam of a
single wavelength towards the sample. Alternatively, multiple
lasers 51a-51f could be operated at once such that an
electromagnetic beam 22 comprising multiple wavelength components
could be emitted towards the sample 16. A separate grating or beam
splitter 21 could be used for example as shown in FIG. 1 to direct
the beam towards a reference channel sample 19, if there is one.
All other aspects of the embodiment can be as shown and described
in FIGS. 1, 2, 16 and/or 18.
Fourth Embodiment
[0502] FIG. 13 shows another alternative embodiment of the
apparatus 10. In this embodiment rather than using a carousel 50,
the six lasers 51a-51f forming the source 11 are arranged to emit
their electromagnetic radiation beam 14a towards respective beam
splitters 130a-130f that redirect the emitted electromagnetic
radiation beam 22 along the sample path 14a. The controller 12 can
control each electromagnetic radiation source 11 in turn to emit a
tune or tuneable wavelength of electromagnetic radiation towards
the sample via the respective beam splitter 130a-130f.
Alternatively, two or more of the lasers 51a-51f could be activated
at once to provide an electromagnetic beam 22 with multiple
wavelength components towards 14a the sample 16. An absorber 135 is
provided behind the beam splitter array to mop up transmitted
energy from the beam splitters. A separate grating or beam splitter
21 could be used for example as shown in FIG. 1 to direct the beam
towards a reference channel sample 19, if there is one. All other
aspects of the embodiment can be as shown and described in FIGS. 1,
2, 16 and/or 18.
Fifth Embodiment
[0503] FIG. 14 shows an alternative embodiment of the apparatus 10.
In this embodiment rather than using a carousel 50, the six lasers
51a-51f forming the source 11 are arranged to emit their
electromagnetic radiation beam 22 towards a prism 140. Each laser
51a-51f is operable to emit a tuned or tuneable wavelength of a
collimated electromagnetic beam 14a towards the prism. The angle of
incidence X on the grating surface for each laser 51a-51f is chosen
that their first order refracted beam 22 emerges 14a at the same
angle Y thereby producing a common optical path 14a for each laser
51a-51f. The controller 12 activates each laser 51a-51f
sequentially to emit a beam of a single wavelength towards the
sample. Alternatively, multiple lasers 51a-51f could be operated at
once such that an electromagnetic beam 22 comprising multiple
wavelength components could be emitted towards 14a the sample 16. A
separate grating or beam splitter 21 could be used for example as
shown in FIG. 1 to direct the beam towards a reference channel
sample 19, if there is one. All other aspects of the embodiment can
be as shown and described in FIGS. 1, 2, 16 and/or 18.
Sixth Embodiment
[0504] FIG. 20 shows an alternative embodiment of the apparatus 10.
In this embodiment rather than using a carousel 50, the six lasers
51a-51f forming the source 11 are arranged to emit their
electromagnetic radiation beam 22 through separate fibre optic
cables 201a-201f towards a planar lightwave circuit (PLC) (fibre
optic combiner) 200. Each laser 51a-51f is operable to emit a tuned
or tuneable wavelength of a collimated electromagnetic beam 14a
towards the PLC 200 via the fibre optic cables 201a-201f. The
controller 12 activates each laser 51a-51f sequentially to emit a
beam of a single wavelength towards the sample. Alternatively,
multiple lasers 51a-51f could be operated at once such that an
electromagnetic beam 22 comprising multiple wavelength components
could be emitted towards 14a the sample 16. A separate grating or
beam splitter 21 could be used for example as shown in FIG. 1 to
direct the beam towards a reference channel sample 19, if there is
one. All other aspects of the embodiment can be as shown and
described in FIGS. 1, 2, 16 and/or 18.
Seventh Embodiment
[0505] FIG. 21 shows an alternative embodiment of the apparatus 10.
In this embodiment rather than using a carousel 50, a single
package 211 comprising 6 lasers forming the source 11 are arranged
to emit their electromagnetic radiation beam 201a-201f towards an
integrated collimating lens 210. The laser is operable to emit a
tuned or tuneable wavelength at each of 6 wavelengths towards the
lens 210. The controller 12 activates the laser to sequentially to
emit a beam 212a-212f of a single wavelength towards the sample.
Alternatively, multiple beams 51a-51f could be operated at once
such that an electromagnetic beam 22 comprising multiple wavelength
components could be emitted towards 14a the sample 16 via the lens
210. A separate grating or beam splitter 21 could be used for
example as shown in FIG. 1 to direct the beam towards a reference
channel sample 19, if there is one. All other aspects of the
embodiment can be as shown and described in FIGS. 1, 2, 16 and/or
18.
ALTERNATIVE EMBODIMENTS
[0506] The nominal analysis range of 1300-2000 nm for selected
wavelengths is chosen as it provides advantages for improved drug
verification or identification. However, it will be appreciated
that the reference to 1300-2000 nm should not be considered
limiting, and wavelengths could be chosen that relate spectral
characteristics in slightly different ranges or other ranges
entirely. The selected wavelengths (and therefore the spectral
characteristics) fall within any analysis range provide for
improved identification/verification for drugs in the liquid
carrier. For example, the analysis range could be a subset of 1300
nm-2000 nm, such as 1300 nm-1900 nm; 1350 nm-1950 nm; 1400 nm-1900
nm; 1500 nm-1800 nm or some other subset. The range could also be
larger, such as 1250-2050 nm; 1200 nm-2100 nm; or 1150 nm-2150 nm
or the like. The analysis range might even be offset from the
nominal range, such as 1200 nm-1900 nm, or 1300 nm-1900 nm. These
are non-limiting examples. In general, the analysis range could
start, for example, anywhere from 1100 nm-1500 nm and end anywhere
from 1800 nm-2150 nm. Even that is non-limiting and the range could
be something different entirely that provides for improved
verification/identification. Further, wavelengths falling outside
these analysis ranges and corresponding to spectral features lying
outside these analysis ranges above could also be used in
combination with wavelengths falling in the analysis ranges
mentioned. Using a plurality of wavelengths corresponding to
spectral characteristics falling within the analysis range provides
improved performance. Preferably any and all wavelengths are
selected within the analysis range, but that does not preclude
using wavelengths falling in other ranges also where that might be
useful.
[0507] The range could be at least partially influenced by
component selection. For example, silicon photodiodes have a
response down to at least 1100 nm, so if used this wavelength might
be used as the bottom end of the range. Preferably, the invention
uses only one detector, so the range might be defined by what a
single detector can cover--for example 1300 nm-2000 nm in the case
of an InGaAs detector.
[0508] Other liquids to water might have other analysis ranges that
provide improved identification/verification.
[0509] Other methods for extracting the information could be known
and used by the skilled in the art.
[0510] In an alternative analysis process, a reference channel is
not used. Rather, the detector output 14c from affected
electromagnetic radiation (from the sample) acquired at an anchor
wavelength is used, rather than the detector output 15c from
affected electromagnetic radiation from the reference in the
reference channel. All other detector output 14c from affected
electromagnetic radiation received relating to other wavelengths is
normalised/corrected using the detector output of affected
electromagnetic radiation at the anchor wavelength. The anchor
wavelength can be one of the wavelengths already selected, although
preferably will be selected to be in the vicinity or within a
region spanning a suitable spectral feature/point in the base
liquid spectrum. For example, the anchor wavelength could be in the
vicinity of or fall within a region spanning a stable region of the
base liquid spectrum. Elimination of the reference channel/detector
output removes variation between the sample and reference channels
that can mask sample differences, thus removal creates a more
sensitive and stable apparatus. The output at the anchor wavelength
can be used to normalise, calibrate or otherwise adjust the output
for the other wavelengths. The output from the anchor wavelength
could be processed in the same manner as the output from the
reference channel as describe previously in order to verify/analyse
the sample. That is, the anchor output can become the reference
information.
[0511] In one possibility, where water is the base liquid, 1450
nanometres is chosen as the anchor point as there is particular
stability in the spectrum of water around this wavelength. This
wavelength corresponds to the maximum optical absorption aqueous
solutions due to the presence of OH bonds. It is a common
transmission medium for sample drugs tested. Data acquired at this
wavelength shows minimum thermal sensitivity and is therefore
provides a highly stable and predictable reference. This is just
one example for water based drug, and is indicative only and should
not be considered limiting as to the wavelengths and anchor points
that might be chosen based on other considerations.
[0512] Each of the previous embodiments describe the optional use
of a reference channel to obtain reference measurements for use in
processing data. In an alternative, the reference channel is not
used. Rather, a photodiode 4 (see FIG. 20) in the laser diode 11
(which is used for power monitoring and control of the laser diode)
can be utilised to obtain reference information. Laser diodes are
often fitted with built-in photo-detector diodes 4 that are used to
monitor the output power of the laser. This is done to stabilise
the laser by allowing the laser driver current to be controlled via
a feedback circuit incorporating the integrated photo-diode
signal.
[0513] This alternative for obtaining reference information can be
substituted in place of the reference channel for any of the
embodiments described. The reference measurements obtained using
the alternative can be utilised in the same manner as described any
previous embodiment.
[0514] The output of the laser diode photodetector 4 which detects
the output power of the source electromagnetic radiation is passed
to the processor 18 and used instead of reference readings obtained
by the reference detector 20 to normalise and/or correct the output
from the detector 17 in the sample channel. This output signal from
the photodetector 4 performs the same function as a reference
channel that would otherwise have been produced more conventionally
by using a beam splitter arrangement involving two separate
measurement channels. Using the photo-diode output from the laser
as a reference signal thereby eliminates the need for
beam-splitting optics and an additional reference sample and
detector.
[0515] In an alternative embodiment, the electromagnetic source 11
is a broadband source with multiple filters 13 at different
wavelengths that can be arranged in between the broadband source
and the sample. The output from each filter provides an
electromagnetic beam 22 with one of the selected wavelengths. The
broadband source could be, for example, a broadband filament
blackbody source and filters. The source 11 could alternatively
take the form of one or more LEDs with or without filters. Any of
the alternative sources could be mounted on a carousel 50 and
operated as described for the first embodiment, or operated in
conjunction with an optical device such as described in embodiments
two to four.
[0516] Any of the sources could be temperature stabilised with a
feedback system, for example by using
thermistors and peltier cooling devices as previously
described.
[0517] The detectors could be in the form of one or more InGaAs
photodiodes or other light sensors.
[0518] A separate photodiode or similar or other detector could be
used for each of the reference and sample channels. Alternatively,
a single photodiode or similar or other detector could be used for
both the sample and reference channels, utilising optical devices
to merge the affected radiation beams of both channels, or
otherwise direct them to the detector. Random errors in
measurements can be reduced by averaging detector readings over
many measurements (e.g. 500). Dark measurements (source off) can be
used to correct measured data.
[0519] For dark current readings, a chopper wheel can optionally be
used that blacks out/blocks the electromagnetic radiation 22
incident on the sample 16 and the reference 20. The chopper could
form part of the optical device 13. For each electromagnetic
reading, the detector 17/20 also takes a "dark" reading when the
chopper blocks the electromagnetic radiation 22. Having a chopper
wheel and dark reading is not essential for the invention and is
described here as one possible option.
[0520] Over the band 1300 nm to 2000 nm, it is also possible to use
a single type of photo-diode detector based on indium gallium
arsenide (InGaAs) technology which further simplifies the detector
system.
[0521] The present invention preferably uses wavelengths in the
analysis region of 1300 nm to 2000 nm or variations thereof. This
region has previously been ignored for drug analysis due to the
perceived disadvantage of broad spectral peaks and troughs that
appear in the absorbance spectrum. Infra-red (IR) spectroscopy
previously has exploited the numerous narrow-band spectral
absorption characteristics that exist for wavelengths longer than
2000 nm. This so-called `finger-print` region exhibits spectral
lines that are characteristic of certain chemical bonds present in
the material under test and offers a highly sensitive technique to
identifying the material. The present inventors have determined
that the 1300 nm-2000 nm analysis range (or portions thereof)
provides an advantage for drug verification or identification or
other analysis. Further, the inventors have established that the
spectral location of salient spectral features in this analysis
region is less affected by temperature variations. The numerous
narrow spectral bands that appear in the region above 2000 nm
exhibit large temperature sensitivity. If this region above 2000 nm
is used for verification or identification, the analysis apparatus
requires very precise wavelength resolution. This resolution can
only be achieved using high-cost sophisticated spectrometers
[0522] More particularly, this type of IR spectroscopic measurement
(above 2000 nm) requires very fine wavelength resolution (typically
a few nanometres) maintained over a wide spectral band in order to
resolve the numerous individual spectral features. The fine
wavelength resolution is especially required to account for any
shift in the narrow spectral lines with respect to temperature
variations.
[0523] The measurement of such highly resolved spectral lines
requires the use of a spectrometer fitted with a sophisticated
monochromator based either on a mechanically rotated diffraction
grating and single detector, or a fixed grating with a linear array
of detector elements. Both options are found in existing
spectrometers and both are expensive to implement.
[0524] As a cost-effective alternative, aimed for example at
water-based intravenous drug verification/identification or other
analysis, it has been determined by the present inventors that it
is advantageous to make measurements within the shorter wavelength
region between 1300 nm and 2000 nm. Whilst the spectral
characteristics/features in this wavelength region are much fewer
in number and much broader spectrally (differing little from those
of water), the inventors have found that there remain sufficient
spectral differences between drugs (or other liquid based samples)
to facilitate verification/identification. The have also found,
that, in the 1300 nm to 2000 nm region, the wavelengths at which
the peaks and troughs (and other spectral characteristics) of each
drug's IR transmission spectrum occur remain highly stable with
respect to temperature for all water-based drugs (or other
samples).
[0525] Importantly, due to the absence of temperature-sensitive
narrow spectral absorption features, they have established there is
no requirement for highly resolved spectral lines to be measured
thereby eliminating the need for an expensive monochromator. A
small number of measurements (5 or 6 typically) made at discrete
wavelengths over the range 1300 nm to 2000 nm is sufficient to
characterise each drug (or other sample). Typically, each
measurement is made over a bandwidth of 12 nm (as determined by a
band-pass filter, illuminated by a broad-band source, for example)
or over a few nanometres for laser-based illumination.
[0526] In general terms, a number of embodiments and variations are
described above. It will be appreciated by those skilled in the
art, combinations of the features of the various embodiments could
be envisaged and the embodiments described should not be considered
limiting
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