Title of Invention

A SYSTEM FOR ANALYSIS OF PHARMACEUTICAL SAMPLES

Abstract A system for analysis of pharmaceutical samples, said system comprising: means for holding a plurality of said samples, wherein said samples are present in the form of a Metered Dry Powder Inhaler formulation; means for moving said plurality of samples along a sample path; means for generating a plurality of incident radiation pulses of different wavelength; means for illuminating at least a respective one of said samples with at least a respective one of said radiation pulses during said movement of said samples, said radiation pulse having a suitable range of radiation wavelengths capable of inducing a fluorescent response; means for detecting a first resultant fluorescence emitted from each of said samples; first control means in communication with said moving means and said incident radiation generating means for synchronizing said means for illuminating each of said samples with said moving means.
Full Text FIELD OF THE PRESENT INVENTION
The present invention relates generally to spectroscopy systems. More particularly, the
invention relates to a method and system for real-time fluorescent determination of trace
elements.
BACKGROUND OF THE INVENTION
Beginning in the early 1970's, it was found that certain medicines could be administered
in dry-powder form directly to the lungs by inhalation through the mouth or inspiration through
the nose. This process allows the medicine to bypass the digestive system, and in some
instances, allows smaller doses to be used to achieve the same desired results as orally ingested
medicines.
Various metered dose powdered inhalers ("MDPI") or nebulizers that provide inhalable
mists of medicines are known in the art. Illustrative is the devices disclosed in U.S. Pat. Nos.
3,507,277; 4,147,166 and 5,577,497.
Most of the prior art MDPI devices employ powdered medicine contained in a gelatin
capsule. The capsules are typically pierced and a metered dose of the powdered medicine is
slowing withdrawn by partial vacuum, forced inspiration of the user or by centrifugal force.
Several MDPI devices, such as that disclosed in U.S. Pat. No. 5,873,360 employs a foil
blister strip. Referring to Fig.l, the foil blister strip 10 includes a plurality of individual, sealed
blisters (or pockets) 12 that encase the powdered medicine. The blisters 12 are similarly
pierced during operation to release the metered dose of powdered medicine.
As will be appreciated by one having ordinary skill in the art, the provision of an
accurate dosage of medicine in each capsule or blister is imperative. Indeed, the U.S..

Government mandates 100% inspection of MDPI formulations to ensure that the formulations
contain the proper amount of prescribed medicine or drug(s).
Various technologies have been employed to analyze MDPI formulations (i.e.,
pharmaceutical compositions), such as X-ray diffraction, high-pressure liquid chromatography
(HPLC) and UV/visible analysis. There are, however, numerous drawbacks associated with the
conventional technologies.
A major drawback of the noted technologies is that most require samples to be collected
from remote, inaccessible, or hazardous environments, and/or require extensive sampling that is
time consuming and prohibitively costly. A further drawback is that detection of minute
amounts of trace elements, including the active ingredient or drug(s), is often difficult or not
possible.
It is therefore an object of the present invention to provide a method and system for
high-speed, real-time, on-line fluorescent assessment of active ingredients and trace elements.
It is another object of the present invention to provide a method and system for high-
speed, real-time, on-line fluorescent detection of minute amounts of active ingredients and trace
elements.
It is yet another object of the present invention to provide a method and system for high-
speed, real-time, on-line fluorescent determination of the identity and concentration of active
ingredients and trace elements.
SUMMARY OF THE INVENTION
In accordance with the above objects and those that will be mentioned and will become
apparent below, the system for real-time fluorescent determination in accordance with this
invention comprises means for moving a plurality of samples along a sample path; means for
generating a plurality of incident radiation pulses of different wavelength; means for
illuminating at least a respective one of the samples with at least a respective one of the
radiation pulses during the movement of the samples, the radiation pulse having a suitable

range of fluorescence radiation wavelengths; means for detecting the resultant fluorescence
emitted from each of the samples; and first control means in communication with the moving
means and the incident radiation generating means for synchronizing the means for illuminating
each of the samples with the moving means.
The method for real-time fluorescent determination in accordance with this invention
generally comprises moving a plurality of said samples having at least one element along a
sample path; generating a plurality of incident radiation pulses of different wavelength;
illuminating at least a respective one of the samples with at least a respective one of the
radiation pulses during movement of the samples, the radiation pulse having a suitable range of
fluorescence radiation wavelengths; detecting the resultant fluorescence emitted from each of
said samples; and comparing the detected resultant fluorescence characteristics,with stored
fluorescence characteristics of pre-determined elements and/or. active ingredients to identify the
element or elements in the samples.
BRIEF DESCRIPTION OF THE DRAWINGS
Further features and advantages will become apparent from the following and more
particular description of the preferred embodiments of the invention, as illustrated in the
accompanying drawings, and in which like referenced characters generally refer to the same
parts or elements throughout the views, and in which:
FIGURE 1 is a perspective view of a prior art foil blister strip;
FIGURE 2 is a side plan view of the foil blister strip shown in FIGURE 1;
FIGURE 3 is a flow chart of a conventional blister strip manufacturing process;
FIGURE 4 is a schematic illustration of the fluorescence detection means according to
the invention;
FIGURE 5 is a partial plan view of the radiation transmission means, illustrating the
travel of the incident and emitted radiation according to the invention;

FIGURE 6 is a further flow chart of a conventional foil blister strip manufacturing
process, illustrating the incorporation of the fluorescence detection means according to the
invention;
FIGURE 7 is a perspective view of a conventional conveyor and the fluorescence
detection means according to the invention;
FIGURE 8 is a partial section, front plan view of the conveyor and fluorescence
detection means shown in FIGURE 7; and
FIGURES 9 and 10 are graphs of incident radiation versus emission radiation for
prepared compounds, illustrating the detection of low concentration active trace elements
according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The method and system of the present invention substantially reduces or eliminates the
drawbacks and shortcomings associated with prior art methods and systems for in-situ detection
and analysis of trace elements. As discussed in detail below, the system generally includes
fluorescence detection means adapted to provide high-speed, accurate, in-situ determination of
the presence, identity and concentration of trace elements and, in particular, active ingredients
in pharmaceutical compositions. By the term "trace element", it is meant to mean and include
an ingredient, component or element of a pharmaceutical composition or MDPI formulation
having a relative concentration (i.e., % of total) of less than 0.5%, including, but not limited to,
an active ingredient or element and medicament.
Referring first to Fig. 4, there is shown a schematic illustration of the fluorescence
detection means (designated generally 20) of the invention. The fluorescence detection means
20 generally comprises at least one radiation transmission means 22 adapted to provide incident
radiation to the sample 14 and detect the fluorescence (emission) radiation from the sample 14,
and first control means 24. As illustrated in Fig. 3, the first control means 24 preferably

includes a light source 26 for providing the desired wavelength of light or radiation to the
radiation transmission means 22 via line 23a, an analyzer 28 for analyzing the emission
radiation detected by the radiation transmission means 22, which is communicated to the
analyzer 28 via line 23b, and storage means for storing fluorescence characteristics of known
elements (or ingredients) for subsequent comparison with detected emission (fluorescence)
radiation from the sample(s) 14.
As discussed in detail below, the fluorescence detection means 20 further includes
second control means 29 preferably in communication with the light source 26, analyzer 28 and
conveyor system 50 for synchronizing the movement of the samples 14 on the conveyor system
50 with the incident radiation transmission and detection of the resultant emission radiation
(See Fig. 7).
As is well known in the art, for fluorescence measurements, it is necessary to separate
the emission (or emitted) radiation from the incident radiation. This is typically achieved by
measuring the emission radiation at right angles to the incident radiation.
However, as illustrated in Fig. 5, in a preferred embodiment of the present invention, the
emission radiation, I0, is measured (or detected) along a line I" that is substantially coincident
to the line I' defined by the travel of the incident radiation I. According to the invention, the
wavelength of the emission radiation I0 is "red shifted" to an upper frequency.
It is further well established that the relationship between the trace element
concentration and the fluorescence intensity (i.e., emission radiation) can be derived from
Beer's Law, i.e.,



It is thus evident that the quantum yield, Φ, is generally less than or equal to unity. It is
further evident from Eq.l that if the product ocbc is large, the term becomes negligible
compared to 1, and F becomes constant:

Conversely, if the product ocbc is small ( ≤0.01), it can be shown (i.e., Taylor expansion
series) that the following provides a good approximation of the fluorescence intensity:

Accordingly, for low concentrations of trace elements, the fluorescence intensity is
directly proportional to the concentration. The fluorescence intensity is also directly
proportional to the incident radiation.
Since the noted relationships hold for concentrations up to a few parts for million, Eq.3
is preferably employed in the method of the invention to determine the concentration of the
trace element(s) detected by the fluorescence detection means 22.
Referring now to Fig. 3, there is shown a flow chart of a conventional blister strip
process, illustrating the primary steps involved in the manufacture of a foil blister strip.
According to the process, the base foil is fed from a coil 30 to the forming operation 32.

After the blisters 12 are formed on the strip 10 (see Figs. 1 and 2), the strip 10 is
inspected for defects 34 and, in particular, pin holes. Each blister 12 on the strip 10 is then
filled 38 with a desired MDPI formulation or pharmaceutical composition.
After filling, the strip 10 is subjected to a second inspection 40. The second inspection
typically comprises a complete chemical analysis of the pharmaceutical composition to
determine the presence of all ingredients or elements and the respective concentrations thereof.
As discussed above, the noted inspection 40 typically involves the removal of a sample,
transfer of the sample to an off-line location or facility, and HPLC or UV/vis analysis. The
operation is thus time consuming and expensive.
After the inspection 40, the appropriate code is applied 42 to the strip 12. The strip is
then transferred to a storage roll.
Referring now to Fig. 6, there is shown a further flow chart of the above discussed
blister strip process, illustrating the incorporation of the fluorescence detection means 20 of the
invention. As illustrated in Fig. 6, the fluorescence detection means 20 is preferably disposed
between the filling 38 and sealing 40 operations.
As will be appreciated by one having ordinary skill in the art, the fluorescence detection
means 20 of the invention is readily adaptable to most processes. Further, due to the inherent
accuracy and tight specifications (that are possible by virtue of the detection means 20), the
conventional inspection (i.e., analysis) operation/step 38 can be eliminated. However, as
illustrated in Fig. 6, the fluorescence detection means 20 can also be employed in conjunction
with the conventional inspection operation 38 (shown in phantom).
Referring to Figs. 7 and 8, the fluorescence detection means 20 of the invention will
now be described in detail. Referring first to Fig. 7, there is shown a conventional conveyor
system 50 adapted to facilitate the transfer of two blister strips 10a, 10b to the above noted
operations 30, 32, 36, 20, 40, 42. As illustrated in Fig. 7, the radiation transmission means 22

is disposed proximate the conveyor system 50 and, hence, blister strips 10a, 10b positioned
thereon.
In a preferred embodiment of the invention, the radiation transmission means 22
comprises a J.Y. Horiba fiuorometer that is adapted to provide two lines of incident radiation
(or incident radiation pulses) 25a, 25b. According to the invention, the first line of incident
radiation 25 a is directed toward and substantially perpendicular to the first blister strip 10a and,
hence, sample path (designated generally SP,) and the second line of incident radiation 25b is
directed toward and substantially perpendicular to the second sample path (designated generally
SP2). In additional envisioned embodiments of the invention, not shown, the radiation
transmission means 22 is adapted to provide one line of incident radiation (e.g., 25a) to
facilitate a single (rather than dual) blister strip process.
In a preferred embodiment of the invention, the first control means 24 generates and
provides a plurality of incident radiation pulses of different wavelengths, preferably in the
range of 200 to 800 nm. According to the invention, at least a respective one of the samples 14
is illuminated with at least a respective one of the incident radiation pulses as it traverses a
respective sample path SP1, SP2. In a preferred embodiment, each sample 14 passing under the
radiation transmission means 22 is illuminated with incident radiation over a pre-determined,
suitable range of wavelengths capable of inducing a fluorescence response in at least one target
element (or ingredient).
Applicants have found that the noted incident radiation wavelength range will induce a
definitive fluorescence response in trace elements and, in particular, active ingredients, having a
relative concentration in the range of 0.3 to 0.5%.
As discussed above, the emission (fluorescence) radiation is detected by the radiation
transmission means 22 and at least a first signal indicative of the sample fluorescence
characteristics is communicated to the analyzer 28. According to the invention, the emission
radiation is then compared to the stored fluorescence characteristics of known elements to

identify the element or elements (or trace element(s)) in the samples 14. The concentration of
the element(s) can also be determined through the formulations referenced above (e.g., Eq. 3).
As also indicated above, the fluorescence detection means 20 is further adapted to be in
synchrony with the conveyor system 50. In a preferred embodiment of the invention, the
fluorescence detection means 20 includes second control means 29 that is in communication
with the first control means 24 and conveyor system 50. The second control means 29 is
designed and adapted to synchronize the movement of the samples 14 on the conveyor system
50 with the illumination of each sample 14 as it traverses a respective sample path SP1, SP2.
Thus, 100% inspection of each sample 14 contained in the blisters 12 is ensured.
Further, the noted synchronized sample fluorescence detection and analysis is preferably
accomplished at a rate (or speed) of approximately 1 sample/sec. Thus, the method and system
of the invention provides high speed, accurate, on-line analysis of MDPT formulations and other
pharmaceutical compositions that is unparalleled in the art.
The present invention will now be illustrated with reference to the following examples.
The examples are provided for illustrative purposes only, and are not intended to limit the scope
of the invention.
EXAMPLE 1
A MDPI formulation comprising >99.5 % lactose and prepared. Referring to Fig. 9, the MDPI formulation and a reference lactose sample were then
subjected to a pre-determined, suitable range of incident radiation to induce a fluorescent
response. As will be appreciated by one having ordinary skill in the art,- the incident radiation
is determined by and, hence, dependent upon the target ingredient or element of the MDPI
formulation.
As illustrated in Fig. 9, a definitive fluorescent response, reflecting the detection of the
active ingredient was provided with an incident radiation level in the range of approx. 350 nm
to 500 nm. The noted fluorescence spectra further indicates that an active ingredient or trace

element having a relative concentration of less than 0.5% can readily be detected by virtue of
the fluorescence detection means of the invention.
As will be appreciated by one having ordinary skill in the art, the noted fluorescence
spectra can be compared to stored calibration (or reference) spectra by conventional means to
identify the detected active ingredient (or trace element). Further, as discussed above, the
concentration of the detected active ingredient can also be determined through known
formulations (See Eq. 3).
Applicants have further found that subjecting the MDPI formulation to subsequent
incident radiation in the same range provides little, if any, variation in detected emission
radiation. Indeed, the fluorescence spectra obtained were virtually identical.
Accordingly, by virtue of the fluorescence detection means of the invention, a tolerance
level of ± .5 nm (i.e., calibration emission radiation ± .5 nm) can be employed. As will be
appreciated by one having ordinary skill in the art, the noted tight "QC" specification is
unparalleled in the art.
EXAMPLE 2
Referring now to Fig. 10, there are shown the fluorescence spectra of similar MDPI
formulations having ~ 0.43% active ingredient (Curve A); ~ 0.42% active ingredient (Curv7e B);
~ 0.41% active ingredient (Curve C); ~ 0.39% active ingredient (Curve D); and ~ 0.37% active
ingredient (Curve E). The noted fluorescence spectra were similarly induced with an incident
radiation level in the range of approximately 350 to 500 nm.
The fluorescence spectra (i.e., Curves A-E) further demonstrate that a sharp, definitive
fluorescent response can be achieved in active ingredients having a relative concentration in the
range of approx. 0.37% to 0.43% by virtue of the fluorescence detection means of the
invention.
As will be appreciated by one having ordinary skill in the art, a narrower band or range
of incident radiation (e.g., 375-475 nm) could also be employed to identify and determine the
relative concentration of an active ingredient. Further, an even narrower range of incident

radiation wavelengths (e.g., 400-425 nm) or incident radiation with a single wavelength within
the noted range (e.g., 410 nm) could be employed to determine active ingredient "presence".
SUMMARY
From the foregoing description, one of ordinary skill in the art can easily ascertain that
the present invention provides a method and system for high speed, real-time, 100% fluorescent
inspection of MDPI formulations and other pharmaceutical compositions. The method and
system of the present invention further provides an accurate determination of (i) the presence
(i.e., qualitative assessment), and (ii) identity and concentration (i.e., quantitative assessment)
of active ingredients and/or other trace elements having a relative concentration in the range of
approximately 0.3 to 0.5%
Without departing from the spirit and scope of this invention, one of ordinary skill can
make various changes and modifications to the invention to adapt it to various usage and
conditions. As such, these changes and modifications are properly, equitably, and intended to
be, within the full range of equivalence of the following claims.

We claim:
1. A system for analysis of pharmaceutical samples, said system comprising: means for holding a
plurality of said samples, wherein said samples are present in the form of a Metered Dry Powder
Inhaler formulation; means for moving said plurality of samples along a sample path; means for
generating a plurality of incident radiation pulses of different wavelength; means for illuminating at
least a respective one of said samples with at least a respective one of said radiation pulses during said
movement of said samples, said radiation pulse having a suitable range of radiation wavelengths
capable of inducing a fluorescent response; means for detecting a first resultant fluorescence emitted
from each of said samples; first control means in communication with said moving means and said
incident radiation generating means for synchronizing said means for illuminating each of said samples
with said moving means.
2. The system as claimed in claim 1, having second control means for analyzing second resultant
fluorescence emitted from each of said samples.
3. The system as claimed in claim 1, wherein said plurality of incident radiation pulses of different
wavelengths is in the range of 200 to 800 nm.
4. A system for determining the presence and concentration of trace elements in a sample, said system
comprising: means for holding a plurality of said samples, wherein said samples are present in the form
of a Metered Dry Powder Inhaler formulation, each of said plurality of samples having at least one of
said trace elements; means for moving said plurality of samples along a sample path; means for
generating a plurality of incident radiation pulses of different wavelengths; means for illuminating at
least a respective one of said samples with at least a respective one of said radiation pulses during said
movement of said samples, said radiation pulse having a suitable range of fluorescence radiation
wavelengths capable of inducing a fluorescent response; means for detecting a resultant fluorescence
response emitted from said trace element; and first control means in communication with said moving
means and said incident radiation generating means for synchronizing said means for illuminating each
of said samples with said moving means.
5. The system as claimed in claim 4, having second control means for storing fluorescence
characteristics of pre-determined elements and means for comparing said detected resultant
fluorescence emitted from said trace element to identify said trace element in said plurality of samples,
said second control means having means for determining the relative concentration of said trace
element in each of said samples.
6. The system as claimed in claim 4, wherein said trace element has a relative concentration in the
range 0.3 to 0.5%.
7. The system as claimed in claim 4, wherein said plurality of incident radiation pulses of different
wavelength range from 200 to 800 nm.
8. A system for analysis of pharmaceutical composition samples, said system comprising: means for
holding a plurality of samples, wherein said samples are present in the form of a Metered Dry Powder
Inhaler formulation, said samples having at least one trace element; means for substantially
simultaneously moving said plurality of samples along a sample path, illuminating at least a respective

one of said samples with incident radiation having one or more suitable wavelengths during said
movement of said plurality of samples, and detecting a result in emission radiation from said samples;
and control means in communication with said illuminating and detecting means for providing a range
of radiation and analyzing said result in emission radiation and fluorescence emitted from said samples.
9. The system as claimed in claim 8, wherein said incident radiation is directed along a first radiation
path that intersects said sample path and is substantially perpendicular thereto.
10. The system as claimed in claim 9, wherein said emitted radiation is substantially detected along a
second radiation path, said second radiation path being substantially coincident with said first radiation
path.
11. The system as claimed in claim 8, wherein said samples are moved by said moving means at a
minimum rate of one sample per second.
12. The system as claimed in claim 8, wherein said incident radiation has a plurality of different
wavelengths in the range of 200 to 800 nm.
13. The system as claimed in claim 8, wherein said trace element has a relative concentration in the
range of 0.3 to 0.5%.

Documents:

220-kolnp-2003-abstract.pdf

220-kolnp-2003-claims.pdf

220-kolnp-2003-correspondence.pdf

220-kolnp-2003-correspondence1.1.pdf

220-kolnp-2003-description (complete).pdf

220-kolnp-2003-drawings.pdf

220-kolnp-2003-examination report.pdf

220-kolnp-2003-examination report1.1.pdf

220-kolnp-2003-form 1.pdf

220-kolnp-2003-form 18.pdf

220-kolnp-2003-form 3.1.pdf

220-kolnp-2003-form 3.pdf

220-kolnp-2003-form 5.1.pdf

220-kolnp-2003-form 5.pdf

220-KOLNP-2003-FORM-27.pdf

220-kolnp-2003-gpa.pdf

220-kolnp-2003-gpa1.1.pdf

220-kolnp-2003-granted-abstract.pdf

220-kolnp-2003-granted-claims.pdf

220-kolnp-2003-granted-description (complete).pdf

220-kolnp-2003-granted-drawings.pdf

220-kolnp-2003-granted-form 1.pdf

220-kolnp-2003-granted-form 2.pdf

220-kolnp-2003-granted-specification.pdf

220-kolnp-2003-others.pdf

220-kolnp-2003-reply to examination report.pdf

220-kolnp-2003-reply to examination report1.1.pdf

220-kolnp-2003-specification.pdf

220-kolnp-2003-translated copy of priority document.pdf

220-kolnp-2003-translated copy of priority document1.1.pdf


Patent Number 248423
Indian Patent Application Number 220/KOLNP/2003
PG Journal Number 28/2011
Publication Date 15-Jul-2011
Grant Date 13-Jul-2011
Date of Filing 21-Feb-2003
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE, GREENFORD, MIDDLESEX, UB6 0NN
Inventors:
# Inventor's Name Inventor's Address
1 WALKER DWIGHT SHEROD C/O GLAXOSMITHKLINE, FIVE MOORE DRIVE, PO BOX 13398 RESEARCH TRIANGLE PARK, NC 27709
PCT International Classification Number G01N 23/00
PCT International Application Number PCT/US2001/26892
PCT International Filing date 2001-08-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/228,673 2000-08-29 U.S.A.