BACKGROUND OF THE INVENTION A"cryogenic liquid"is generally defined as a fluid which would be a vapor under ambient conditions of temperature and pressure. Typical examples of cryogenic liquids include liquid oxygen, liquid nitrogen, liquid argon, liquid methane, liquid helium, liquid neon, liquid hydrogen and liquid fluorinated hydrocarbons (i. e., Frelon :).

Cryogenic liquids are employed in a variety of applications, such as coolants, cleaning agents and polymer transfer agents. In pharmaceutical inhalation systems, the inhalation formulation (i. e., active ingredient) is typically carried to the patient in an aerosol propellant stream of chemically inert and biologically safe material. The most commonly employed propellants are fluorinated hydrocarbons.

Cryogenic liquids are often produced by the cryogenic distillation of a feed, such as air, in a cryogenic distillation plant comprising one or more cryogenic distillation columns.

In order to ensure that the plant is operating properly and also to ensure that product of

requisite purity is being produced, samples of the cryogenic liquid must be routinely obtained and analyzed.

After production, the cryogenic liquids are transported from the production facility to the new site, generally in cylinders or tanker trucks. The cryogenic liquids are then often stored at the use site in storage tanks. In order to ensure that the cryogenic liquid has not been contaminated in transportation and/or storage, additional samples of the cryogenic liquid are typically obtained and analyzed.

Further, in the event of a cryogenic liquid being employed as a pharmaceutical propellant, since the propellant and inhalation formulation are introduced directly into a patient's lungs, it is absolutely imperative that the propellant be free of residual components and contaminants (i. e., impurities). Such materials generally arise during general maintenance and/or cleaning of the drug delivery lines. Thus, after maintenance and/or cleaning of the lines, the propellant must be analyzed to detect the presence of any trace materials.

Various methods (and systems) have been employed to ensure that a cryogenic liquid is free of residual components or contaminants. However, as discussed below, the conventional methods have several drawbacks and/or disadvantages.

One method of sampling a cryogenic liquid is the batch technique wherein a sample of the cryogenic liquid is caused to flow into a capture device or cell. The flow of cryogenic liquid is then shut off and the sample is warmed to produce a gas, which is passed on to one or more analyzers. Typical analyzers include a gas chromatograph, a paramagnetic oxygen analyzer or an electro-chemical oxygen analyzer.

The batch method is disadvantageous for several reasons. First, a large amount of sample is vented and thus lost. Second, the batch capture system is complicated and costly.

Third, and perhaps most important, the batch technique is inherently limited in timeliness of the information obtained.

Another method of sampling a cyrogenic liquid involves the coupling of an analyzer system to a cyrogenic liquid source via a conduit which is sufficiently long to enable the cryogenic liquid to vaporize prior to reaching the analyzer or analyzers. Two major problems arise with this continuous sampling method. First, the vaporization of the cyrogenic liquid in the conduit results in local pressure increases, which cause liquid to flow back out of the conduit and into the cyrogenic liquid source.

Another problem with the continuous method is that the requisite long conduit affords an opportunity for a significant amount of trace impurities within the sample to plate onto the inside surface of the conduit. Still further, the long conduit results in a long response time from the acquisition of the sample to the analysis itself.

It is therefore an object of the present invention to provide an improved method and system for sampling cryogenic liquids.

It is another object of the present invention to provide a simple, accurate and reliable method of detecting trace materials in cryogenic liquids.

It is another object of the invention to provide a method and system for detecting trace materials in cryogenic liquids at multiple locations within a production environment.

It is yet another object of the invention to provide a method of continuous sampling and analyzing of a cyrogenic liquid by means of near infrared spectroscopy.

SUMMARY OF THE INVENTION In accordance with the above objects and those that will be mentioned and will become apparent below, the method of detecting a trace material in a cryogenic liquid in accordance with this invention comprises the steps of (i) measuring the absorption spectrum of the cryogenic liquid by passing light in the infrared region through the cryogenic liquid, said cryogenic liquid absorption spectrum having a first reference energy, (ii) measuring the

absorption spectrum of at least one impurity alone by passing light in the infrared region through said impurity, (iii) passing a cryogenic liquid sample into a flow cell, wherein the maximum pressure drop of the cryogenic liquid sample across said flow cell is in the range of 0.5 to 5.0 lb./in., (iv) measuring the absorption spectra of the cryogenic liquid sample by passing light in the infrared region through the cryogenic liquid sample while the cryogenic liquid sample is within the cell, (v) comparing the cryogenic liquid sample absorption spectra to the cryogenic liquid and impurity spectra, (vi) confirming the presence of the sample absorption spectrum associated with the impurity, the sample absorption spectrum associated with the impurity having a second reference energy, and (vii) determining the concentration (C) of said impurity in the cryogenic liquid sample by the following relationship, kC = log second reference energy first reference energy where k is a fixed proportionality constant.

The system of the invention comprises (i) source of cryogenic liquid sample, (ii) conduit means in flow communication with the source of cryogenic liquid sample for transferring the cryogenic liquid sample to a plurality of locations, (iii) at least one flow cell in flow communication with the conduit means, the flow cell being adapted to maintain a maximum pressure drop across the cell in the range of 0.5 to 5.0 lb./in. 2, (iv) analyzer means for respectively measuring the absorption intensity of the base cryogenic liquid, target impurity and cryogenic liquid sample by separately passing near infrared light through the base cryogenic liquid, impurity and cryogenic liquid sample, (v) means for comparing the absorption intensities of the base cryogenic liquid, impurity and cryogenic liquid sample to determine the presence of the impurity in the cryogenic liquid sample, and (vi) means for determining the concentration of the impurity.

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 schematic illustration of a pharmaceutical mixing and delivery system employing the sampling and analysis system of the present invention; FIGURE 2 is a partial section plan view of a mixing chamber and flow cell of the present invention; FIGURE 3 is a plan view of a cryogenic liquid storage column employing the sampling system of the present invention; FIGURE 4 is a schematic illustration of a production facility employing an additional embodiment of the sampling and analysis system of the present invention; and FIGURE 5 are absorption curves for methanol measured in an embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present invention substantially reduces or eliminates the di avantages and shortcomings associated with prior art cryogenic liquid sampling and analysis methods. As discussed in detail below, the present invention provides for simple, accurate and reliable continuous sampling and analysis of a cryogenic liquid to determine the presence and identity of trace components and/or contaminants. By the term"cryogenic liquid", as used herein, it is meant to mean a liquid that would be a vapor at a temperature of 15°-25°C at 1.0 atmosphere. The term"cryogenic liquid"thus includes liquid oxygen, liquid nitrogen, liquid argon, liquid methane, liquid helium, liquid neon, liquid hydrogen, and liquid fluorinated

hydrocarbons, including, hydrofluorocarbons, chlorofluorocarbons, hydrofluoroalkanes and derivatives thereof.

The terms"components","contaminants"and"impurities", as used herein, are meant to include (i) materials having vibration energies in the range of 3 x 10el4-12el4Hz, (ii) materials containing OH, CH, SH, CO and NH bonds and (iii) volatile organics.

As indicated above, the conventional cryogenic liquid sampling methods and systems have numerous drawbacks and/or disadvantages. The methods and systems are generally complex, inherently limited in timeliness and limited in location of sampling (e. g., site). In contrast to the conventional systems, applicant's method and system provides prompt, accurate data and is readily adaptable to any location (or multiple locations) within the production environment, including the cryogenic liquid delivery lines.

Referring to Figure 1, there is shown a simplified representation of a pharmaceutical mixing and delivery system 5 employing the sampling system 30 of the present invention.

The mixing and delivery system 5 includes a cryogenic liquid (i. e., Freon) reservoir 10 for containing the cryogenic liquid material 7, a cryogenic liquid feed line l 2, a feed valve 14, a filling unit 16, a recirculation line 18, a mixing chamber 20, which facilitates mixing of the cryogenic liquid and the pharmaceutical formulation, and a pump 22.

The sampling (and analysis) system 30 of the invention includes a flow cell 32 an analyzer 52 to determine the presence and identity of trace components and/or contaminants (i. e., impurities) in the cryogenic liquid 7 and processing means 54 to control the analyzer and process data therefrom. In a preferred embodiment, the analyzer 52 comprises an infrared spectroscopic analyzer.

It is well known that when the molecules are exposed to electromagnetic rays (i. e., infrared light) of a wavelength which has a photon energy equivalent to their value of the vibration energy level, the molecules absorb the electromagnetic waves as their own vibration energy. The amount of absorption is proportionate to the abundance of the

molecules present. When this vibration energy level value is converted to photon energy, ordinarily, it will correspond to wavelengths in the infrared region.

Accordingly, as discussed in detail below, when infrared light from the light source 50 is passed through the cryogenic liquid 7 (i. e., sample) within the flow cell 32 (see Fig. 2), each trace material (i. e., component and contaminant) contained in the cryogenic liquid will exhibit a distinctive absorption spectrum. The identity of a selective one of the trace materials (i. e., target impurity) is then determined from the absorption spectrum (i. e., the wavelength of the light absorbed) associated with the target impurity. Further analysis of the absorption spectra (e. g., quantitative determination) is achieved by virtue of the processing means 54 of the invention, which, in a preferred embodiment, comprises a computer.

Referring back to Figure 1, the flow cell 32 of the invention is preferably in flow communication with the mixing chamber 20. According to the invention, the flow cell 32 provides substantially uniform and continuous flow of the cryogenic liquid (with and without the pharmaceutical formulation) therethrough with a maximum pressure drop across the flow cell 32 in a range of 0.5 to 5.0 lb./in., preferably 0.75 to 1.5 lb./in. 2. More preferably, the maximum pressure drop is approximately 1.0 lb./in. 2.

According to the invention, the flow cell 32 is preferably constructed of copper, stainless steel, or another like material and is vacuum insulated to ensure that the cryogenic liquid 7 remains in its liquid state (i. e., does not vaporize). In additional envisioned embodiments, the flow cell 32 includes cooling means (shown in phantom in Figure 2) comprising a cell liner 38 and control means 39 to control the temperature of the cryogenic liquid 7 within the flow cell 32.

As illustrated in Figures 1 and 2, the flow cell 32 further includes couplings 33,34, which are adapted to receive a light source line 51 and analyzer line 53, respectively. The couplings 33,34 are further adapted to facilitate communication by and between (i) the light source line 51 and tungsten halogen lamp 35 and (ii) analyzer line 53 and analyzer probe 36, respectively.

As indicated above, an advantage of applicant's system is that the flow cell 32 and, hence, the system is readily adaptable to virtually any location of cryogenic liquid flow within a production environment. Such locations include pharmaceutical delivery lines, such as those illustrated in Figures 1 and 2, and a transfer line 42 proximate a storage tank or column 40, as illustrated in Figure 3. Thus, multiple flow cells 32 may be disposed at various key locations within a production environment to provide random or continuous analysis of the cryogenic liquid.

Referring to Figure 4, there is shown a schematic illustration of a simple production facility employing a multiple cell system of the invention. The production facility is housed within a building structure 60 and includes a cryogenic liquid storage column 62, disposed externally of the building structure 60, a delivery line 64 (adapted to provide product, denoted by Arrow P), a valve 65, a plurality of pumps 66a, 66b in flow communication with the delivery line 64, a mixing chamber 68 and a component feed line 70 (adapted to feed a component into the mixing chamber 68, denoted by Arrow I). The facility further includes a plurality of flow cells 32a, 32b and the light source 50, analyzer 52 and processing means 54 of the invention.

In the noted embodiment, the light source 50 includes two light source lines 5 la, 5 Ib.

The light source lines 51 a, 51 b are in communication with cells 32a and 32b, respectively.

The analyzer 52 of the invention is similarly provided with two analyzer lines 53a, 53b. The analyzer lines 53a, 53b are also in communication with cells 32a and 32b, respectively.

In additional envisioned embodiments, a plurality of analyzers 52,52a (shown in phantom) are employed. In this embodiment, analyzer line 53c is directly connected to cell 32b and an additional processing means line 55a is employed.

According to the invention, data from each respective cell 32a, 32b (i. e., location) is selectively acquired and processed by the processing means 54 of the invention, which is in

communication with the analyzer 52 via processing means line 55 (or analyzers 52,52a via processing means lines 55,55a).

As stated above, the analyzer 52 of the invention is adapted to determine the presence of trace components and contaminants in the cryogenic liquid. According to the invention, the determination of a trace component or contaminant is preferably accomplished by conducting a first scan of the base cryogenic liquid to establish a first absorption spectrum having a first reference energy (i. e., absorption energy). A second scan of at least one target material (i. e., component or contaminant) is then conducted to determine an impurity absorption spectrum associated with the target material. The first and second scans preferably comprising near infrared light in the range of 900-2200 nanometers.

The first absorption spectrum and impurity absorption spectrum (or spectra) are then stored in the processing means 54 memory. During on-line analysis, the cryogenic liquid sample is scanned while the sample is contained in a selected cell (i. e.,'j7,32a, 32b) to obtain the sample absorption spectra. The sample absorption spectra are then compared to the stored absorption spectra via the processing means 54 to distinguish among and confirm the presence of the cryogenic liquid sample absorption spectrum associated with the target material, the sample absorption spectrum associated with the impurity having a second reference energy. The method thus provides accurate and reliable identification of a trace material in a cryogenic liquid sample.

According to the invention, further analysis and/or processing of the stored absorption spectra and the sample absorption spectra is provided by the processing means 54 of the invention. Such additional analysis includes a determination of the concentration of the componeria or contaminant, and component and contaminant concentration profile (s) at selected cell locations.

The concentration (C) of the component or contaminant is preferably determined as follows: kC = log E2

E, where: E, = reference energy (i. e., absorption energy) of the base cryogenic liquid absorption spectrum; E2 = reference energy of the sample absorption spectrum associated with the target material; and k = fixed proportionality constant.

To demonstrate the superior performance of applicant's method and system, a sample of FreonX was spiked with known concentrations of methanol. Methanol, an organic solvent, is typically employed to flush pharmaceutical filling lines between different product runs.

The solutions were then introduced into the mixing chamber 20 and ultimately into the flow cell 32.

Near infrared light (NIR) in the range of 900-2200 nanometers was then passed through the sample within the flow cell 32. The resultant infrared absorption spectra (i. e., absorption curves), which were obtained using a Rosemount Analytical AOTF-NIR analyzer, are shown in Figure 5.

As illustrated in Figure 5, methanol and, hence, impurity concentrations of less than 0.01 % are readily detected, distinguished and determined by the method and system of the invention. Such sensitivity in"in-situ"liquid analysis is unparalleled in the art.

The results of the trace determination experiment further indicate that trace amounts of an impurity-component and/or contaminant-can be accurately detected and quantified "on-line"at levels well below the pharmaceutical industry standard of < 0.02%. The results were also achieved in a fraction of the time generally required for prior methods and systems.

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 usages 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.