Partial pressure detection device and method

Abstract

To provide partial pressure detection apparatuses and methods of detecting a partial pressure of a gas species.SOLUTION: A partial pressure detection apparatus comprises: a thermal conductivity vacuum gauge configured to sense a pressure of a mixture of gases within a vacuum chamber; an input unit configured to receive a total pressure reading from a gas species-independent pressure sensor of the mixture of gases in the vacuum chamber; and a controller configured to provide an output proportional to a partial pressure of a given species of gas in the vacuum chamber as a function of the pressure sensed by the thermal conductivity vacuum gauge and the received total pressure reading. The controller has a resolution scaled to a range of expected partial pressures of the gas species.SELECTED DRAWING: Figure 6

Description

Related Applications

[0001] This application is a continuation of U.S. Patent Application No. 15 / 975,473, filed May 9, 2018, the entire teachings of which are incorporated herein by reference. [Background technology]

[0002] Lyophilization is a costly and time-consuming process used in the pharmaceutical industry to freeze-dry unstable chemicals. Lyophilization, also called freeze-drying, removes water and other solvents from a formulation by sequential freezing (thermal treatment), vacuum sublimation (primary drying), and vacuum desorption (secondary drying). Lyophilization can extend the shelf life of a formulation significantly beyond that of hot air drying. Most lyophilization systems operate without sensors to measure water content during operation. Therefore, the primary and secondary drying times within a lyophilization process are selected during process development and are not adjusted for each process. These fixed drying times can result in formulations that are not completely dried and can lead to over-drying, resulting in wasted time during production. As part of the emerging Process Analytical Engineering (PAT) initiative in the pharmaceutical industry, lyophilization systems are increasingly including endpoint detection methods and sensors for the primary and secondary drying steps. Summary of the Invention [Problem to be solved by the invention]

[0003] Partial pressure detection devices and methods for detecting partial pressure of gaseous species are provided. Such devices and methods can be used to detect the partial pressure of water and other solvents in a freeze-drying process with higher unit resolution than typical Pirani gauges. Advantageously, such devices and methods can accurately detect endpoints, particularly the endpoint of the secondary drying process where water content is low. [Means for solving the problem]

[0004] The partial pressure sensing device includes a thermal conductivity gauge, such as a Pirani gauge, configured to sense the pressure of a gas mixture in a vacuum chamber, and an input configured to receive a total pressure reading of a gas species independent pressure sensor for the gas mixture in the vacuum chamber. The partial pressure sensing device further includes a controller configured to generate an output proportional to the partial pressure of a given gas species in the vacuum chamber as a function of the pressure sensed by the thermal conductivity gauge and the received total pressure reading. The resolution of the controller may be scaled to a range of expected partial pressures of the gas species.

[0005] The partial pressure detection device may also include a housing that houses the controller and at least partially houses the thermal conduction gauge. The thermal conduction gauge may be configured to detect a thermal response of a thin wire to a gas mixture in a vacuum chamber.

[0006] A method for detecting partial pressure includes detecting a pressure of a gas mixture in a vacuum chamber with a thermal conductivity gauge, such as a Pirani gauge, and detecting a total pressure of the gas mixture in the vacuum chamber with a species-independent pressure sensor. The method further includes generating an output proportional to the partial pressure of a given gas species in the vacuum chamber as a function of the pressure detected by the thermal conductivity gauge and the total pressure detected by the species-independent pressure sensor. The output is generated by a controller whose resolution is scaled to the expected range of partial pressures of the gas species.

[0007] The function may include a pressure difference between the measured pressure and the received total pressure reading, for example, as follows: ΔTP=TP PG -TP=xPP S (1) (wherein ΔTP represents the weighted partial pressure of the gas species, and TP PG is the pressure detected by the thermal conductivity gauge (e.g., a Pirani gauge), TP is the total pressure received from the gas species-independent pressure sensor, x is a gas species-dependent coefficient, and PP S is the partial pressure of said gas species. The output may be a function of the weighted partial pressure of the gas species in the chamber (e.g., ΔTP) or the partial pressure of the gas species in the chamber (e.g., PP S ) The latter can be obtained, for example, by transforming the function of equation (1) into the following, or by both equations:

[0008]

number

[0009] When the gas species is water, the coefficient, which is dependent on the gas species, may be approximately 0.4.

[0010] The controller may also be configured to generate a second output representative of a total pressure of the gas mixture in the vacuum chamber based on the thermal response detected by the thermal conduction gauge, and the controller may also be configured to adaptively average the outputs (including the outputs representative of partial pressures of the gas species and / or the outputs representative of the total pressure).

[0011] The gas species independent pressure sensor may be a capacitance manometer other than a capacitance diaphragm gauge. Alternatively, the gas species independent pressure sensor may be a piezoelectric diaphragm gauge, a fiber optic diaphragm gauge or a fiber Bragg grating (FBR) sensor. The partial pressure detection device may comprise an input port configured to connect to an output of the gas species independent pressure sensor. Alternatively, the partial pressure detection device may comprise the gas species independent pressure sensor. For example, the gas species independent pressure sensor in this case may be housed or partially housed in a housing together with the thermal conduction gauge.

[0012] The partial pressure detection device may also include a trigger configured to zero the output of the controller, allowing calibration against a more accurate sensor, such as a gas species independent sensor, connected to the same vacuum chamber.

[0013] The gas species can be the solvent (e.g., water, a mixture of solvents, etc.) of the sample undergoing lyophilization in the vacuum chamber. For example, the gas species can consist of water and a co-solvent such as tert-butanol. The mixture of gases in the vacuum chamber can be a binary mixture. Alternatively, the mixture of gases can consist of three or more gases, provided that at least one of the gases has a different thermal conductivity than the other gases.

[0014] A thermal conduction gauge is a type of gas species-dependent pressure sensor. The partial pressure detection device and partial pressure detection method described above may include any gas species-dependent vacuum gauge configured to detect the pressure of a mixed gas in a vacuum chamber. Examples of gas species-dependent vacuum gauges include thermal conduction vacuum gauges such as Pirani sensors, thermocouple vacuum gauges, ionization vacuum gauges, spinning rotor vacuum gauges, resonant pressure sensors, photonic pressure sensors, and the like. In addition, the partial pressure detection device and partial pressure detection method may include any combination or permutation of the configurations described in this specification.

[0015] The foregoing will become apparent from the following more detailed description of exemplary embodiments, as illustrated in the accompanying drawings, in which like reference numerals refer to like structures / components throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the embodiments. [Brief description of the drawings]

[0016] [Figure 1] 1 is a graph illustrating a prior art freeze-drying process. [Diagram 2] 1 is a graph illustrating a prior art approach for detecting the endpoint of a primary drying process. [Diagram 3] FIG. 1 is a diagram of a constant pressure freeze-drying system. [Figure 4A] FIG. 1 is a circuit diagram of a prior art Pirani vacuum gauge. [Figure 4B] 4B is a graph showing the response of the Pirani gauge of FIG. 4A. [Figure 5A]FIG. [Figure 5B] FIG. 13 is a diagram of another partial pressure detection device. [Figure 6] FIG. 1 is a flow diagram of a calibration process. [Figure 7] FIG. 13 is a diagram of yet another partial pressure detection device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In the following, exemplary embodiments are described.

[0018] Partial pressure detection devices and methods for detecting partial pressure of gaseous species are provided. Such devices and methods can be used to detect the partial pressure of water and other solvents in a freeze-drying process with higher unit resolution than a typical Pirani gauge. Advantageously, such devices and methods can provide accurate endpoint detection.

[0019] A typical freeze-drying process is shown in FIG. 1. In the initial loading step, a sample is placed in a freeze-drying chamber. Typically, the sample is a vial, flask, or tray containing a formulation (e.g., protein, microorganism, pharmaceutical, tissue, plasma, etc.). The sample is then frozen in a process that may take about 2 to about 6 hours. Following the initial loading and freezing steps, the drying process begins. In the primary drying step, frozen water (and other solvents) are sublimated away from the formulation. Sublimation is the process of changing from a solid to a gas without passing through an intermediate liquid phase. As shown in FIG. 1, sublimation occurs at pressures and temperatures below the triple point of water. To begin the primary drying step, a vacuum is applied to the freeze-drying chamber to reduce the pressure in the chamber and thermal energy is applied. This causes sublimation from the formulation. This sublimation process may take about 10 to about 168 hours, depending on the size of the chamber, the number of samples contained in the chamber, and the moisture content of the samples. In the primary drying step, most of the moisture content of the sample is removed.

[0020] Next, a secondary drying process is performed to remove bound water molecules by desorption. As shown in FIG. 1, in the secondary drying process, the pressure in the chamber is further reduced and heat is further applied to release bound water molecules from the formulation. Since the free ice in the sample has been removed in the primary drying process, the formulation will not melt or disintegrate even if the temperature is increased in the secondary drying process. This desorption process may take about 5 to about 24 hours. After both drying processes are completed, the sample is removed from the chamber.

[0021] An important consideration in the lyophilization process is determining the endpoints of both the primary and secondary drying steps. The moisture content can be, for example, in the range of about 5% to about 10% at the end of the primary drying step, and about 0.5% to about 3% at the end of the secondary drying step. Adding heat too early in the lyophilization process (e.g., before sublimation is complete) can cause the formulation to melt or collapse (often referred to as "cake collapse"). However, for cost reasons, it is undesirable to unnecessarily prolong the time of the primary drying step. Different formulations may also have different acceptable thresholds of residual moisture content. Generally speaking, the more moisture removed, the longer the shelf life can be. However, some biologics can become overdried if the moisture content falls below an acceptable threshold.

[0022] One approach to detect the end point of the drying process is to measure the temperature of the sample vial during the drying process with a thermocouple (e.g., wired thermocouple, wireless thermocouple, etc.). It is believed that once the frozen water is gone, the sample will heat up because the heat added to the sample can no longer be removed by water sublimation. However, a major drawback of such an approach is that a thermocouple touching the sample can induce nucleation of the formulation in the vial, falsely reporting the completion of the drying process (i.e., not a bulk measurement).

[0023] Another approach is to measure the moisture content in the chamber during the drying process. This approach involves the addition and use of sensors such as Pirani gauges, plasma emitters, and residual gas analyzers that can detect water in the system. One specific approach is to use a Pirani gauge in conjunction with a capacitance diaphragm gauge (also known as a capacitance manometer) to measure the moisture content during the primary and secondary drying stages. This approach (described in detail in Patel, Sajal M., Takayuki Doen, and Michael J. Pikal. “Determination of End Point of Primary Drying in Freeze-Drying Process Control.” AAPS PharmSciTech 11.1 (2010): 73-84) has been shown to reduce the time wasted during long primary drying stages. This technique, often referred to as Comparative Pressure Measurement (CPM), is suitable for freeze-drying processes that maintain a constant total pressure in the system.

[0024] In the constant pressure freeze-drying process, the pressure is monitored by a capacitance diaphragm gauge, and if the water vapor pressure drops during the drying process, an inert gas such as nitrogen is introduced into the system as needed to maintain a constant total pressure. In constant pressure freeze-drying, the heat exchange between the sample vial contained in the freeze-drying chamber and the gas phase is sustained, which speeds up the drying cycle (especially the drying cycle of the primary drying process). For this reason, the constant pressure freeze-drying method is gaining popularity in the industry. As described in detail below, in constant pressure systems, the endpoint detection function of the drying process is performed by the CPM technique.

[0025] Figure 2 shows the pressure response of a Pirani gauge and a capacitance diaphragm gauge during a constant pressure freeze-drying process, with the output of a gas species independent capacitance manometer 201 and the output of a water vapor sensitive Pirani gauge 203 overlaid on the process diagram of Figure 1. As shown in Figure 2, initially when water dominates the gas composition, the Pirani gauge reading overestimates the total pressure, but as water is removed from the chamber and the gas composition is dominated by nitrogen, the reading eventually matches the capacitance diaphragm gauge reading.

[0026] 3 is a diagram of a constant pressure freeze-drying system 300. The total pressure (TP) of the gas in the freeze-drying chamber is measured by both a capacitance manometer (CM) 301 and a Pirani gauge (PG) 302. Since the capacitance manometer is gas species independent, its total pressure reading can be given by the sum of the partial pressures: TP=PP N2 +PP H2O (3) The Pirani gauge, calibrated on pure N2, overestimates the pressure reading of water by about 40%, so the total pressure reported by the Pirani gauge can be given by the sum of the partial pressures, with the water partial pressure weighted to account for the Pirani gauge overestimate: TP PG =PP N2 +1.4PP H2O (4)

[0027] Both sensors are calibrated based on pure N2, so when the water is removed from the system and the gas in the freeze-drying chamber is pure N2, the CM reading and the PG reading (i.e., TP and TP PG ) is expected to coincide. Therefore, in the CPM process, the pressure readings TP and TP PG are compared and the drying process is considered complete when the two readings converge or the ratio of the two values ​​is 1 as shown in FIG.

[0028] One of the major advantages of the CPM technique is that the Pirani gauge, unlike a thermocouple, has no adverse effect on the sample. Pirani gauges, a type of thermal conductivity gauge, are known in the art to measure absolute pressure by determining heat loss through a hot wire. A typical Pirani gauge consists of a Wheatstone bridge connected to a wire maintained at a constant temperature. The power required to maintain the wire at a constant temperature is used as a measure of pressure.

[0029] FIG. 4A is a circuit diagram of an example of a typical Pirani vacuum gauge 100. In this vacuum gauge, a temperature sensitive resistor R S are connected as one arm of the Wheatstone bridge 110. Typically, R3 is a temperature-sensitive resistor designed so that the temperature rise caused by the current i3 is negligible. Typically, R2 and R1 are constant resistances. S (typically R3 as well) is exposed to the environment where pressure is to be measured. S may extend into the envelope.

[0030] The resistances of resistors R1, R2 and R3 are connected to a pressure-dependent voltage V bridge When is applied to the top of the bridge, V left =V right When the thin wire R S The resistors are selected to be fixed at (R1 × R3) / R2. The voltage V bridge V left and V right The voltage difference between the two inputs can be automatically controlled by an op-amp to be maintained at 0V. left From V right The bridge is considered to be balanced when the potential drop across is zero. At bridge balance, the following conditions hold: i S =i3(5) i1=i2(6) i s ×R S = i1 × R1 (7) i2×R2=i3×R3 (8) Dividing equation (7) by equation (8) and utilizing equations (5) and (6) gives: R S =βR3 (9) (In the formula, β = R1 × R2 (10) Let us assume that.)

[0031] In other words, when the bridge is balanced, R S is a constant fraction β of R3. At any given pressure, R S For steady state to hold, the following equation must be satisfied: R S Power input to = R S Power emitted from +R S Power lost from the end of +R S Power lost from the

[0032] Sensor resistance R S Since the amount of power required to maintain a constant temperature and constant resistance increases with pressure, the voltage V bridge also depends on pressure. This relationship is shown in Figure 4B as S Pressure range in the space occupied by vs. voltage V bridge As shown, the voltage V bridge A typical Pirani gauge is calibrated at a few known pressures. This allows the unknown pressure P x and the power lost to the gas (or more conveniently, the bridge voltage). Then, assuming that the end losses and exhaust losses are constant, we can find the relationship between the power lost to the gas (P) and the unknown pressure P x can be determined directly from the power lost to the gas or can be correlated to the bridge voltage at bridge balance.

[0033] Thus, Pirani gauges such as gauge 100 provide a simple configuration for measuring pressure. However, Pirani gauges are not as accurate as capacitance diaphragm gauges (CDGs). This makes their use problematic in pharmaceutical measurement laboratories where measurement accuracy comparable to CDGs is required. Furthermore, measurement laboratories are not always familiar with Pirani gauge calibration procedures and often lack the experience to determine how often such gauges need to be calibrated or how long it takes for such gauges to show signs of degradation. Today, Pirani gauges used in the CPM process of freeze-drying systems have an accuracy of approximately 15%, while capacitance diaphragm gauges have an accuracy of approximately 0.25% or less. If the accuracy difference between Pirani gauges and capacitance diaphragm gauges is not considered or the Pirani gauge is not properly calibrated, endpoint detection discrepancies can occur. Due to the accuracy difference between Pirani gauges and capacitance diaphragm gauges, Pirani gauges must be periodically recalibrated to account for both accuracy and drift.

[0034] Moreover, Pirani gauges can have inconsistencies in their output signal (e.g., S-shaped curves), making it difficult for pharmaceutical system integrators to integrate them into their tool's data acquisition system. Pirani gauges used today in CPM processes have limited pressure resolution and cannot detect small changes in water volume. The low unit resolution of the Pirani gauge's analog pressure output limits its ability to detect water, especially at the end of the secondary drying process when the water volume is low.

[0035] For example, the output resolution of a typical Pirani gauge used in constant pressure freeze drying processes may be ±10 mV. The unit resolution of such a gauge (assuming a logarithmic analog output = 1 V / decade) may be given by the following formula:

[0036]

number

[0037] (where P is pressure and V is voltage.)

[0038] Thus, the unit resolution of a typical Pirani gauge for a process performed at pressure = 0.1 Torr is ±4.3E-4 Torr by substituting the following values ​​into equation (11):

[0039]

number

[0040] The unit resolution of ±4.3E-4 Torr is considered insufficient as it does not provide a satisfactory detection limit, and also falls short of the four orders of magnitude dynamic range offered by capacitance diaphragm gauges.

[0041] Some commercially available Pirani gauges are capable of providing higher resolution. For example, a Pirani gauge with a 10V scale & 16-bit digital-to-analog converter (DAC) can be programmed to produce a linear analog output scaled for the pressure range: 0 to 0.1 Torr. The unit resolution of such a gauge can be given by the following formula:

[0042]

number

[0043] Such Pirani gauges offer the advantage of improved unit resolution, which is more appropriate for freeze-drying processes, and also have a linear output, which results in a simple relationship between voltage and pressure. Nevertheless, there exists a large accuracy difference between Pirani sensors and capacitance diaphragm gauges, and a gauge capable of providing even better unit resolution is desired.

[0044] A partial pressure detection device is provided that includes a Pirani sensor and is configured to generate an output representative of the partial pressure of a given gas species based on the readings of the Pirani sensor and a gas species independent pressure sensor, such as a capacitance diaphragm gauge. Advantageously, such a partial pressure detection device can provide a high unit resolution pressure measurement indicative of water content, thereby improving detection of small changes in the amount of water during the freeze-drying process. Also, such a partial pressure detection device can include a trigger that nulls the differential output of the partial pressure detection device, thereby simplifying calibration to a gas species independent pressure sensor, such as a capacitance diaphragm gauge.

[0045] 5A illustrates an example of a partial pressure detection device 400. The partial pressure detection device 400 includes a Pirani gauge (also known as a Pirani sensor) 402, a controller 404, and a pressure input port 406 that receives a total pressure reading from a gas species independent pressure sensor, such as a capacitance manometer 301. A housing 410 may enclose the controller 404 and at least a portion of the Pirani sensor 402.

[0046] The pressure input port 406 may be connected to the capacitance manometer 301 in an analog or digital manner so that the total pressure reading of the capacitance manometer 301 can be continuously provided to the controller 404. If the reading is provided digitally, the controller 404 can query the capacitance manometer for pressure directly. If analog, the capacitance manometer will provide a range of pressures to the controller 404 and the capacitance manometer signal can be correlated with pressure.

[0047] As shown in FIG. 5A, the output 320 of the capacitance manometer 301 produces a total pressure reading (TP) that is independent of the gas species. In a typical constant pressure freeze-drying system, the total pressure reading (TP) represents the sum of the partial pressure of N2 gas and the partial pressure of water vapor. As previously mentioned, the Pirani gauge produces a total pressure reading (TP) that is gas species dependent. PG ) to generate the total pressure reading (TP PG) will overestimate the total pressure in the presence of water.

[0048] The partial pressure sensing device 400 is configured to generate a differential output 430 instead of or in addition to the Pirani gauge absolute pressure 420. From equations (3) and (4) (which are restated below for convenience): TP=PP N2 +PP H2O (3) TP PG =PP N2 +1.4PP H2O (4) Pirani sensor 402 pressure reading (TP PG It can be seen that the difference (ΔTP) between the pressure reading (TP) of the capacitance manometer 301 and the pressure reading (TP) of the capacitance manometer 301 is an output proportional to the partial pressure of water in the system: ΔTP=TP PG -TP=0.4PP H2O (14)

[0049] As shown in FIG. 5A, output 430 may be configured to generate ΔTP, which represents a weighted partial pressure of water (e.g., a partial pressure weighted by a factor of 0.4 that indicates the amount by which the Pirani gauge overestimates the water content). As shown in FIG. 5B, output 430′ may alternatively or additionally generate a partial pressure of water (PP H2O ) can also be generated. H2O can be generated by incorporating the coefficient for water = 0.4. Specifically, by rearranging equation (14), H2O can be measured directly as follows:

[0050]

number

[0051] Thus, the differential output 430, 430' of the partial pressure sensing device 400 directly determines the amount of water in the constant pressure freeze-drying system.

[0052] The output resolution of the partial pressure sensing device 400 can be scaled to the expected range of partial pressures of water, rather than to the range of total water pressures, such scaling can improve unit resolution for pressure measurements most relevant to the endpoint of the freeze-drying process.

[0053] For example, consider a constant pressure freeze-drying process that starts at 0.1 Torr and has a maximum starting water content of 20%. The maximum partial pressure of water (PP H2O ) is expected to be 0.02 Torr. At this maximum partial pressure, using equation (14), the output of the partial pressure sensing device 400 of FIG. 5A is 0.008 Torr. The output of the partial pressure sensing device can be scaled to a pressure range of 0 to 0.01 Torr, rather than the pressure range of 0 to 0.1 Torr required to report a total pressure measurement. For example, if the partial pressure sensing device is a 10V scale & 16 bit digital to analog converter (DAC) with a linear analog output scaled to a pressure range of 0 to 0.01 Torr, the unit resolution of such a gauge can be given by:

[0054]

number

[0055] In this manner, the differential output of the partial pressure sensing device can provide a signal directly proportional to the partial pressure of water with a resolution of units sufficient for the freeze drying process, including the secondary drying step. In the above example, the analog output is scaled to use the full range of the DAC for a narrow pressure range (e.g., 0-0.01 Torr), providing a resolution 100 times better than a typical Pirani gauge that is scaled to a wide pressure range (e.g., 1.1-1.2 Torr) to report absolute pressure. While the above example describes an analog signal implementation, a digital communication port could alternatively provide the differential pressure measurement. The differential output of the partial pressure sensing device may be initially saturated (e.g., reporting a partial or weighted partial pressure at the high end of the pressure range to which the sensing device is scaled, even if the pressure is actually higher). Nevertheless, as the concentration of water approaches zero, the differential output allows the actual partial or weighted partial pressure of water to be reported with a resolution of units that is higher than the resolution of units when reporting total pressure. In such cases, the partial pressure sensing device may be switched to report total pressure (e.g., output 420) at the beginning of the process and partial pressure or weighted partial pressure (e.g., outputs 430, 403') toward the end of the process. For example, the total and partial pressure outputs may be multiplexed within the sensing device. Also, although a linear output has been described, the partial pressure sensing device may alternatively produce a logarithmic output.

[0056] The partial pressure sensing device may further include a trigger 408 that zeros the differential output, simplifying the calibration procedure to adjust the output of the Pirani gauge to a more accurate gas species independent gauge, such as a capacitance diaphragm gauge.

[0057] 6 shows an example process 600 for calibrating the partial pressure sensing device prior to freeze-drying. First, the vacuum chamber is brought up to the nominal process total pressure in the absence of water (step 602). Next, the differential output of the partial pressure sensing device can be zeroed and the accuracy offset for ΔTP=0 in the presence of pure nitrogen gas at the process pressure can be stored (step 604). The freeze-drying process can then be started (the differential output is a measure of the water content in the vacuum chamber) (step 606). Zeroing the differential output at the beginning of the process allows for addressing differences in accuracy between the Pirani gauge and the capacitance diaphragm gauge, as well as differences that may be due to drift that may occur over time.

[0058] The calibration procedure of Figure 6 may be performed at the beginning of any process, including after the end of the primary drying process and before the start of the secondary drying process, where the high resolution of the partial pressure detection device is most beneficial in view of the low water content. Alternatively or additionally, valving may be included to isolate both vacuum gauges 301, 402 from the lyophilization chamber and expose them to pure N2 (=process pressure). Such valving allows the partial pressure detection device to be calibrated with a formulation sample in the lyophilization chamber.

[0059] The Pirani gauge included in the partial pressure detection device 400, 400' may be of any type of Pirani sensor configuration, including, for example, the Pirani gauge configuration shown in FIG. 4A. Other configurations of Pirani sensors and types of thermal conductivity gauges other than Pirani sensors are possible and known in the art. Examples of thermal conductivity gauges that may be included in the partial pressure detection device include thermal conductivity gauges described in U.S. Pat. Nos. 6,799,468, 6,938,493, and 7,249,516, the entire contents of which are incorporated herein by reference. Examples of Pirani gauges include the 901P Loadlock Vacuum Transducer, 905 MicroPirani® Ultra Compact Vacuum Sensor, 925 MicroPirani® Vacuum Transducer, 275 Mini-Convectron® Module, and 275 Convectron Pirani Vacuum Gauge, manufactured by MKS Instruments, Inc. (Andover, Massachusetts, USA).

[0060] 5A and 5B, a housing 410 contains a control 404 and at least a portion of a Pirani gauge 402. A port 406 provides connection to a capacitance manometer 301 that is external to the housing. However, alternatively, the capacitance manometer 301 may be contained within the housing 410, as shown in partial pressure sensing device 700 of FIG. 7, such that the partial pressure sensing device includes both types of gauges.

[0061] Although the exemplary apparatus and methods described above have described a capacitance manometer (particularly a capacitance diaphragm gauge) as the gas species independent pressure sensor, other gas species independent pressure sensors may be included instead of or in addition to a capacitance manometer. For example, the partial pressure detection device may include a piezoelectric diaphragm (RPD) gauge and / or a fiber optic diaphragm gauge and / or a fiber Bragg grating (FBR) sensor.

[0062] The partial pressure detection device control unit 404, in addition to reporting the partial pressure, also detects TP, TP PG PP and ΔTP, or a combination of these. H2O By increasing the amount of averaging as approaches zero, the resolution of the pressure measurement can be further improved.

[0063] Although the partial pressure sensing apparatus has been described in the context of a freeze-drying process with nitrogen gas as the process gas and water vapor as the gas species of interest, other combinations of process and solvent gases are possible. Generalizing equation (14), the difference output can be expressed as: ΔTP=TP PG -TP=xPP S (1) (In the formula, PP S is the partial pressure of the gas species to be detected, which may contain solvents other than water instead of or in addition to water, and x is a coefficient that depends on the gas species. By rearranging equation (1), it is possible to directly measure the gas species as follows:

[0064]

number

[0065] Water may be the only solvent present in the sample, however, in the case of water-immiscible formulations, a solvent other than water may be included in place of water or a co-solvent may be included together with water.

[0066] For example, tert-butanol is a non-aqueous co-solvent that is often included in formulations. The inclusion of tert-butanol, typically at 10% of the solvent mixture, can promote sublimation in the formulation sample. Both water and tert-butanol have higher thermal conductivities than nitrogen, so the amount of solvent present in the system can still be represented by the differential output of the partial pressure detector. Additionally, co-solvents typically used in formulations have higher vapor pressures than water, so the co-solvents can sublime from the sample early in the lyophilization process. Thus, the composition of the subliming gas can be time-dependent, with different gas species contributing to the differential output at different points in the process.

[0067] It is possible to directly measure the solvent gas with equation (2), assuming that the gas species dependent coefficient is known for the solvent, co-solvent or solvent mixture. However, even if the gas species dependent coefficient is not known, the difference output of equation (1) can still represent the amount of solvent remaining in the system and can be used to determine the end point of the freeze-drying process, even if the mixture is made up of three or more gases.

[0068] Although exemplary partial pressure sensing devices such as sensing devices 400, 700 have been described as including a thermal conductivity gauge such as a Pirani sensor, they may alternatively include a gas species dependent sensor other than a thermal conductivity gauge such as a thermocouple gauge, an ionization gauge, a spinning rotor gauge, a resonant pressure sensor, a photonic pressure sensor, etc. Provided that the response of the gas species dependent gauge in the presence of the monitored gas species differs from the response of a gas species independent sensor (e.g., a capacitance manometer), a differential output may be provided to indicate the amount of the gas species remaining in the system.

[0069] In addition to freeze-drying, any process involving the analysis of a binary gas can benefit from a partial pressure detector such as detector 400. Specifically, the purity of a binary gas mixture can be determined if the impurity has a thermal conductivity different from that of the main gas. For example, a partial pressure detector can be used to detect air in helium gas. In such a process, the partial pressure detector can be calibrated for the main gas at the beginning of the process, as described above in connection with N2 in the freeze-drying process. The impurity in this case can be the gas species for which partial pressure is to be measured.

[0070] The partial pressure detection device can also be used to verify the correct composition of a binary gas mixture used in a reactive sputtering process. For example, reactive sputtering processes typically have a carefully controlled Ar / O2 ratio, and partial pressure detection can advantageously allow for close monitoring of one of the gas species. Other examples of reactive sputtering compositions include nitrogen-methane, nitrogen-acetylene, etc. In such processes, the partial pressure detection device can be calibrated for one of the two gas species at the beginning of the process, as described above in connection with N2 in the freeze-drying process. The other of the two gas species can be the gas species for which partial pressure is measured.

[0071] Advantageously and conveniently, partial pressure sensing devices such as sensing devices 400, 700 allow operators of freeze-drying systems (or other gas systems, such as binary gas systems) to easily measure the actual amount of water (or other gas species) in the system. Today's constant pressure freeze-drying system operators determine when the amount of water remaining in the system is low enough that the process should be terminated by reading both the capacitance manometer total pressure output and the Pirani gauge total pressure output separately and calculating the ratio of the two outputs. Alternatively, the operator may incorporate the gauges into a central software program and have the central software program display the total pressure output of the two gauges and / or calculate the ratio of the total pressure readings of the two gauges. Alternatively, the operator may predetermine an acceptable difference between the total pressure from the Pirani gauge and the total pressure from the capacitance manometer. In either case, however, the operator must determine a tolerance that indicates the end point of the drying process and rely on the total pressure reported by the Pirani gauge and the more accurate capacitance manometer, which are not calibrated against each other, to estimate the acceptable moisture content that will be the end point of the process.

[0072] In contrast, partial pressure sensing devices such as sensing devices 400, 700 can output a direct measurement of the amount of water in a system, e.g., a weighted partial pressure of water or an actual partial pressure of water, thereby simplifying the operator's determination of a process endpoint based on water tolerance. Moreover, because partial pressure sensing devices can provide such an output with a single device, they advantageously reduce or eliminate the need to separately install and calibrate multiple independent sensors and / or set up separate software applications that integrate the outputs of multiple sensors.

[0073] Additionally, partial pressure sensing devices such as sensing devices 400, 700 can advantageously provide high sensitivity for detecting changes in moisture content. Because the output resolution is scaled to the expected partial pressure range rather than the total pressure, the unit resolution for measurements most relevant to the process endpoint can be significantly improved. With improved unit resolution and more accurate moisture content measurements, more consistent endpoint detection can be achieved for both the primary and secondary drying processes.

[0074] Advantageously, a trigger to zero the output of the partial pressure detector is included, simplifying the procedure for calibrating the thermal conductivity gauge against a more accurate gas species independent sensor. In today's freeze-drying systems, the Pirani sensor and the capacitance manometer are not calibrated against each other. Rather, the Pirani sensor is independently calibrated against a number of known pressures. Because the Pirani sensor is susceptible to drift, operators are often tasked with monitoring the accuracy of the Pirani sensor and periodically performing complex calibration procedures. In contrast, partial pressure detectors such as the detectors 400, 700 can be calibrated with a relatively simple procedure. Advantageously, zeroing the output of the thermal conductivity gauge, such as the Pirani gauge, against a more accurate gas species independent sensor can address the inherent accuracy differences between the two types of sensors and any drift that may occur over time. The calibration process can be performed with minimal effort before each freeze-drying process, resulting in more consistent endpoint detection.

[0075] The entire teachings of all patents, published patent applications and publications cited herein are incorporated by reference.

[0076] Although exemplary embodiments have been specifically shown and described, those skilled in the art will recognize that various changes in form and detail may be made therein without departing from the scope of the embodiments encompassed by the appended claims. The present invention includes the following embodiments. [Aspect 1] a thermal conductivity gauge configured to detect a pressure of the gas mixture in the vacuum chamber; an input configured to receive a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; a controller configured to generate an output proportional to the partial pressure of a given gas species within the vacuum chamber as a function of the pressure sensed by the thermal conductivity gauge and the received total pressure reading; wherein a resolution of the control unit is scaled to a range of expected partial pressures of the gas species. [Aspect 2] 2. The partial pressure detection device of claim 1, wherein the function comprises a pressure difference between the pressure detected by the thermal conduction gauge and the received total pressure reading. [Aspect 3] In the partial pressure detection device according to aspect 2, the function is expressed by the following formula: ΔTP=TP PG -TP=xPP S (wherein ΔTP represents the weighted partial pressure of the gas species, and TP PG is the pressure detected by the Pirani sensor, TP is the total pressure received from the gas species independent pressure sensor, x is a gas species dependent coefficient, and PP S is the partial pressure of said gas species. A partial pressure detection device according to the present invention. Aspect 4 In the partial pressure detection device according to aspect 3, the output is a partial pressure (PP S ) A partial pressure detection device. Aspect 5 4. The partial pressure detector of claim 3, wherein the gas species is water and x is about 0.4. Aspect 6 6. The partial pressure detection device according to claim 1, wherein the controller is further configured to generate a second output representing a total pressure of the mixed gas in the vacuum chamber detected by the thermal conduction vacuum gauge. Aspect 7 7. The partial pressure detection device according to any one of the first to sixth aspects, wherein the thermal conduction vacuum gauge is a Pirani vacuum gauge. Aspect 8 8. The partial pressure detection device according to any one of the first to seventh aspects, wherein the gas species-independent sensor is a capacitance-type diaphragm vacuum gauge. Aspect 9 The partial pressure detection device according to any one of the first to eighth aspects, further comprising: an input port configured to connect to an output of the gas species independent pressure sensor; A partial pressure detection device comprising: Aspect 10 The partial pressure detection device according to any one of the first to ninth aspects, further comprising: The gas type independent pressure sensor; A partial pressure detection device comprising: Aspect 11 The partial pressure detection device according to any one of the first to tenth aspects, further comprising: a trigger configured to zero the output of the control unit; A partial pressure detection device comprising: Aspect 12 12. The partial pressure detection device according to any one of the first to eleventh aspects, wherein the control unit is further configured to adaptively average the output. Aspect 13 Housing and a thermal conductivity gauge at least partially contained within the housing and configured to detect a thermal response of a thin wire to a gas mixture in a vacuum chamber; A control unit accommodated within the housing; The control unit includes: measuring a pressure of the gas mixture in the vacuum chamber based on the thermal response detected by the thermal conductivity gauge; receiving a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; generating an output proportional to the partial pressure of a given gas species within said vacuum chamber as a function of said measured pressure and said received total pressure reading; The partial pressure detection device is configured as follows. Aspect 14 14. The partial pressure detection device of claim 13, wherein the function comprises a pressure difference between the measured pressure and the received total pressure reading. Aspect 15 In the partial pressure detection device according to aspect 14, the function is expressed by the following formula: ΔTP=TP PG -TP=xPP S where ΔTP represents the weighted partial pressure of the gas species, TPPG is the pressure detected by the Pirani sensor, TP is the total pressure received from the gas species independent pressure sensor, x is a gas species dependent coefficient, and PP S is the partial pressure of said gas species. A partial pressure detection device according to the present invention. Aspect 16 In the partial pressure detection device according to aspect 15, the output is a partial pressure (PP S ) A partial pressure detection device. Aspect 17 16. The partial pressure detector of claim 15, wherein the gas species is water and x is about 0.4. Aspect 18 18. The apparatus of claim 13, wherein a resolution of the controller is scaled to a range of expected partial pressures of the gas species. Aspect 19 19. The partial pressure detection device of claim 13, wherein the controller is further configured to generate a second output representing a total pressure of the mixed gas in the vacuum chamber measured based on the thermal response detected by the Pirani sensor. Aspect 20 20. The partial pressure detection device according to any one of aspects 13 to 19, wherein the thermal conduction vacuum gauge is a Pirani vacuum gauge. Aspect 21 21. The partial pressure detection device according to any one of aspects 13 to 20, wherein the gas species-independent pressure sensor is a capacitance-type diaphragm vacuum gauge. Aspect 22 The partial pressure detection device according to any one of aspects 13 to 21, further comprising: an input port configured to connect to an output of the gas species independent pressure sensor; A partial pressure detection device comprising: Aspect 23 The partial pressure detection device according to any one of aspects 13 to 22, further comprising: The gas type independent pressure sensor; A partial pressure detection device comprising: Aspect 24 24. The partial pressure detection device according to claim 23, wherein the gas species-independent pressure sensor is contained within the housing. Aspect 25 The partial pressure detection device according to any one of aspects 13 to 24, further comprising: a trigger configured to zero the output of the control unit; A partial pressure detection device comprising: Aspect 26 26. The partial pressure detection device of any one of aspects 13 to 25, wherein the controller is further configured to adaptively average the output. Aspect 27 1. A method for detecting a partial pressure of a gas species, comprising: A process of detecting the pressure of a gas mixture in a vacuum chamber using a thermal conductivity gauge; detecting a total pressure of the gas mixture in the vacuum chamber with a gas species independent pressure sensor; generating an output proportional to the partial pressure of a given gas species within the vacuum chamber as a function of the pressure sensed by the thermal conduction gauge and the total pressure sensed by the gas species independent pressure sensor; wherein the output is generated by a controller whose resolution is scaled to match the expected partial pressure range of the gas species. Aspect 28 28. The method of claim 27, wherein the function comprises a pressure difference between the pressure detected by the thermal conductance gauge and the total pressure detected by the gas species independent pressure sensor. Aspect 29 29. The method of claim 28, wherein the function is represented by the following formula: ΔTP=TP PG -TP=xPP S (wherein ΔTP represents the weighted partial pressure of the gas species, and TP PG is the pressure detected by the Pirani sensor, TP is the total pressure received from the gas species independent pressure sensor, x is a gas species dependent coefficient, and PP S is the partial pressure of said gas species. Follow the method. Aspect 30 30. The method of claim 29, wherein the output is a partial pressure of the gas species (PP S ) a method. Aspect 31 30. The method of claim 29, wherein the gaseous species is water and x is about 0.4. Aspect 32 The method according to any one of aspects 27 to 31, further comprising: generating a second output representative of the total pressure of the gas mixture in the vacuum chamber as sensed by the thermal conductivity gauge; A method comprising: Aspect 33 33. The method of any one of aspects 27 to 32, wherein the gaseous species is a solvent of a sample undergoing freeze-drying in the vacuum chamber. Aspect 34 34. The method of any one of aspects 27 to 33, wherein the gas mixture is a binary gas. Aspect 35 35. The method of any one of aspects 27 to 34, wherein the thermal conductivity gauge is a Pirani gauge. Aspect 36 36. The method of any one of aspects 27 to 35, wherein the gas species independent sensor is a capacitance diaphragm gauge. Aspect 37 The method according to any one of embodiments 27 to 36, further comprising: calibrating the control unit to the gas species independent pressure sensor; A method comprising: Aspect 38 The method of embodiment 37, further comprising: A step of setting the output of the control unit to zero; A method comprising: Aspect 39 The method according to any one of embodiments 27 to 38, further comprising: adaptively averaging said outputs; A method comprising: Aspect 40 a gas species dependent sensor configured to detect a pressure of the gas mixture in the vacuum chamber; an input configured to receive a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; a controller configured to generate an output representative of the amount of a given gas species in the vacuum chamber as a function of the pressure sensed by the gas species dependent sensor and the received total pressure reading; wherein a resolution of the control unit is scaled to a range of expected partial pressures of the gas species.

Claims

1. a thermal conductivity sensor configured to detect a pressure of the gas mixture in the vacuum chamber; an input configured to receive a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; a total pressure output representing the total pressure of the mixed gas in the vacuum chamber detected by the thermal conductivity sensor; a partial pressure output proportional to the partial pressure of a gas species within the vacuum chamber; a controller configured to generate the total pressure output with a resolution scaled to a process total pressure and to generate the partial pressure output proportional to the partial pressure of a given gas species in the vacuum chamber as a function of the pressure sensed by the thermal conductivity sensor and the received total pressure reading, the function including a pressure difference between the pressure sensed by the thermal conductivity sensor and the received total pressure reading; a control unit having a resolution that is scaled to a range of expected partial pressures of the gas species in generating the partial pressure output that is substantially less than the range of the process total pressure and that is substantially greater than the resolution of the total pressure output.

2. 2. The partial pressure detection device according to claim 1, wherein the function is expressed by the following formula: ΔTP=TP ＰＧ -TP=xPP Ｓ (where ΔTP represents the weighted partial pressure of the gas species, TP ＰＧ is the pressure detected by the thermal conductivity sensor, T is the total pressure received from the gas species independent pressure sensor, x is a coefficient that depends on the gas species, and P Ｓ is the partial pressure of said gas species.) A partial pressure detection device according to the present invention.

3. 3. The partial pressure detection device according to claim 2, wherein the partial pressure output is a partial pressure (PP Ｓ ) a partial pressure detection device.

4. 3. The partial pressure detector of claim 2, wherein the gas species is water and x is 0.

4.

5. 5. The partial pressure detection device according to claim 1, wherein the thermal conduction sensor is a Pirani sensor.

6. 6. The partial pressure detection device according to claim 1, wherein the gas species independent sensor is a capacitance manometer.

7. The partial pressure detection device according to any one of claims 1 to 6, further comprising: an input port configured to connect to an output of the gas species independent pressure sensor; A partial pressure detection device comprising:

8. The partial pressure detection device according to any one of claims 1 to 7, further comprising: The gas type independent pressure sensor, A partial pressure detection device comprising:

9. The partial pressure detection device according to any one of claims 1 to 8, further comprising: a trigger configured to zero the voltage divider output of the control unit; A partial pressure detection device comprising:

10. 10. The partial pressure detection device according to claim 1, wherein the control unit is further configured to adaptively average the partial pressure output.

11. 11. The apparatus of claim 10, wherein the control unit is further configured to adaptively average the total pressure output.

12. Housing and a thermal conductivity sensor at least partially contained within the housing and configured to detect a thermal response of the wire to a gas mixture in the vacuum chamber; A control unit accommodated within the housing; The control unit includes: generating a total pressure output of the gas mixture in the vacuum chamber based on the thermal response detected by the thermal conductivity sensor with a resolution scaled to a process total pressure; receiving a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; generating a partial pressure output proportional to a partial pressure of a given gas species within the vacuum chamber as a function of a total pressure sensed by the thermal conductivity sensor and the received total pressure reading, the function being configured to include a pressure difference between the total pressure sensed by the thermal conductivity sensor and the received total pressure reading; the controller, in generating the partial pressure output, is scaled to a range of expected partial pressures of the gas species that is substantially smaller than a range of the process total pressure and has a resolution that is substantially greater than a resolution of the total pressure output. Partial pressure detection device.

13. 13. The partial pressure detection device according to claim 12, wherein the function is expressed by the following formula: ΔTP=TP ＰＧ -TP=xPP Ｓ (where ΔTP represents the weighted partial pressure of the gas species, TP ＰＧ is the pressure detected by the thermal conductivity sensor, T is the total pressure received from the gas species independent pressure sensor, x is a coefficient that depends on the gas species, and P Ｓ is the partial pressure of said gas species.) A partial pressure detection device according to the present invention.

14. 14. The partial pressure detection device according to claim 13, wherein the partial pressure output is a partial pressure (PP Ｓ ) a partial pressure detection device.

15. 14. The apparatus of claim 13, wherein the gas species is water and x is 0.

4.

16. 16. The partial pressure detection device according to claim 12, wherein the thermal conduction sensor is a Pirani sensor.

17. 17. The partial pressure detection device according to claim 12, wherein the gas species independent pressure sensor is a capacitance manometer.

18. The partial pressure detection device according to any one of claims 12 to 17, further comprising: an input port configured to connect to an output of the gas species independent pressure sensor; A partial pressure detection device comprising:

19. The partial pressure detection device according to any one of claims 12 to 18, further comprising: The gas type independent pressure sensor, A partial pressure detection device comprising:

20. 20. The apparatus of claim 19, wherein the gas species independent pressure sensor is contained within the housing.

21. The partial pressure detection device according to any one of claims 12 to 20, further comprising: a trigger configured to zero the voltage divider output of the control unit; A partial pressure detection device comprising:

22. 22. The partial pressure sensing device of claim 12, wherein the control unit is further configured to adaptively average the partial pressure output.

23. 23. The apparatus of claim 22, wherein the control unit is further configured to adaptively average the total pressure output.

24. 1. A method for detecting a partial pressure of a gas species, comprising: A process of detecting the pressure of the mixed gas in the vacuum chamber using a thermal conductivity sensor; detecting a total pressure of the gas mixture in the vacuum chamber with a gas species independent pressure sensor; generating a total pressure output representative of the total pressure of the gas mixture in the vacuum chamber as detected by the thermal conductivity sensor with a resolution scaled to a process total pressure, and generating a partial pressure output proportional to a partial pressure of the gas mixture in the vacuum chamber as a function of the pressure detected by the thermal conductivity sensor and the total pressure detected by the gas species independent pressure sensor, the function including a pressure difference between the pressure detected by the thermal conductivity sensor and the total pressure detected by the gas species independent pressure sensor; Equipped with wherein the partial pressure output generated by a controller has a resolution that is scaled to a range of expected partial pressures of the gas species that is substantially smaller than the range of the process total pressure and is substantially greater than the resolution of the generated total pressure output.

25. 25. The method of claim 24, wherein the function is of the following formula: ΔTP=TP ＰＧ -TP=xPP Ｓ (where ΔTP represents the weighted partial pressure of the gas species, TP ＰＧ is the pressure detected by the thermal conductivity sensor, T is the total pressure received from the gas species independent pressure sensor, x is a coefficient that depends on the gas species, and P Ｓ is the partial pressure of said gas species.) Follow the method.

26. 26. The method of claim 25, wherein the partial pressure output is a partial pressure of the gas species (PP Ｓ ) a method.

27. 26. The method of claim 25, wherein the gaseous species is water and x is 0.

4.

28. 25. The method of claim 24, wherein the gaseous species is a solvent of a sample undergoing freeze-drying in the vacuum chamber.

29. 25. The method of claim 24, wherein the gas mixture is a binary gas.

30. 25. The method of claim 24, wherein the thermal conductivity sensor is a Pirani sensor.

31. 25. The method of claim 24, wherein the gas species independent sensor is a capacitance manometer.

32. 25. The method of claim 24 further comprising: calibrating the control unit to the gas species independent pressure sensor; A method comprising:

33. 33. The method of claim 32 further comprising: A step of setting the divided voltage output of the control unit to zero; A method comprising:

34. 25. The method of claim 24 further comprising: adaptively averaging the divided voltage output; A method comprising:

35. 35. The method of claim 34 further comprising: adaptively averaging said total pressure output; A method comprising:

36. a gas species dependent sensor configured to detect a pressure of the gas mixture in the vacuum chamber; an input configured to receive a gas species independent pressure sensor total pressure reading for the gas mixture in the vacuum chamber; a total pressure output representing the total pressure of the gas mixture in the vacuum chamber as sensed by the gas species dependent sensor; and a partial pressure output proportional to the partial pressure of a gas species within the vacuum chamber; a controller configured to generate the total pressure output with a resolution scaled to a process total pressure and to generate the partial pressure output, representative of an amount of a given gas species in the vacuum chamber, as a function of the pressure detected by the gas species dependent sensor and the received total pressure reading, the function including a pressure difference between the pressure detected by the gas species dependent sensor and the received total pressure reading; Equipped with a control unit having a resolution that is scaled to a range of expected partial pressures of the gas species in generating the partial pressure output that is substantially less than the range of the process total pressure and that is substantially greater than the resolution of the total pressure output.

Images