Chemistry: analytical and immunological testing – Including sample preparation
Reexamination Certificate
2000-10-05
2004-04-20
Warden, Jill (Department: 1743)
Chemistry: analytical and immunological testing
Including sample preparation
C073S863220, C055S318000, C055S319000, C209S133000
Reexamination Certificate
active
06723568
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to recovering and handling for analysis samples comprising a particle impactor. Cascade impactors are widely used for size distribution measurement of aerosols. For purpose of this invention, particles suspended in a gas are referred to as an aerosol. The gas borne particles can be a solid, a liquid, or a mixture of both. The particle size is usually between 0.002 um and 100 um.
Impactor is an aerosol-sampling device for collecting aerosol particles onto a substrate by the inertial effect of the particles. One stage of the device usually consists of a nozzle plate in close proximity to a collection plate. The nozzles in each plate which are of substantially the same size, accelerate the gas to a high velocity. The gas jets then impinge on the collection plate to cause particle collection by inertia. The particle size at which 50% of the particles are collected is known as the impactor cut-point. A cascade impactor is then several impactor stages in series, arranged so that the larger particles with large nozzle openings are collected first, followed by smaller and smaller particles.
Cascade impactors are widely used for size distribution analysis of aerosol particles. Particulate air pollutants, aerosols in the work place environment, as well as other aerosols of practical interest are usually polydiverse, with particle sizes spread over a wide range of values. Cascade impactors can be used to separate particles by size into narrower size intervals. The collected particles can then be analyzed to determine their mass size distribution or their chemical composition as a function of particle size.
An important application of the cascade impactor is the determination of size distribution of therapeutic aerosols produced by aerosol drug delivery devices such as the metered dose inhaler (MDI) and the dry-powder inhaler (DPI). Traditionally, drugs delivered in aerosol form have been used to treat asthma and other respiratory diseases. Recently, insulin delivered in aerosol form has also been found effective for the treatment of diabetes. Aerosol drug delivery is becoming increasingly important and the use of cascade impactor for testing aerosol drug delivery devices is also becoming more wide spread. For such applications, large numbers of impactor samples must be analyzed for their medicinal content. The accuracy and the efficiency with which the cascade impactor samples can be recovered and analyzed are becoming increasingly important.
Because impactor testing of drug delivery devices is very labor intensive, attempts have been made to improve the impactor design to make the process more efficient. The parent application identified above and included as part of this disclosure describes several approaches to improving the productivity of impactors. Methods to monitor the performance of the impactor are described in U.S. patent application Ser. No. 09/360,466 filed Jul. 23, 1999 to ensure consistency of operation. Productivity is limited by present particle recovery techniques.
For Recovery Of Particles
The common practice now routinely used in the laboratories to recover samples from impactors for chemical analysis is to manually place the impactor plate or cup (called substrates) on which the particles are collected in a beaker or in a funnel attached to a volumetric flask and to add solvent to dissolve the chemical compound of interest. The solution is then transferred to a sample vial by a syringe or pipette for chemical analysis by the High Performance Liquid Chromatograph (HPLC) or ultraviolet spectroscopy. The usual sample recovery process involves the following steps:
1. Disassemble the impactor and remove the sample substrates
2. Place the substrates into separate containers, such as beakers or petri dishes. For cascade impactors, as shown herein, separate containers are needed, one for each substrate.
3. A measured amount of solvent, such as methanol, is added to a substrate container. This would involve the separate steps of using a pipette to draw the required volume of the solvent, for instance, 25 ml, from the solvent reservoir, and releasing the solvent into the substrate container.
4. The substrate is allowed to remain in the container until the collected sample is dissolved into the solvent.
5. A syringe is used to withdraw the required volume of sample, for example, 1 ml, from the substrate container, and inject into a sample vial.
Steps 3, 4 and 5 usually must be repeated a total of eight to ten times, one for each of the sample substrate following sample transfer to a vial, the unused solution in the container is discarded, and the container and the impaction plate or substrate must then be cleaned for reuse.
Because of the many manual steps involved in sample recovery and impactor cleaning, a laboratory technician may take ½ to one hour to recover the samples from one impactor test run and to prepare the impactor for re-use. Because of the tedious and repetitive nature of these and related tasks, robotic impactor testing systems have been developed, for example, Novi Systems has developed a robotic system that mimics the human steps involved in sample recovery. The efficiency and speed equals the human operator, but run around the clock and are substantially error free. Robotic systems are expensive and can malfunction which shuts down the entire system.
SUMMARY OF THE INVENTION
The present invention provides for appliances to facilitate the use of cascade impactors for metered-dose and dry-powder inhaler testing including the various steps of substrate coating, particle dissolution, sample acquisition, waste solvent disposal, and washing and rinsing the substrates. It includes apparatus and procedure to make sample recovery to be more efficient, more repeatable, and with consistency.
The present invention uses individual appliances or stations for carrying out the required steps with various levels of mechanization, including manually operated, computer driven, semi-automatic and robotic appliances. The individual substrates as shown, a cup tray for example that has sample cups in it with the classified particles carried in the cup and classified according to the structure and description shown in this application. The tray is placed into a support, in the dissolution station and solvent that will dissolve the chemical or component of interest is dispensed by an automatic solvent dispenser in each cup. As will be shown this can be done either manually, semi-automatically, or utilizing a grid type syringe carrier, fully automatically. Computer controls are used for most of these steps and can be programmed to drive a syringe carrier in two mutually perpendicular directions to register the carrier with any of the cups desired according to the input program. The solvent dispenser is controlled automatically as well, to dispense the required solvent in, and if the particles are collected on substrates that are removable as small plates from the impactor, these substrates will be place into -a separate cup tray so that solvent can be added to extract the sample.
Agitation can be provided by fluid motion, that is drawing in a portion of the liquid sample and expelling it back into the cup holding it, or by ultrasonic vibration, stirring, or similar agitation techniques.
Then, a syringe can be moved into a required position for sample transfer, by drawing a portion of the sample into the syringe and moving it then to a place where it would be dispensed into a vial through a seal septum. Again, the movement of a syringe used to withdraw samples can be done on a computer controlled three axis handler.
To accurately measure the amount of solvent dispensed, a calibration cell is used for weighing by electronic balance after the particles of interest have been dissolved.
The apparatus shown can also be used for manual manipulation, rocking, decanting and the like. Different types of supports, cups and other apparatus can also be used.
In the process, the cups or the substrates for collecting particles can b
Liu Benjamin Y. H.
Marple Virgil A.
Roberts Daryl L.
MSP Corporation
Siefke Sam P.
Warden Jill
Westman Champlin & Kelly P.A.
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