Dried chemical compositions

Details Dried chemical compositions Dried chemical compositions

1998-04-24

2001-06-26

Alexander, Lyle A. (Department: 1743)

Chemistry: analytical and immunological testing

Optical result

Including reagent preparation

C436S010000, C210S198200, C252S186370

Reexamination Certificate

active

06251684

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to novel compositions comprising dried chemical compounds and to methods for their preparation. In particular, it relates to novel dried beads useful in a number of applications such as preparation of pharmaceutical compositions or analytical reagents.
In preparing chemical compounds for various uses such as convenient and efficient testing of clinical biological samples, it is frequently important to obtain dry chemical blends in uniform, discrete amounts. These compositions must be efficiently and economically prepared in small precisely measured quantities. Chemical compositions comprising organic materials, however, tend to spoil or degrade on storage, thus creating quality control problems. Thus, various chemical compositions are typically provided in dried form to increase stability. Current technology for producing dry chemical blends involves procedures such as dry blending, spray drying, or fluid bed drying. All three of these procedures, however, have limitations that make them costly, inefficient or difficult to carry out.
In dry blending technology, it is difficult to obtain homogeneous blends of chemicals that have different densities. Moreover, homogeneity is particularly difficult to achieve when very small amounts of ingredients are mixed with large amounts of others. Once made homogeneous, it is extremely difficult to reproducibly (within 1 percent) dispense small amounts (less than about 10 mg) of the blended chemicals.
Spray drying technology provides more homogenous blends of chemicals because the reagents are first dissolved in liquid. Using spray drying, however, it is difficult and costly to obtain precisely sized amounts of blended chemicals. As generally practiced, this process yields particles with size distributions having coefficients of variation greater than 20 percent. The resulting particles have to be reprocessed (usually agglomerated) to obtain uniform particle sizes. After agglomeration, the particles are generally less soluble than the original spray dried particles. Moreover, these procedures typically use fluorocarbon cryogenic solutions which are hazardous to the environment.
Fluid bed technology relies upon spraying a liquid reagent blend onto a particle and drying the liquid to obtain a particle coated with the blended reagents. Using this procedure, it is difficult to obtain uniformly sized particles and to produce a uniform coating.
Of particular interest to the present invention are reagents useful in analyzing biological samples, such as blood plasma or serum, in centrifugal analyzers. The rotors used in such analyzers measure volumes of the sample to be tested, mix the sample with an appropriate diluent and separate fluid from cellular components. The rotors also provide a plurality of separate test wells containing chemical reagents in which discrete volumes are optically tested.
Analysis of biological samples in the test wells of centrifugal rotors impose a number of requirements on the reagents used for analysis. In particular, because the analysis is typically highly automated, speed of analysis is at a premium. In addition, many clinical diagnostic analyses require that measurements be made within a short time after the sample is added to the reagent. Thus, the dried reagent preparations must dissolve quickly in the sample solution. In addition, rapid rehydration of the reagents can cause bubble formation, which adversely affects results by interfering with optical measurement.
The prior art thus lacks dried chemical compositions which avoid the above problems. In addition, the prior art lacks economical and reliable dried chemical which dissolve quickly in sample solutions. The present application addresses these and related problems.
2. Description of Background Art
U.S. Pat. Nos. 3,721,725 and 3,932,943 relate to methods for producing lyophilized reagents comprising spraying a solution containing the reagents into a moving bath of fluorocarbon refrigerants and lyophilizing the resultant frozen droplets. U.S. Pat. No. 4,848,094 discloses methods for the generation of essentially spherical frozen droplets and improved methods for removing frozen droplets from a cryogenic liquid. U.S. Pat. No. 4,655,047 describes methods for freezing drops of relatively thick liquids by dropping them from a small height into a cryogenic material. U.S. Pat. No. 3,819,488 provides stable lyophilized diagnostic compositions for determining glutamic oxalic transaminase and glutamic pyruvic transaminase activities. U.S. Pat. No. 4,588,696 relates to preparation of tablets used in testing for formaldehyde and/or glutaraldehyde. U.S. Pat. Nos. 4,295,280, 4,351,158, and 4,712,310 all relate to methods for preparing homogenous preparations comprising compounds which are incompatible. U.S. Pat. No. 4,820,627 discloses a fluidized bed process for preparing particles suitable for tableting into diagnostic reagents. U.S. Pat. No. 4,115,537 relates to diagnostic tablets containing ion exchange resins. U.S. Pat. No. 4,755,461 is directed to tableted blood plasma compositions. U.S. Pat. Nos. 4,678,812 and 4,762,857 both relate to diagnostic tablets comprising trehalose as an excipient and stabilizer. The use of TRITON® X-100 is also disclosed. U.S. Pat. No. 4,716,119 discloses the addition of tetramethylammonium acetate to blood serum. Romanian Patent Appln. No. 85,155 relates to enzymatic alkaline phosphatase reagent tablets comprising p-nitrophenyl phosphate. Driscoll et al.,
Clin. Chem.,
29:1609-1615 (1983) discloses an instrument/reagent system comprising tableted reagents for performing photometric assays.
SUMMARY OF THE INVENTION
The present invention provides methods for forming dried chemical compositions. The method comprise forming a solution comprising a desired compound, dispensing uniform, precisely measured drops of the solution into a cryogenic liquid, preferably unagitated liquid nitrogen, and drying the frozen drops to form dried beads comprising the compound.
The step of drying is preferably accomplished by lyophilizing the frozen drops for about 4 hours to about 24 hours at about 50 to about 450 mTorr.
A variety of solutions and compounds can be used in the methods. Typically, the solution is an aqueous solution and the compound is a reagent for the analysis of a biological sample. Exemplary compounds include sodium fluoride and potassium oxalate.
The dried beads produced by the methods typically have a mean diameter between about 1.5 mm and about 5 mm and are uniform in size and weight. The coefficient of weight variation of the beads is preferably less than about 3.0%. The uniform, precisely measured drops used to form the beads typically have a volume between about 1.5 &mgr;l and about 25 &mgr;l. To increase uniformity, the aqueous solution can be degassed before dispensing the drops.
The beads typically comprise fillers in a concentration sufficient to facilitate formation of a chemical lattice in the beads. Preferred fillers include polyethylene glycol, myo-inositol, polyvinylpyrrolidone, dextran, sodium cholate, mannitol, bovine serum albumin, trehalose, or a combination thereof.
The beads may also comprise a surfactants at a concentration sufficient to inhibit bubble formation when the dried beads dissolve. Exemplary surfactants include octoxynol 9 or polyoxyethlene 9 lauryl ether.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides dried chemical composition, typically in the form of beads. The compositions can be used in any application in which stable, dried chemical compositions are required. Because the compositions are dry and free-flowing, they may be used to provide precisely measured quantities of particular compositions. In addition, the compositions are typically in the form of a dried homogenous, mixture of components in a precise ratio. Thus, the problems of accurately dispensing dry mixtures is avoided using the compositions of the invention.
The compositions can comprise essentially any compound which can be prepare

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