NL1006813C1 - Packaging containing solid reaction carrier for chemical synthesis - Google Patents

Abstract

A packaging consists of a layer of chemically inert plastic, preferably polypropylene or polystyrene, formed into at least one hollow and filled with a reactive carrier, and then sealed with a second layer of chemically inert plastic. Also claimed is a method of solid phase chemical synthesis with a reagent using the packaging described above.

Description

PACKAGING FOR A FIXED REACTION CARRYING MEDIA

The invention relates to packages containing a reaction support medium for use in solid support chemical synthesis.

Solid chemical-supported chemical synthesis is of increasing importance in, for example, the pharmaceutical industry, in particular in combination with a range of techniques known under the English name "combinatorial chemistry". In the solid-supported synthesis with the so-called "split-pool" method, molecules are bound to a solid support medium, often in the form of a granular resin. A large amount of about 10 carrier medium can be divided many times into portions. The individual portions can undergo different series of syntheses and then be reassembled and mixed together.

A problem with this approach is that the individual parts of the reaction vehicle, such as, for example, the granules of resin, cannot be identified, making it impossible to recognize their individual paths through the reaction sequences.

In a known method, chemical labels are attached to the beads at each synthesis step. The laborious chemical analysis allows the decoding sequence of an individual grain to be decoded.

Chemists working in the field of solid-state synthesis have attempted to solve this coding problem by packaging small amounts of resin granules in perforated or porous polypropylene bags, commonly referred to as "tea bags" in the literature (see RA Houghton, Proc, Natl, Acad, Sci, USA, 82, 5131-5135, 1985). Each portion of resin in a bag can then be coded, typically by writing a number on the bag with a felt-tip pen.

Although the "teabags" provided a useful and simple solution to the above problem, they are not adapted to the requirements of modern industry. They are prepared as required by the chemist in the laboratory and their structure is such that they are not suitable for automated processing. Nor are they adapted to handling by robots, which play an important role in the field of combinatorial chemistry.

It is an object of the invention to provide a solution to these problems by providing an article directly suitable for mass production "in-line" and automated handling by robots. The packages according to the invention take the form of molded impressions in a plastic layer, which are commonly known as "blisters". Blisters are a very well-known packaging for, for example, pharmaceutical tablets and electrical components. However, the blister technology has never been used for use in articles for the solid-state synthesis.

A first embodiment of a package according to the invention consists of a first layer of a chemically inert plastic material formed in such a way that at least one cavity is created, which cavity can contain the reaction carrier medium, while the opening of said cavity is closed by a second layer of chemical inert plastic material attached to it.

The term "chemically inert plastic material" refers to a plastic (plastic) that is not significantly affected by the solvents and reagents used in a typical chemical synthesis. Examples of these materials are polypropylene, polystyrene, polycarbonate and the like polymers. The materials may optionally contain additives normally used in changing properties of these materials. The material preferably used by the invention will be polypropylene or polystyrene, preferably polystyrene.

The reaction carrier medium can also consist of such a material. Examples of useful mediums are well known in the solid-state synthesis field and include various papers and activated gels as well as resin beads or resin beads. Preferably, the reaction carrier medium consists of granules of synthetic resin, such as a polystyrene resin, polyamide resin or a macroreticular resin, preferably polystyrene resin.

The first and second layers of the chemically inert plastic material can be bonded together by any suitable known bonding technique, such as gluing, hot melt bonding or heat welding. Fusion welding is preferred. The second layer of chemically inert plastic material may be flat or may also have formed depressions defining voids complementary to the depressions in the first layer of chemically inert plastic material.

Although it is possible to produce and use a package according to the invention, in the form of a single cavity or blister, a typical package will usually consist of a plurality of such blisters contained in a large sheet or a long tape. Although this package can be of any shape, it is an advantage to arrange this multiplicity of blisters in one or more rows so that the tape can be wound on reels or bobbins for automated processing. Such a tape can typically contain 1,000 to 100,000 blisters.

A second embodiment of packages according to the invention is a package as defined above in the form of a tape or sheet containing a multiplicity of sealed cavities, each cavity containing an amount of reaction carrier medium.

When using a package according to the invention, it is necessary that the chemical reagents can come into contact with the reaction vehicle in the cavity. This can be accomplished either by making at least the first or second layer of chemically inert plastic material porous, or by perforating at least the first or second layer of chemically inert plastic material at an appropriate stage of the production or synthesis process. Perforation can be performed by any known method, including mechanical methods or with a laser. When a laser is used for perforation, this can if desired be done if the package according to the invention is immersed in a reagent inside a vessel made of a transparent material, for example glass. Such in situ perforation has the advantage that the reaction support medium is protected against chemical and biological contamination until just before the reaction.

In a further embodiment, the perforations are arranged such that it is possible to close perforations again by heating.

In a further embodiment, the first and second layers of chemically inert plastic material that define the cavity together can both be made of a porous material or perforated so that there is a continuous flow of chemical reagents and biological test fluids from one side of the cavity to the other side of the cavity.

The cavities of the packages according to the invention can have any shape that can be made with known molding techniques, such as, for example, those used in the manufacture of blister packs. For example, the cavities can have a mainly square, rectangular, oval or round cross section in top view. The dimensions of the cavities vary with the amount of the reaction carrier medium to be packaged therein, which again depends on the amount of product to be made with the envisaged synthesis. The capacity of the cavities in a typical embodiment will range from 5 to 500 mm3, most likely between about 100 and 200 mm3. The cavity is required to have a 1006813 4 capacity greater than the amount of reaction support medium it contains since the known reaction support media swell strongly in contact with the solvents used. The swelling of the different reaction media upon exposure to different solvents is well documented and can be used to calculate the minimum required volume of the cavity for a given weight of reaction media.

Solid-state chemical synthesis using the packaging of the invention is achieved by treating the packaging with a chemical reagent such that the chemical reagent passes through the porous or perforated first or second layer of chemically inert plastic material to contact the reaction medium. This step can be repeated using selected chemical reagents needed for a complete synthesis sequence. If necessary or desired, the packaging can be rinsed between the different reagent treatments. When the desired reaction sequence of a synthesis is complete, the product of the reaction support medium can be separated by conventional means and eluted from the package. Alternatively, the packages can be opened, for example by cutting the first or second layer of chemically inert plastic material with a knife or with a laser, so that the reaction carrier medium is released for separating the product.

The packages according to the invention containing a multiplicity of cavities can, if desired, be divided into smaller packages, for instance shorter lengths of tape, each containing one or more cavities.

For example, in a typical method, a package containing a plurality of voids, such as a sheet or tape, can be subjected to a first chemical reaction. Subsequently, the package can be divided into two or more smaller packages, each of which is subjected to a different second chemical reaction. Following this second chemical reaction, the smaller packages can be redistributed into even smaller packages, each of which is again subjected to a different third chemical reaction. This process can be repeated as many times as desired.

In a related method, it is also possible to have each different cavity in a large package undergo a different chemical reaction.

For the purpose of tracking the sequence of chemical reactions that a cavity has undergone, it is desirable that each cavity can be identified with a unique code. In a typical method, this code is marked in, on or at the edge of the first and / or second layer of chemically inert plastic material that define the cavity. This code may be applied as a whole to a cavity during the packaging production process, or it may be a growing code generated by adding new subcodes at each reaction step. The code can be applied by any useful method such as applying dyes, ink, paint, scratching or piercing by mechanical means or by perforating. In a preferred method, the code will be applied by generating an optical contrast in the first or second layer of chemically inert plastic material by means of a laser. On that pointer, for example, a white, slightly colored or colorless chemically inert plastic material can be darkly marked by carbonization, and a dark colored chemically inert plastic material can be lightly marked by superficial foaming.

If desired, the packages according to the invention can be frozen, for example for refrigerated storage, or sterilized with steam or gamma radiation.

A method of making and applying representative packages according to the invention will now be described with reference to the drawings in which: la shows milking an indentation in a plastic layer,

Fig. lb shows a cross section of an injection molded blister,

Fig. 2a shows the closure of a blister filled with reaction vehicle,

Fig. 2b shows an arrangement for US or HF-assisted blister closing,

Fig. 3a shows the location of the perforations of a blister, FIG. 3b The special shape of resealable perforations shows,

Fig. 4 shows a typical embodiment of packages according to the invention.

The following description is illustrative of the invention only and is not limited thereto. The drawings are schematic and not to scale, in which, as a rule, like parts are designated with like numbers.

The first manufacturing step is to form the first layer of chemically inert plastic material into an indentation or depression. Two methods can be used in particular for this.

In a first method, for low temperature applications (typically below 110 ° C), the blisters can be formed in a tape or sheet of thermoplastic material (1) by means of a doom (2) and an anvil (3) as shown in figure la. In any case, the process temperature is above the glass transition temperature of the chemically inert plastic material (of the order of 150 ° C) depending on the properties of the 1 006 8 1 3 6 material used. The essence is that a blister-like impression is formed in the heated foil by mechanical forces or by a gas pressure. After deformation, the material is cooled so that the mechanical stress is "frozen" in the solid material. As long as the operating temperature remains sufficiently far below the glass transition temperature of the polymeric material, in practice the mechanical shape of the impression will be sufficiently retained.

In a second method, blisters that are free from frozen tension can be used for higher temperature applications (see Figure 1b). These blisters can be made by injection molding from a molten phase. They can be injection molded as loose 10 parts (4) in holes punched in a carrier film (5), or they can be made with the film as a whole.

Foil and cover film materials can be thermoplastics such as polyethylene, polypropylene, polystyrene, polycarbonate or other polymers that can withstand the typical reaction conditions to which they are subjected. The polymers can be used with or without additives or fillers used to control their properties.

The second step in the package making method of the invention is to fill the blisters with weighed amounts (13) of the reaction vehicle. A liquid or gaseous protective agent can be added at this stage if desired. After this, the cavity is closed by applying a second layer of chemically inert plastic material and joining the two plastic layers in such a way that a completely closed connection is formed around the mouth of the cavity. For example, this compound can be effectively applied in the form of a welded joint with a punch (8) and an anvil (9) heated to a temperature close to the melting point of the chemically inert plastic material (Figure 2a). The polymeric material will melt locally and the two parts will be joined. It is very effective to assist the operation of the heated stamps anvils with an ultrasonic excitation using a custom sonotrode (1) (Figure 2b) or with a high-frequency electromagnetic field generator (11), which heating inside out by elastic and dielectric losses, respectively.

The third step in the method of making packaging according to the invention is applying a perforation in one or both layers of plastic. This can be done mechanically, or in the case of the injection-molded blisters, the holes can be formed directly in the production process. However, a very elegant method is to melt a large number of small holes 1006813 7 (14) through the foil with a finely focused pulsed laser beam with a spot which is moved over the surface, for example (figure 3a). The foil must be designed in such a way that the laser radiation is sufficiently absorbed.

In a special method, a gas pressure can be applied at the same time, whereby burrs (15) are formed at the hole edges when they break through. With injection-molded blisters, these specially shaped hole edges can be formed. If reclosing the holes is necessary at a later stage of an application, this can be accomplished by burr with a suitable IR radiator, for example a laser, or hot air. The burr will melt and shrink, closing the hole (16).

10

A further step in the method for making packaging according to the invention is placing an identification code on or with all individual blisters. The typical technology for this is laser coding. Three different methods can be used for this.

In a first method, a code in a surface of a foil can be marked by discoloration of the surface. The polymeric material can be loaded with a light-colored substance or a pigment, such as, for example, titanium dioxide, which decomposes in dark-colored contrasting compounds together with the plastic matrix upon laser irradiation. It is also possible to use a dark colored polymer and to generate a light contrast by means of superficial foaming. Each blister thus receives its own unique code for recognition. With this method, machine-readable dot codes or bar codes, or human-readable alphanumeric engravings can be realized (for example, with a combination of seven A-Z and 0-9 characters, approximately 7.8 x 10 ° unique code words can be generated).

In a second method of forming visual contrast on a polymeric material, the material can be heated very locally very quickly, so that a dark carbonization is formed at the location of the impact of the laser pulse. Both markings are indelible, but the contrast depends on the material properties.

In a third method, a code, especially a dot code, can be applied by burning 30 melting holes through a dark colored foil. With backlighting, a very high contrast is obtained for reading the code. This marking is also indelible and insensitive to disturbance. A typical embodiment of a finished package according to the invention will have a shape as shown in figure 4.

1006813

Claims (2)

Claim 6. A package according to any preceding claim, characterized in that the reaction carrier medium consists of synthetic resin granules, Claim 7. A package according to any preceding claim, characterized in that each hollow has a capacity of 5 to 500 mm 3, Claim 8 A package according to any preceding claim, characterized in that each hollow is identified by a code, Claim 9. A method of solid-state chemical synthesis comprising treating a package according to claims 3 to 8 with a chemical reagent, Claim A method according to claim 9, characterized in that the perforation of at least said first or second layer of chemically inert plastic material is carried out in the presence of a chemical reagent. 1006813 Claim 11. A method according to claim 9, characterized in that said first or second layer of chemically inert plastic material is perforated for treatment g of the package with a chemical reagent and optionally reclosed after intended treatment. Claim 12. A method according to claims 10 or 11, characterized in that the perforation is applied by means of high-intensity electromagnetic radiation originating from a laser source, Conclusion 13. A method according to claim 12, characterized in that reclosing is achieved by deformation of raised edges of the perforations. 1006813