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WO1999004895A1 - Compositions de stockage et d'administration de particules reactives en phase solide et technique d'utilisation - Google Patents

Compositions de stockage et d'administration de particules reactives en phase solide et technique d'utilisation Download PDF

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Publication number
WO1999004895A1
WO1999004895A1 PCT/US1998/013396 US9813396W WO9904895A1 WO 1999004895 A1 WO1999004895 A1 WO 1999004895A1 US 9813396 W US9813396 W US 9813396W WO 9904895 A1 WO9904895 A1 WO 9904895A1
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WIPO (PCT)
Prior art keywords
solid phase
reactive particles
polymers
phase reactive
packaging material
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1998/013396
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English (en)
Inventor
Wayne Devonport
Owen W. Gooding
Jeffrey W. Labadie
John Anthony Porco, Jr.
Paul Van Eikeren
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Argonaut Technologies Inc
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Argonaut Technologies Inc
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Priority to AU83769/98A priority Critical patent/AU8376998A/en
Publication of WO1999004895A1 publication Critical patent/WO1999004895A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00457—Dispensing or evacuation of the solid phase support
    • B01J2219/00459—Beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/005—Beads

Definitions

  • the instant invention relates to solid phase reaction chemistry such as solid phase synthesis, and more particularly to compositions and methods for the storage and delivery of reactive particles which are commonly used in solid phase reaction chemistry.
  • the synthesis of libraries of molecules via parallel and combinatorial synthesis methods frequently relies on the use of reactive particles.
  • these particles are used as solid supports on which the growing molecule is synthesized, supports for immobilized reagents, or supports for separation and purification agents required during synthesis.
  • the general techniques of solid phase synthesis, including automated solid phase synthesis are documented in the art .
  • Manual dispensing may be amenable to automation by employing an automated resin loader such as that commercially available from Bohdan Automation, Inc., of Mundelein, IL.
  • automated loaders are costly and may not be adaptable to all types of reactive particles.
  • compositions of the present invention facilitate the storage and delivery of solid phase reactive particles by providing protection from atmospheric conditions during storage and transportation and by facilitating the accurate transfer of a pre-measured quantity of such particles to reaction vessels.
  • the present invention provides a composition useful for the storage and delivery of solid phase reactive particles.
  • the composition comprises a) a plurality of solid phase reactive particles typically having one or more functional groups covalently linked thereto, wherein the particles are substantially insoluble in both aqueous and organic solvents; and jb) a packaging layer substantially surrounding the plurality of solid phase reactive particles.
  • the packaging layer comprises a packaging material which is substantially insoluble in aqueous solvents and at least 80% by weight of 0.1 g of the packaging material dissolves in 1000 g of organic solvent at 40°C. The solid phase reactive particles are released from the packaging layer upon dissolution of the packaging material.
  • the present invention provides a method for delivering a plurality of solid phase reactive particles to a reaction vessel for solid phase synthesis.
  • the method comprises a) adding to the reaction vessel a composition comprising i) a plurality of solid phase reactive particles, typically having one or more functional groups covalently linked thereto, wherein the solid phase reactive particles are substantially insoluble in both aqueous and organic solvents; and ii ) a packaging layer substantially surrounding the plurality of solid phase reactive particles; and jb) contacting the packaging layer to an organic solvent that dissolves the packaging material and releases the solid phase reactive particles from the packaging layer.
  • the present invention provides a method for protecting solid phase reactive particles, which typically have one or more functional groups covalently linked thereto, from atmospheric moisture.
  • the method comprises enclosing the solid phase reactive particles in a packaging layer, which comprises a packaging material that is substantially insoluble in aqueous solvents and at least 80% by weight of 0.1 g of the packaging material dissolves in 1000 g of organic solvent at 40°C.
  • the packaging layer is substantially impermeable to atmospheric moisture.
  • Solid phase reactive particle (s) refers to solid particles which are substantially insoluble in aqueous solvents and organic solvents at the temperatures and pressures typically employed in solid phase synthesis reactions, and which react with other reactants in a solid phase synthesis reaction.
  • substantially insoluble means that less than 20 percent of 1 g of the specified compound (e.g., particles or packaging material) will solubilize in 1000 g of the specified solvent at 40°C and atmospheric pressure.
  • substantially soluble means that at least 80 percent or more of 0.1 g of the specified compound (e.g., packaging material) will solubilize in 1000 g of the specified solvent at 40°C and atmospheric pressure.
  • Molecular weight refers to average molecular weight and particularly to weight average molecular weight .
  • compositions and Methods for the Preparation Thereof The present invention provides compositions and methods which are useful for the storage and delivery of solid phase reactive particles.
  • the compositions generally comprise a plurality of solid phase reactive particles and a packaging layer which substantially surrounds the particles and which is substantially insoluble in aqueous solvents but substantially soluble in organic solvents.
  • compositions are useful for the delivery of solid phase reactive particles from one location to another, such as one laboratory to another and for delivery to a solid phase synthesis reaction vessel.
  • the compositions and methods of the present invention enable a "unit-dose” approach to introducing a plurality of solid phase reactive particles into a reaction vessel.
  • the compositions are advantageously employed in solid phase synthesis, such as solid phase organic synthesis.
  • compositions of the present invention may be employed in solid phase synthesis, where the solid-phase is used as a support for the chemical structure undergoing synthetic elaboration, and in solution phase synthesis, where the solid phase acts as a source of reagents or acts as a means to covalently or ionically remove excess reagents, impurities, or other undesired components .
  • compositions and methods of the present invention provide a number of advantages.
  • One advantage provided by the present invention is that the introduction of solid phase reactive particles in a multitude of reaction vessels for use in parallel or combinatorial synthesis of compound libraries is now possible with significantly less labor and time as compared to the conventional method of individually weighing and transferring reactive particles to each reaction vessel .
  • the present invention eliminates the problem of contaminating the sealing surfaces between the reaction vessel and the vessel cover with solid phase reactive particles, which can compromise the containment properties of the vessel under pressure.
  • Another advantage is based upon the unexpected finding that solid phase reactive particles introduced by the method of the present invention are well dispersed in reagent solutions without adhering to the wall of the vessel or aggregating at the bottom of the reaction vessel. Good dispersion of reactive particles in reagent solutions helps to ensure chemically reactive contact between reactive particles and reagents and can lead to higher product yield.
  • the solid phase reactive particles of the composition include particles conventionally employed as solid phase supports or solid supports in solid phase synthesis. These reactive particles are typically functionalized with one or more functional groups. That is, the particles have one or more functional usually groups usually covalently linked thereto.
  • the functional groups may be incorporated into the matrix that forms the particle, such as a polymer matrix, or may be covalently attached to the surface of the particle.
  • the functional groups provide a reactive site for solid phase synthesis.
  • compositions of the present invention may include any of the many different known types of solid phase reactive particles and is not limited by the nature of the functional group (s) linked to the particles. The only requirement is that the solid phase reactive particles must be substantially insoluble in aqueous and organic solvents.
  • Solid phase reactive particles include those commonly used for the synthesis of polypeptides, oligopeptides , oligonucleotides, or polynucleotides . These particles comprise polymerized resins having functional groups attached thereto (i.e., "functionalized resins").
  • a functionalized resin is hydrophobic polymerized styrene crosslinked with divinyl benzene (typically at about 0.5 to about 2 weight percent) .
  • the polymerized resin is typically provided in the form of a bead,- which is further reacted to provide a known quantity of substituted benzyl moieties attached to the polymerized resin.
  • the substituted benzyl moieties typically contain a reactive functional group through which the subunits of the biopolymer to be synthesized may be covalently linked by a selectivity severable or cleavable bond, usually called a "linker" in the art.
  • the reactive substituted benzyl moieties are typically added to the particle after the resin bead has been prepared. These particles are general characterized as crosslinked polystyrene-divinyl benzene) resins that include a known quantity of disubstituted benzene cross-links.
  • the functional groups of the substituted benzyl moieties may be amino groups, halogens (such as chlorobenzyl moieties), hydroxy groups, thiol groups or combinations of any two or more of the above .
  • chloromethyl styrene resins Polymerized, crosslinked styrene-divinyl benzene resins containing chlorobenzyl moieties are sometimes referred to in the art as "chloromethyl styrene resins," while resins containing aminobenzyl moieties are sometimes referred to as “amino- styrene” or “aminomethyl-styrene resins.”
  • Chloromethyl styrene resins are commercially available from NovaBiochem of San Diego, CA under the tradename MERRIFIELD RESINTM. These materials typically contain from about 0.1 to about 2 milliequivalents of chlorine per gram of particle.
  • Resinous particles having aminobenzyl moieties may be prepared by reacting polymerized crosslinked styrene- divinyl benzene with N- (hydroxymethyl) phthalimide under
  • Particles having aminobenzyl moieties are also commercially available from NovaBiochem of San Diego, CA under the name Aminomethyl Polystyrene Resin. Typically, the particles contain from about 0.1 to about 1.5 millimoles of aminobenzyl moiety per gram of particle.
  • polystyrene resin particles which may be employed in the compositions of the present invention include but are not limited to polymerized polystyrene having carboxyl functional groups (i.e., carboxypolystyrene) , polymerized polystyrene having hydroxymethyl functional groups (i.e., hydroxymethyl polystyrene) , polymerized polystyrene having formyl functional groups (i.e., formyl polystyrene), and polystyrene having bromomethyl functional groups (i.e., bromomethyl polystyrene) and oxime resin.
  • carboxyl functional groups i.e., carboxypolystyrene
  • polymerized polystyrene having hydroxymethyl functional groups i.e., hydroxymethyl polystyrene
  • polymerized polystyrene having formyl functional groups i.e., formyl polystyrene
  • bromomethyl functional groups
  • grafted polystyrene resin solid phase reactive particles which may be employed in the compositions of the present invention include the ARGOGELTM resins which are commercially available from Argonaut Technologies Inc. of San Carlos, CA, and the TENTAGELTM resins which are commercially available from Rapp Polymere of Tubingen, Federal Republic of Germany.
  • these resins are poly (ethyleneoxide) -grafted polystyrene resin particles having functional groups which include alcohol groups, alkyl amine groups, alkyl halide groups, alkyl thiol groups, or combinations thereof. These resins are provided with a range of intermediate linking groups of the kind described hereinbelow.
  • polystyrene solid phase reactive particles include the TRITYLTM resins which are commercially available from NovaBiochem of San Diego, CA. These particles are polystyrene resin particles having functional groups which include 2-chlorotritylchloride, trityl chloride, 4 -methyltrityl chloride, 4-methoxytrityl chloride, diaminoethane trityl, diaminobutane trityl, diaminohexane trityl, cysteamine 4-methoxytrityl, cysteamine 2-chlorotrityl, glycinol 2-chlorotrityl, phenylalinol 2-chlorotrityl, prolinol 2-chlorotrityl, 5-nitoranthranilic acid 2-chlorotrityl, hydrazine 2-chlorotrityl, ethylene glycol 2-chlorotrityl, thiol
  • the solid phase reactive particles of functionalized polymers may also include an intermediate linking group which provides a covalent linkage between the functional group of the resin particle and the first monomer or subunit in the solid phase synthesis.
  • an intermediate linking group which provides a covalent linkage between the functional group of the resin particle and the first monomer or subunit in the solid phase synthesis.
  • a 4- (oxymethyl) phenoxy group may be bound to a reactive benzyl moiety to serve as an intermediate linking group as reported by Meienhofer et al . , Int . J. Peptide Protein Res . 13:35 (1979).
  • Particles containing this linking group are also commercially available from NovaBiochem under the name of polystyrene-wang resin, and are reported to contain about 0.5 to about 1.5 millimoles of 4- (oxymethyl) phenoxy group per gram of particle.
  • Additional intermediate linking groups include:
  • linking groups have the desired amino group protected with the Fmoc moiety, which can be readily removed by methods well known in the art.
  • Some intermediate linking groups are designed for selective reactivity. Selective reactivity permits removal or "scavenging" of dissolved reagents present in solution and as such, particles bearing these intermediate linking groups are used in purification strategies as described in Gayo, et al . , Tetrahedron Letters 38:513 (1997) and Kaldor et al . , Tet Lett 37:7193 (1996) .
  • An example of solid phase reactive particles having functional groups which include an intermediate linking group of selective reactivity is ion-exchange particles which scavenge charged species .
  • Additional examples include particles bearing reactive groups capable of covalently attaching to the species to be scavenged.
  • Reactive groups include, but are not limited to isocyanate, thiol, acid chloride, and aldehyde.
  • Another type of useful solid phase reactive particles include silica-containing particles such as porous glass beads and silica gel. Examples of these particles are described in A. Guyot, et al . , Makromol . Chem . Macromol Symp . , 70/71:265 (1993) .
  • a third type of useful solid phase reactive particles are composites of a resin and another material, both of which are substantially inert to the organic synthesis reaction conditions.
  • the second material may be a resin as well.
  • One representative example of a composite particle is reported in Scott et al . , J Chro . Sci . 9:577 (1971). Essentially, this composite particle includes glass particles coated with hydrophobic, polymerized, crosslinked styrene containing reactive chloromethyl groups and is commercially available from Northgate Laboratories of Hamden, CT.
  • a further type of reactive particles includes polymeric reagents (reactive, low molecular weight molecules bound to an insoluble, polymeric carrier) , whose use is well recognized in the art. See for example, P. Hodge and D.C. Sherrington, Eds. POLYMER- SUPPORTED REACTIONS IN ORGANIC SYNTHESIS
  • solid phase reactive particles include but are not limited to: polymeric phosphines, halogenating agents, bases, acids, coupling agents, acylation/alkylating agents, and catalysts as described by Akelah et al , Chem. Rev. 81:557 (1981) and J.M.J. Frechet, Tetrahedron 37:663 (1981).
  • polymeric reagents may be included together as reactive particles, since the reactive groups do not come into contact because they are solids. An example of such particles are set forth in J. Parlow, Tetrahedron Letters 1395(1995).
  • the reactive particles useful in the compositions and methods of the present invention are substantially insoluble in both organic solvents and aqueous solvents.
  • less than 20 percent of 1 g of the particles will solubilize in 1000 g of an aqueous or organic solvent at 40°C and atmospheric pressure.
  • less than 15 percent of 1 g of the solid phase reactive particles will solubilize in 1000 g of an aqueous or organic solvent at 40°C and atmospheric pressure.
  • Preferably, less than 10 percent of 1 g of the solid phase reactive particles will solubilize in 1000 g of aqueous or organic solvent at 40°C and atmospheric pressure .
  • the solid phase reactive particles may be provided as a plurality of distinct particles in granular or powder form.
  • the reactive particles may be aggregated or agglomerated in a form suitable for introduction into the reaction vessel.
  • the plurality of solid phase reactive particles may be aggregated to form a core comprising the plurality of solid phase reactive particles in the shape of spheres, pellets, cylinders, elliptices, discs, tablets, or caplets.
  • the size of the core may vary depending upon the particular application. However, the core size should be sufficient to enable introduction into the reaction vessel. Typical core dimensions range from about 0.4 inch to about 1 inch in length and about 0.1 inch to about 0.4 inch in diameter.
  • Cores comprising the plurality of solid phase reactive particles may be produced using conventional tableting techniques, such as by a tablet press, centrifugal granulator, or deposition of a particle slurry on a surface to produce a disc.
  • reactive particles are incorporated into a tablet matrix, which rapidly disperses the particles after dissolution of the packaging material.
  • Binding agents which are suitable for this purpose include, but are not limited to, micro-crystalline cellulose (AVICELTM) , soy polysaccharide (EMCOSOYTM) , pre-gelatinized starches (STARCH 1500TM, National 1551TM) , and polyethylene glycols
  • the binding agent may be present in the range of from 5 percent to 75 percent based on weight, and is preferably present in the amount of from 25 percent to 50 percent based on weight.
  • the core may also incorporate a disintegrant in order to aid the dispersion of the solid phase reactive particles after dissolution of the packaging layer.
  • Suitable disintegrants include, but are not limited to, crosslinked sodium carboxymethyl cellulose (AC-DI-SOLTM) , sodium starch glycolate (EXPLOTABTM, PRIMOJELTM) , and cross-linked polyvinyl- polypyrrolidone (PLASDONE-XLTM) .
  • Disintegrants may be included in the range of from 3 percent to 15 percent based on weight, and are preferably included in the amount of from 5 percent to 10 percent based on weight.
  • Lubricants can also added in the production of the core to assure proper tableting. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, and hydrogenated vegetable oil . Lubricants may be present in the amount from 0.1 percent to 10 percent based on weight and are preferably present in the amount of from 0.3 percent to 3.0 percent based on weight .
  • a tablet or caplet shaped core comprising a plurality of solid phase reactive particles may be formed as follows: the solid phase reactive particles are introduced into a mixer along with a binder, a disintegrant, and a lubricant, and mixed at low shear conditions for a number of minutes.
  • the resulting homogeneous blend is then introduced into the hopper of a conventional tablet press.
  • the compression force used to produce the core is adequate to form a tablet but insufficient to fracture the solid phase reactive particles.
  • Cores in the shape of spheres, granules and pellets can be prepared with the use of a centrifugal granulator. In using the centrifugal granulator, the desired size distribution of the particles should be considered. Fluid-bed coaters can also be employed to make spheres with good size distribution.
  • Cores in the shape of flat discs can be prepared by vacuum drying measured amounts of solid phase reactive particle slurries, containing 8 percent to 20 percent solids, that have been deposited on a flat surface.
  • the Packaging Layer The plurality of solid phase reactive particles, whether aggregated into a core or in the form of a powder or granulation, are surrounded by a packaging layer.
  • the packaging layer encloses, encases, or envelops the plurality of solid phase particles so that the particles are contained within the packaging layer and are prevented from release therefrom. Accordingly, the packaging layer typically substantially completely surrounds the plurality of solid phase reactive particles.
  • the packaging layer provides a convenient tool for delivery of a premeasured unit dose of solid phase reactive particles from one lab to another or for delivery to the reaction vessel.
  • the packaging layer provides 1) a means for containing the particles, 2) a layer of protection for the particles from the atmosphere, 3) a layer of protection for the individual charged with the handling of the particles, and 4) a delivery tool which can be introduced into a reaction vessel and solubilized in an organic solvent to release the solid phase reactive particles.
  • the packaging layer may comprise one or more components.
  • the packaging layer comprises a packaging material which is substantially insoluble in aqueous solvents and substantially soluble in organic solvents.
  • the packaging layer comprises a container having one or more openings therein together with the packaging material .
  • the packaging material covers the openings in the container so that the solid phase reactive particles are enclosed within the container by the packaging material .
  • the container is substantially insoluble in aqueous solvents and may be insoluble in organic solvents.
  • the packaging material which covers the openings in the container must be substantially soluble in organic solvents.
  • Aqueous solvents referred to herein include solvents which consist primarily of water, normally greater than 90 weight percent water, and can be essentially pure water in certain circumstances.
  • an aqueous solvent can be distilled water, tap water, or the like.
  • an aqueous solvent can include water having substances such as pH buffers, pH adjusters, organic and inorganic salts, alcohols (e.g., ethanol) , sugars, amino acids, or surfactants incorporated therein.
  • the aqueous solvent may also be a mixture of water and minor amounts of one or more cosolvents which are miscible therewith.
  • Less than 20 percent of 1 g of the packaging material will dissolve or solubilize in 1000 g of an aqueous solvent at 40°C and atmospheric pressure. More typically, less than 15 percent of 1 g of the packaging material will dissolve in 1000 g of an aqueous solvent at 40°C and atmospheric pressure.
  • the packaging material Preferably, less than 10 percent of 1 g of the packaging material will dissolve in 1000 g of aqueous solvent at 40°C and atmospheric pressure.
  • the packaging material is also substantially impermeable to atmospheric moisture .
  • the packaging material is substantially soluble in organic solvents.
  • the organic solvents which may be utilized to dissolve the packaging material and thereby release the solid phase reactive particles include those organic solvents which are capable of dissolving the packaging material, but are inert to the solid phase reactive particles within the composition. In particular, suitable solvents will be incapable of solubilizing the solid phase reactive particles or reacting with the functional groups thereon. Accordingly, the choice of appropriate organic solvent or combination of organic solvents for dissolving the packaging material of a given composition of the present invention will depend upon the particular packaging material employed and the nature of the solid phase reactive particles of the composition. One element of the present invention involves reliance upon the high differential solubility of the reactive particles relative to the packaging material in organic solvent .
  • Examples of preferred organic solvents include but are not limited to isopropyl alcohol, ethanol, methanol, phenol, hexafluoroisopropyl alcohol, pentane, hexane, heptane, benzene, toluene, xylene, m-cresol, dimethyl formamide, dimethyl acetamide, N-methylpyrolidone, dimethyl sulfoxide, acetonitrile, dichloromethane, methyl ethyl ketone, cyclohexanone, acetone, dichloromethane, chloroform, trichloroethylene, and tetrahydrofuran.
  • the organic solvent is selected from the group consisting of toluene, dimethyl formamide, N- methylpyrolidone, dimethyl sulfoxide, acetonitrile, dichloromethane, and tetrahydrofuran.
  • At least about 80 percent of 0.1 g of the packaging material will dissolve or solubilize in 1000 g of the organic solvent at 40°C and atmospheric pressure. More typically, at least about 85 percent of 0.1 g of the packaging material will dissolve in 1000 g of the organic solvent at 40°C and atmospheric pressure.
  • at least about 90 percent of 0.1 g of the packaging material will dissolve in 1000 g of organic solvent at 40°C and atmospheric pressure.
  • the packaging material is also substantially impermeable to atmospheric moisture.
  • the desired dissolution temperature and the desired dissolution time of the packaging material should be considered. It is often desirable to choose a packaging material that dissolves in the organic solvent at a low solvent temperature, so that the compositions of the invention will be useful over a wide range of solvent temperatures. Operating at higher temperatures is often useful for reasons of faster dissolution rate of the packaging material and faster dispensing of the solid phase reactive particles. Additionally, it is often desirable to choose a packaging material that dissolves in the organic solvent in a short period of time, so that the reactive particles can be delivered into a reaction vessel in a minimum amount of time. Useful packaging materials include those that dissolve at an organic solvent temperature from about 0°C to about 150°C.
  • the packaging material will dissolve at a solvent temperature of about 20 °C.
  • useful packaging materials include those that dissolve in organic solvent in time periods of 1 minute to 120 minutes.
  • packaging materials include those that dissolve in organic solvent in time periods of 15 minutes or less.
  • packaging materials useful in the compositions and methods of the present invention comprise uncrosslinked polymers.
  • "Uncrosslinked polymers" as referred to herein refers to linear polymers that are substantially devoid of crosslinks.
  • uncrosslinked polymers Preferably, uncrosslinked polymers have crosslinks at concentrations less than 0.1 mole percent. Most preferably, uncrosslinked polymers contain no crosslinks at all. Uncrosslinked polymers are prepared by polymerization of the appropriate monomer in the absence of cross-linking agents.
  • the molecular weight of the polymer should be of such a size that the polymer is a solid at the temperature of storage and delivery (typically room temperature) and inert to the solid phase reactive particles (i.e., the polymer does not undergo reaction with the reactive particles.
  • the molecular weight of uncrosslinked polymers will be below about 2,000,000 Daltons and preferably below 500,000 Daltons .
  • Crosslinking polymer chains is known to increase the molecular weight of the polymer and to thereby decrease the solubility of the polymer in solvents.
  • the packaging materials of the present invention are preferably readily soluble in organic solvents.
  • the polymer packaging material also exhibits good mechanical properties (e.g., as defined by tensile modulus for glassy and crystalline polymers) .
  • Preferred packaging materials typically exhibit a tensile modulus of greater than about 1,000 Mpa and an elongation to break of greater than about 5%.
  • Preferred packaging materials also exhibit good thermal properties, expressed as T g and mp, the glass transition temperature and the melting temperature for glassy and crystalline polymers, respectively.
  • Preferred materials exhibit a T g or a mp above room temperature. Many of these polymers are available from commercial sources such as Aldrich Chemical Company, St Louis, MO.
  • polymers suitable for use as the packaging material in the compositions of the present invention include cellulose ester polymers, polycarbonate polymers, low average molecular weight polyalkene polymers, polystyrene polymers, polyvinyl ester polymers, polyvinyl ether polymers, polysiloxane polymers, polyacrylate polymers, polyamide polymers, polyether polymers, polysulfone polymers, polyester polymers, and polyethersulfone polymers.
  • cellulose ester polymers include cellulose acetate and cellulose butyrate .
  • polycarbonate polymers include Bisphenol A poly (carbonates) and those described hereinbelow.
  • Low molecular weight polyalkene polymers include polyalkene polymers having a molecular weight of less than about 500,000 Daltons.
  • Specific examples of low molecular weight polyalkene polymers include poly (ethylene) , poly (propylene) , poly (vinylidene fluoride), poly (tetrafluoroethylene) , poly (1 , 2 -dimethyl-1-butenylene) , poly (1-bromo-butenylene) , poly (1-butene) , poly (1-chloro-l- butenylene) , poly (1-decyl-l-butenylene) , poly (1-hexene) , poly (1 -isopropyl -1-butenylene) , poly (1-pentene) , poly (3- vinylpyrene) , poly (4 -methoxy- 1-butenylene) ; poly (ethylene
  • polystyrene polymers include poly (2 , 4 -dimethyl styrene), poly (2 -methyl styrene), poly (3- methyl styrene), poly (4 -methoxy-styrene) , poly(4- methoxystyrene-costyrene) , poly (4 -methyl styrene), poly- (vinyltrimethylstyrene) , poly (isopentyl styrene), and poly (isopropyl styrene).
  • polyvinyl ester polymers and polyvinyl ether polymers include poly (benzoylethylene) , poly (butoxyethylene) , poly (cyclohexyloxy-ethylene) , poly (decyloxyethylene) , and poly (vinyl acetate) .
  • polysiloxane polymers include poly (dimethylsiloxane) and poly (diethylsiloxane) .
  • polyacrylate polymers include poly (ethyl methacrylate), poly (hexadecyl methacrylate-co- methyl methacrylate), poly (methyl acrylate-co-styrene) , poly(n-butyl methacrylate), poly (n-butyl-acrylate) , poly (cyclododecyl acrylate), poly (benzyl acrylate), poly (butyl acrylate), poly (sec-butyl acrylate), poly(hexyl acrylate), poly(octyl acrylate), poly(decyl acrylate), poly(dodecyl acrylate), poly (2 -methyl butyl acrylate), poly (adamantyl methacrylate), poly(benzyl methacrylate), poly(butyl methacrylate), poly (2 -methyl
  • polyamide polymers include poly (iminoadipoyliminododecamethylene) and poly (iminoadipoyliminohexamethylene) .
  • polyether polymers include poly (octyloxyethylene) , poly (oxyphenylethylene) , polyoxypropylene), poly (pentyloxyethylene) , poly (phenoxy styrene), poly (sec-butoxyethylene) , and poly (tert-butoxyethylene) .
  • polyester polymers are: poly (ethylene terephthalate) and poly (butylene terephthalate) .
  • a specific example of a polysulfone polymer is poly (oxy-1 , 4-phenylenesulfonyl-1 , 4-phenylene) .
  • co-polymers may represent useful packaging materials for use in the compositions of the present invention.
  • Co- polymers are produced by the co-polymerization of two or more monomers via methods well known to those skilled in the art.
  • Specific co-polymers useful for the present invention include acrylonitrile-butadiene co-polymer, butadiene-styrene co- polymer, acrylonitrile-butadiene styrene co-polymer, butadiene-acrylonitrile co-polymer, and styrene-acrylonitrile co-polymer.
  • polymer blends may also be useful in the present invention. Polymer blends consist of mixtures of two or more polymers. Such blends often exhibit properties that are intermediate to the properties of the polymers composing the blend.
  • organic solvent for dissolving the packaging material to release the polymeric particles from the packaging layer depends in part upon the composition of the packaging material.
  • Table 1 lists a number of polymeric packaging materials and preferred organic solvents for solubilizing the same. The list is not intended to be comprehensive, but rather to provide one skilled in the art with a variety of examples which will guide the skilled artisan in the choice of organic solvents for a particular packaging material and enable the skilled artisan to determine additional suitable organic solvents for the packaging materials listed and/or suitable organic solvents for other packaging materials without the need for undue experimentation.
  • polycarbonate polymeric packaging materials are currently preferred because of their relatively low cost and their solubility characteristics in organic solvents.
  • Preferred polycarbonate polymers for use as the packaging material of the present invention include but are not limited to polycarbonate polymers of the general formula:
  • each R 2 and each R 2 are individually selected from the group consisting of H, C ⁇ alkyl, and CF 3 ; and R is selected from the group consisting of: H H H CH 3 H 3 C CH3 NC 7 CF 3 H s / CH 2 CH 2 H 3 H 3 C CH 2 CH 2 C H 3
  • the parenthesis indicate the repeating unit where n corresponds to the number of repeating units.
  • the unit may be repeated a number of times to provide a polycarbonate polymer of suitable molecular weight.
  • the molecular weight of poly (carbonates) is in the range of about between about 10,000 and about 500,000.
  • Packaging materials comprising polycarbonate polymers are soluble in a range of solvents including acetone, chloroform, dichloromethane, dichloroethylene, dimethylformamide, and hexane/dimethylformamide mixtures. Solutions of the polymer can be used to make coatings or can be cast into films. Polycarbonate films of appropriate thickness have adequate tensile strength and pliability under use conditions. The physical properties of poly (carbonates) are controlled by molecular weight. Poly (carbonates) are thermoplastics, where the thermal properties are described by the T g , the glass-transition temperature. Typically, where the thermal properties of the polymer are used, a T g range of from about 20°C to about 200 °C is preferred.
  • Certain solid phase reactive particles are subject to negative effects of atmospheric moisture, as described above.
  • the present invention provides a method for protecting the solid phase reactive particles from atmospheric moisture, which includes enclosing the solid phase reactive particles in a packaging layer comprising a packaging material, which is substantially impermeable to moisture.
  • Preferred packaging materials for protecting the solid phase reactive particles from atmospheric moisture exhibit a low permeability to gaseous water so as to provide a moisture barrier.
  • Representative materials suitable for this method of the present invention include, but are not limited to the following: polyalkenes, such as low molecular weight polyethylene or polypropylene; moisture proofed cellulose esters; polyester; polyvinyl chloride; polycarbonate; polymethyl methacrylate; polyacrylonitrile; and polyvinylidene chloride.
  • Packaging materials may be used singly or in laminates . The selection of material for the water impervious packaging layer is determined by a number of factors including the cost of the packaging material and the required strength. Permeability of packaging material is reflected in the permeability coefficient of the packaging material. See, POLYMER HANDBOOK, J. Brandrup and E. Immergut, Eds, Wiley-
  • water permeability is dependent on temperature and the thickness of the packaging material.
  • the amount of water that permeates through the packaging material is dependent on the time period of exposure.
  • Packaging materials having permeability coefficients to water of less than 2xl0 ⁇ 5 cm 3 STP- cm/cm 2 -sec-cmHg are suitable for the present invention.
  • the packaging materials exhibit a permeability coefficient of less than 3xl0 "6 cm 3 STP-cm/cm 2 -sec-cmHg; most preferably the packaging material exhibits a permeability coefficient of less than 6xl0 "7 cm 3 STP-cm/cm 2 -sec-cmHg.
  • another suitable type of packaging materials comprise natural waxes including insect and animal waxes, vegetable waxes, and mineral waxes; and synthetic waxes.
  • Preferred waxes have a melting point above room temperature and exhibit substantial solubility in the organic solvent.
  • insect and animal waxes include Chinese insect wax, beeswax, spermacetic, fats and wool wax.
  • vegetable waxes include bamboo leaf wax, candelilla wax, carnauba wax, Japan wax, ourieury wax, Jojoba wax, bayberry wax, Douglas-Fir wax, cotton wax, cranberry wax, cape berry wax, rice-bran wax, castor wax, Indian corn wax, hydrogenated vegetable oils (e.g., castor, palm, cottonseed, soybean) , sorghum grain wax, Spanish moss wax, sugarcane wax, caranda wax, bleached wax, Espario wax, flax wax, Madagascar wax, orange peel wax, shellac wax, sisal hemp wax and rice wax.
  • bamboo leaf wax candelilla wax, carnauba wax, Japan wax, ourieury wax, Jojoba wax, bayberry wax, Douglas-Fir wax, cotton wax, cranberry wax, cape berry wax, rice-bran wax, castor wax, Indian corn wax, hydrogenated vegetable oils (e.g., castor, palm, cottonseed, soybean) , sorghum grain wax
  • mineral waxes include Montn wax, peat waxes, petroleum wax, petroleum ceresin, oxokerite wax, micro-crystalline wax and paraffins.
  • synthetic waxes include polyethylene wax, Fischer-Tropsch wax, chemically modified hydrocarbon waxes and cetyl esters wax.
  • Preferred organic solvents for dissolving wax-based packaging materials include toluene, dimethylformamide, N- methylpyrolidone, dimethyl sulfoxide, acetonitrile, dichloromethane, and tetrahydrofuran.
  • coloring can be added to the packaging material to produce opaque or transparent colors such as red, white, pink, green, reddish brown, blue , yellow, black, and the like. Such coloring can lead to colored coatings, capsules or films, which provide a specialty product and distinctive appearance.
  • titanium oxide can be added to the packaging material to form a white colored packaging material, or to make an opaque colored packaging material. The use of colored packaging materials facilitates identification, product differentiation, and brand identification.
  • the packaging layer may be provided in any of a variety of suitable configurations.
  • the packaging layer may be a sealed film bag, pouch, packet, pillow, package, or sack (all of which are generically referred to herein as "pouches") of packaging material which encloses the plurality of solid phase reactive particles.
  • the packaging layer is a coating with covers the plurality of solid phase reactive particles.
  • the packaging layer is a capsule that encapsulates the plurality of solid phase reactive particles.
  • the packaging layer is a container that contains the plurality of solid phase reactive particles and has one or more of openings therein which are covered by the packaging material .
  • the packaging material may conveniently be provided in the form of a film which can be manipulated to produce the desired configuration having the plurality of solid phase reactive particles therein.
  • Films of polymeric packaging material are commercially available and/or can be prepare using conventional techniques. Examples of commercially available polymeric films which can be used to prepare the packaging layer of the composition include polycarbonate films available under the tradename LEXAN ® from several manufacturers including GE Plastics, Fairfield, CT, ASN Plastics, Inc., Indianapolis, IN, and Westlake Plastics Co., Lenni , PA; polyetherimide films available under the tradename ULTEM ® from these same manufacturers; and polybutylterephthalate films available under the tradename VALOX ® , also from these manufacturers.
  • Films used in preparing the packaging material of the present invention are generally manufactured in a film thickness of from about 1 to about 10 mils. In the preferred embodiment, the film thickness is from about 1.0 to about 4.0 mils. One side of the film may be etched or roughened in order to increase surface area for contact to the organic solvent if desired.
  • the use of films are particularly well suited to the fabrication of packaging layers in any of the pouch configurations.
  • the pouch configuration allows a maximum surface area of packaging material to be in contact with solvent for rapid dissolution of packaging material and efficient dispersion of reactive particles.
  • the pouch may be fabricated using a film which is etched on one side in order to increase surface area. This side of the film may be oriented to contact the organic solvent to speed the dissolution of the packaging material in the organic solvent.
  • the inside of the package is generally smooth.
  • the pouch dimensions will be governed by the desired use of the solid phase reactive particles enclosed therein.
  • the size of the pouch will depend on the amount of solid phase reactive particles needed for the reaction, but will be small enough to fit through the opening of the reaction vessel.
  • the shape of the pouch is not particularly relevant, and the pouches may be fabricated in any desired shape.
  • the pouches are preferably fabricated in a shape which is capable of being produced by a conventional apparatus.
  • a range of suitable shapes are contemplated, including but not limited to circular, oval, square, rectangular, and cylindrical. Rectangular and cylindrical shapes are currently preferred shapes of pouches.
  • the pouch may be made by sealing adjacent layers of a film composed of packaging material by any means known to those of skill in the art. Such means include the use of adhesives, ultrasonic sealing, heat sealing, pressure sealing, and organic-solvent sealing.
  • the finished pouches are heat sealed.
  • the pouches can be constructed from a single piece of flat-sheet-film packaging material by folding over the sheet and then sealing the two parallel edges to form an open pouch.
  • the pouch can be constructed from two pieces of flat-sheet-film packaging material and then sealing two parallel edges and a third edge. Sealing can be accomplished with heat sealing by pressing the two film edges together between a heated surface, which melts the polymer film and cements the two pieces together.
  • Other sealing methods can include the use of adhesives selected from those that after drying or curing are substantially soluble in the organic solvents employed for the dissolution of the packaging material .
  • the packaging layer is configured as a coating which covers the plurality of solid phase reactive particles.
  • Cores coated with the packaging layer may be packaged in bulk containers for convenient individual use .
  • Coated cores may be produced by coating the core with a film of the appropriate packaging material . Several methods, such as the solution process and the thermal process can be used to coat the core with the packaging material .
  • the packaging material is dissolved in an appropriate solvent or solvent mixture.
  • the solution is used to coat the core and the solvent is allowed to evaporate to yield a precipitated coating of packaging material on the core.
  • the solution can be delivered by dipping the core into the solution of packaging material or by spraying the solution of packaging material onto the core.
  • the thickness of the coating can be increased by increasing the concentration of packaging material in the solution, leading to an increase in viscosity of the solution or by increasing the spray rate of the solution.
  • the core can be pre-coated with a layer of packaging material that employs a solvent which does not induce swelling.
  • a packaging material or mixture of packaging material and solvent is melted by heating.
  • the hot melt is used to coat the core. Cooling the hot melt surrounding the core results in precipitation of the packaging material, and the formation of the coating surrounding the core .
  • Tablets and caplets are sometimes coated using pan coating systems such as the Vector-Freund Hi-Coaters sold by Vector Corporation, of Marion, Iowa, or the GC-1000 sold by Glatt Air Techniques, of Ramsey, NJ.
  • a pan coating system has a perforated pan or drum which revolves in a manner similar to a standard clothes dryer. The system includes an air- atomization spray gun which is inserted into the center of the drum for spraying a fine mist of a solution of packaging material.
  • a batch of tablet, caplet or pellet cores comprising a plurality of solid phase reactive particles is typically introduced into the cylindrical pan, and tumbled. The tumbling action tends to smooth out any rough edges on the cores prior to coating with the solution of packaging material.
  • Cores may also be coated by immersing the cores in coating solution.
  • the abstract of Japanese Pat. No. 69027916 (Sankyo Co. Ltd.) is directed to gelatin coated tablets and processes for producing the coated tablets by feeding raw tablets at continuous intervals into a support and immersing the tablets in a coating solution. The tablets are recovered and held on a holder where excess coating solution deposited at the lower surface of the tablet is removed by an eliminating plate, and finally the tablet is released into a cooling solution from which it is recovered and dried to produce a seamless tablet coating.
  • the method described in this patent is suitable for coating a core comprising a plurality of solid phase reactive particles with the packaging material to provide a composition according to the present invention.
  • Capsules Another embodiment of the present invention employs capsules or canisters (hereinafter generically referred to as "capsules") comprised of packaging material that encapsulate (i.e., are filled with) a plurality of solid phase reactive particles. Capsules typically comprise two parts: a capsule body and a capsule cap, however, multi-part capsules are also contemplated. Capsules comprised of suitable packaging material can be purchased from commercial sources . For example, polycarbonate capsules are available from Universal Plastics & Engineering Company of Rockville, MD.
  • Capsules are generally available in sizes which range from a cut length for the cap of from about 5 to about 35 mm, a double wall thickness of from about 0.33 to 0.39 mm, a dome thickness of from about 0.33 to about 0.39 mm, an outer diameter of from about 14.6 to about 23.5 mm, and a pre-locked length of from about 34 to 91.5 mm.
  • Capsules for use in the present invention can be produced by any conventional means including dip-coating mandrels in a solution of packaging material that has a viscosity between 1000 and 3000 cps at a temperature above ambient but below the boiling point of the solvent.
  • the coated mandrels are then air-dried at room or elevated temperature to evaporate the solvent and precipitate the packaging material as a capsule over the mandrel.
  • the capsules are slipped off the mandrels after they are dried.
  • the mandrels can be coated with a release agent such as silicone or lecithin lubricants prior to dip-coating so the capsules can be removed easily.
  • Capsules formed by this procedure typically have a wall thickness of about 200 ⁇ m.
  • Capsules can also be produce by automated equipment. For example, empty capsules are manufactured using automated equipment. This equipment employs rows of stainless steel pins, mounted on bars or plates, which are dipped into a solution maintained at a uniform temperature and fluidity. The pins are then withdrawn from the solution, rotated, and inserted into drying kilns through which a strong blast of filtered air with controlled humidity is forced. A crude capsule half is thus formed over each pin during drying. Each capsule half is then stripped, trimmed to uniform length, filled and joined to an appropriate mating half. Such capsule making systems are sold by Cherry-Burrell of Cedar Rapids, Iowa. Additional references illustrating suitable methods of producing capsules for use in the compositions of the present invention include US Pat. Nos. 4,667,498, 4,990,358, 4,966,771, and 4,867,983. In addition, capsule bodies and caps can also be prepared by vacuum forming methods, which are well known in the art, using a suitable film of packaging material, preferably polycarbonate.
  • Capsules are filled in a two-step process including filling the body of a two-part capsule with the plurality of solid phase reactive particles, and attaching the cap. Filling can be accomplished using a manual process such as that exemplified by the Mini-Loader distributed by Torpac Inc. of Fairfield, NJ, or the Fast-Cap Capsule Filling Machine distributed by Capsugel of Greenwood, SC. Additionally, one may use a semi -automated system exemplified by AC-TA-fill 800 semi-automatic capsule filling machine which is sold by Acta Pharmacal Company of Sunnyvale, CA. Other well-known conventional means of producing filled capsules also may be used to provide the compositions of the present invention.
  • the packaging layer comprises two components; a container and the packaging material .
  • the container has one or more openings or pores .
  • the container may or may not be soluble in the organic solvent, but is substantially insoluble in aqueous solvents.
  • Suitable containers include metal, glass, plastic, and ceramic containers.
  • the container should be inert to the solid phase reactive particles, meaning that the container does not react with the particles.
  • a preferred container is made of glass.
  • the openings in the container must be large enough to permit the passage and release of the solid phase reactive particles or core of solid phase reactive particles therethrough.
  • the size of the openings in the container will depend upon the size of the solid phase reactive particles which must be capable of passing therethrough. For example, openings to permit the passage of a core of solid phase reactive particles are larger than openings required to permit the passage of free form granule of solid phase reactive particles.
  • the openings will have a diameter of from about 0.1 to about 1.0mm.
  • a suitable container is a test tube.
  • Another example of a suitable container is an open ended vial .
  • a third example of a suitable container is a glass tube with openings at both ends.
  • the containers are filled with the solid phase reactive particles or core comprising a plurality of solid phase reactive particles, and the openings are covered and/or sealed with the packaging material .
  • the packaging material may be provided in the form a film which is placed over the opening and sealed thereover, for example by the application of heat .
  • the openings must be covered with the packaging material in a manner which prevents the release of the solid phase reactive particles therethrough while the packaging material is in place.
  • the openings of the container Upon dissolution of the packaging material, by exposure to the organic solvent, the openings of the container are exposed and the solid phase reactive particles are released from the container through the openings.
  • the container is comprised of a suitably inert material which is not affected by the organic solvent employed, the container may be retrieved after release of the solid phase reactive particles, refilled, resealed with packaging material, and reused in another synthesis.
  • composition comprising the plurality of solid phase reactive particles may also include additives if desired, such as for example, conventional excipients.
  • additives which may be incorporated into the composition according to the present invention include but are not limited to antioxidants, stabilizers, pH controlling agents, binding agents, disintegrants, lubricants, glidants, adsorbents, inert diluents, and the like. More specifically, suitable binding agents which may be incorporated into the composition include carboxymethyl cellulose, hydroxyethyl cellulose, acacia gum, guar gum, micro-crystalline cellulose, starch, sodium alginate, polyethylene glycols, calcium phosphate, and ethyl cellulose-. Suitable disintegrants which may be incorporated into the composition include micro- fine silicas, corn starch, micro-crystalline cellulose and talc.
  • Suitable adsorbents which may be incorporated into the composition include silicas and starches. Suitable inert diluents which may be incorporated into the composition include micro-crystalline cellulose, calcium phosphate, and calcium sulfate. Other possible additives include drying reagents, solid or liquid reagents, or catalysts. Solid reagents may include reagents necessary for the first step of a synthesis to act on a protecting group or linker segment (e.g. 1,8- diazobicyclo [5.4.0] undec-7-ene (“DBU”), 4- dimethylaminopyridine (“DMAP”), 4 -pyrrolidonopyridine, and other similar bases for Fmoc removal) .
  • a protecting group or linker segment e.g. 1,8- diazobicyclo [5.4.0] undec-7-ene (“DBU"), 4- dimethylaminopyridine (“DMAP”), 4 -pyrrolidonopyridine, and other similar bases for Fm
  • silica-modified reagents such as piperidine modified silica gel for Fmoc deprotection as described in L.A. Carpino, J. Org. Chem . 48:666 (1983).
  • the present invention provides methods for the delivery of a plurality of solid phase reactive particles to a reaction vessel which comprise the steps of a) adding the compositions of the present invention to the reaction vessel and b) contacting the packaging layer to an organic solvent which dissolves the packaging material and releases the solid phase reactive particles from the packaging layer.
  • the method is carried out by introducing one or more compositions according to the present invention into the reaction vessel.
  • the reaction vessel has a filter frit at the bottom of the vessel, which allows the easy separation of solids from liquids. Frits generally have pore sizes that are smaller than the solid phase reactive particles.
  • a volume of organic solvent is added to dissolve the packaging material and release the solid phase reactive particles from the packaging layer.
  • the dissolution of the packaging material may be carried out at elevated temperature if desired, to facilitate rapid dissolution of the packaging material.
  • the dissolution may be carried out at temperatures of from about 0°C to 150°C.
  • the dissolution should be carried out below the boiling point of the organic solvent employed, preferably from about 10 °C to about 80 °C, and more preferably from about 20 °C to about 40 °C. Many dissolution reactions can advantageously be carried out at room temperature. It is often helpful to employ agitation in conjunction with heating to increase the rate and extent of dissolution of the packaging material .
  • the organic extract is removed by filtration employing the reaction vessel frit, although alternative means to separate the reactive particles from the extract may be used, such as centifugation followed by decanting the liquid extract.
  • the organic solvent can remain in the reaction vessel so long as it is compatible with the synthetic reaction conditions being used.
  • the dissolution procedure described above may be repeated one, two, or more times. In cases where the reactive particles retain a significant amount of dissolved packaging material, it is advantageous to repeat the process more than twice. Typically, one or two final rinses of reactive particles removes the last traces of dissolved packaging material. If the composition includes a container which is insoluble in the organic solvent, the container may be removed from the reaction vessel at this time. At this point the solid phase reactive particles can be subjected to a change in solvent or can be dried prior to use in solid phase synthesis.
  • Polycarbonate (LEXAN ® ) film (0.003 in. thick available from GE Plastics, Fairfield, CT) packets were prepared having approximate dimensions of approximately % in. wide and 1 in. long using a 1/8 in. to 3/32 in. track seal on three sides. The edges were sealed with a heat sealer such as the Thermal Impulse Heat Sealer (Vertrod Corporation, Brooklyn, NY) .
  • Capsule bodies and caps size #3 (body 0.216 in. o.d. by 0.533 in. long ; cap 0.219 in. o.d. by 0.325 in. long) constructed from polycarbonate were obtained from Universal Plastics & Engineering Company, Rockville, MD .
  • Two-part capsules (body and cap) exhibited an average weight of 0.067 + 0.004 g.
  • Capsules were filled to capacity with reactive particles (chloromethylstyrene-styrene-divinyl benzene copolymer; PL-CMS ® resin obtained from Polymer Laboratories, Church Stretton, Shropshire, United Kingdom) using one of the two following methods.
  • a pre- weighted amount of resin is added to the capsule body and sealed by the addition of a capsule cap.
  • semi-automated filling is achieved using a capsule filler ("Mini -Loader") obtained from Torpac Inc. (Fairfield, NJ.
  • Capsule bodies and caps can be formed from commercially available polymers.
  • a polymer like polystyrene available commercially from Aldrich Chemical Co.
  • toluene 20%; w/w
  • a madrel in the shape of a capsule body is dipped into the hot polymer solution; removed; and allowed to cool in a stream of air. Cooling and evaporation of the solvent causes precipitation of the polymer, forming a capsule body.
  • Using a mandrel whose diameter is slightly larger than the one used above allows the fabrication of capsule caps.
  • the capsule bodies and caps are removed from the mandrels and trimmed to the proper length with a razor blade.
  • Capsule bodies are loaded with active particles as described in Example 2, and sealed with a capsule cap.
  • Example 4 Manual Dissolution of Capsules
  • the polycarbonate capsules of Example 2 filled with about 101 mg of ARGOGEL '" -NH 2 polyethylene oxide grafted polystyrene particles (available from Argonaut Technologies, Inc., San Carlos, CA) , were tested for rapid dissolution and disintegration. Dissolution is accomplished by the following sequence: (1) a sequence of three incubations with agitation using 4 ml of THF for 10 min. followed by removing the solvent by filtration; and (2) a sequence of two rinses with 4 ml each of THF.
  • the resin was examined by infrared spectroscopy .
  • a sample of resin was subjected to trifluoroacetic acid stress test, which serves to quantify the amount of extractables present in resins that are subject to extraction with trifluoroacetic acid water mixtures (95/05; w/w), i.e., conditions typical of many linker cleavage processes.
  • the extracts were pooled and evaporated and checked by NMR to look for the presence of poly (carbonate) .
  • These results were compared with a control, 100-mg samples of ARGOGEL *" -NH 2 that underwent the same protocol sequence but were not enclosed in a capsule. The results showed that there was no detectable retention of polycarbonate in the resin after completion of the dissolution and washing protocol.
  • Polycarbonate capsules containing ARGOGEL TM -NH 2 were produced as described in Example 4. Capsules, and appropriate controls, were introduced to reaction vessels in a Nautilus 2400 Chemistry Development Workstation (Argonaut Technologies Inc., San Carlos, CA) and subjected to a dissolution protocol consisting of the following: (1) a sequence of three incubations using 4 ml of dichloromethane for 10 min. each; and (2) a sequence of two rinses with 4 ml each of dichloromethane. Incubations consisted of adding the solvent and agitating (rocking) the mixture for 10 min. at room temperature. Rinsing consisted of adding the solvent and agitating the mixture a few cycles.
  • the polycarbonate capsules of Example 2 were filled with 100 mg Polystyrene-Wang ("PS-Wang”), a cross-linked polymer of styrene and divinyl benzene (1 wt%) , available from Calbiochem-NovaBiochem International, San Diego, CA, and 90 mg ARG0P0RE TM -WANG a macroporous resin cross-linked polymer of styrene and divinylbenzene (50 wt%) , available from Argonaut Technologies Inc., San Carlos, CA. Both types of particles were functionalized to contain the linker p-benzyloxybenzyl alcohol commonly referred to as Wang linker.
  • PS-Wang Polystyrene-Wang
  • Wang linker linker p-benzyloxybenzyl alcohol
  • Multi-particulate cores of reactive particles can be prepared as tablets by compressing blends of reactive particles and beneficial agents (e.g., conventional tableting excipients) using conventional tableting methods.
  • beneficial agents e.g., conventional tableting excipients
  • Tablet cores are then coated with a polymer film coating by dip-coating, or spray coating.
  • dip-coating tablet cores are dipped into a 20 weight percent solution of polystyrene in toluene. It is preferable to apply three to five coats by dipping. In between dips, the solvent is allowed to evaporate.
  • spray- coating the tablet cores are sprayed with a 5 weight percent solution of polystyrene in toluene in a pan coater using a commercial air-
  • ARG0GEL TM -WANG-C1 consists of a polyethylene oxide grafted polystyrene backbone bearing the activated linker p-benzyloxybenzyl chloride.
  • results when plotted on a graph of weight gain as a function of time show that the packing material in empty polycarbonate capsules do not absorb a measurable amount of water.
  • results indicate that 150 g samples of molecular sieves which are not enclosed in packaging material rapidly absorb water from the atmosphere to their saturation level of approximately 30 mg .
  • results further indicate that molecular sieves packaged according to the present invention exhibit a dramatic reduction in the rate of water absorption as a result of the moisture barrier provided by the packaging material, i.e., the polycarbonate capsule .

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Abstract

Ces compositions utilisées pour stocker et administrer des particules réactives en phase solide, comporte, (a) plusieurs particules réactives en phase solide, ces particules étant quasiment insolubles dans des solvants aqueux et organiques, et, (b), une couche de conditionnement enveloppant sensiblement les particules réactives en phase solide. Cette couche de conditionnement comporte un matériau de conditionnement sensiblement insoluble dans des solvants aqueux et sensiblement soluble dans des solvants organiques. Les particules réactives en phase solide s'échappent de la couche de conditionnement après dissolution du matériau de conditionnement.
PCT/US1998/013396 1997-07-24 1998-06-26 Compositions de stockage et d'administration de particules reactives en phase solide et technique d'utilisation Ceased WO1999004895A1 (fr)

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WO2001068598A3 (fr) * 2000-03-17 2002-02-21 Lundbeck & Co As H Forme de dosage pour support polymere, utilisation de ladite forme dans la synthese chimique organique et procede de fabrication de ladite forme de dosage
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6410643B1 (en) 2000-03-09 2002-06-25 Surmodics, Inc. Solid phase synthesis method and reagent
WO2001068599A3 (fr) * 2000-03-17 2001-12-13 Lundbeck & Co As H Forme dose pour reactifs, utilisation de cette forme en synthese organique et production de cette forme dose
WO2001068598A3 (fr) * 2000-03-17 2002-02-21 Lundbeck & Co As H Forme de dosage pour support polymere, utilisation de ladite forme dans la synthese chimique organique et procede de fabrication de ladite forme de dosage
WO2006000227A1 (fr) * 2004-06-28 2006-01-05 H. Lundbeck A/S Article poreux pour la liberation de substances chimiques
CN115155473A (zh) * 2016-11-22 2022-10-11 瑞典仿生3000有限公司 长形固相体

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