Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
1999-12-22
2002-07-16
Kiliman, L. (Department: 1773)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C428S407000, C428S516000, C428S520000, C427S220000, C427S221000, C210S198200, C210S502100, C210S504000, C210S503000, C210S506000, C210S635000, C210S638000, C210S656000
Reexamination Certificate
active
06420028
ABSTRACT:
TECHNICAL FIELD AND BACKGROUND ART
The present invention relates to coated polymer articles and processes for the production thereof and use of the article as chromatography medium. Specifically the invention relates to coated articles with the coating covalently bound to the polymer surface via pending double bonds of the polymer surface. An example of pending groups are residual vinyl groups remaining after polymerisation of vinyl monomers, such as divinyl benzene monomers.
In the context of the present invention the term “coated”/“coating” means that pending alken groups on the surface has been derivatized to introduce novel functionaities that may be adapted to two specific uses of the article (chromatographic support and support for oligopeptide and oligonucleotide synthesis). “Coat” thus has a somewhat different meaning compared to coating in the sense of physical adsorption and stabilization by crosslinking of an adsorbed layer (coat) within the layer and/or to the original surface.
The stationary phase (support, matrix) in liquid chromatography is composed of a porous matrix and is most commonly in bead form. A wide variety of materials are used for chromatography matrices, both inorganic and organic materials. The demands on the matrix are several. It should be chemically and physically stable and be able to withstand extreme pH conditions. The matrix should be rigid to allow high flow rates in columns packed with particles of small diameters. It must also be possible to produce particles with a broad range of porosities.
The surface characteristics of the matrix is important. By introduction of new chemical structures on the surface of the matrix it is possible to design stationary phases which interact more or less specifically with a particular molecule. In chromatographic separation of proteins in aqueous solution the matrix is usually hydrophilic. In reversed phase chromatography (RPC) for peptide or protein separation, silica gels have been used as chromatography medium. Silica gels are rigid enough to withstand high flow rates and different hydrophobicities are available (C4, C8, C18). However, silica gels are not stable above pH 8.0 and hence can not be cleaned by using alkali. In stead it is common to use rigid matrices of organic polymers e.g. polymethacrylate or polystyrene/polystyrene-divinylbenzene. Polystyrene-divinylbenzene particles are hydrophobic in aqueous solutions and large amounts of organic solvents have to be used to eluate the absorbed molecules. The selectivity is also limited. Due to the fact that there is only a small variation in hydrophobicity of these particles, the use of them is limited. In contrast the ratio hydrophobicity/hydrofilicity of silica particles can be varied by chemical reactions. There are a large variety in chemistry available for modification of the hydrofilic silica surface. To increase the possibilities to use particles of polystyrene-divinylbenzene and other hydrophobic polymers, it is recognized that the surface of the particles must be modified to be more hydrophilic before they can be used as chromatographic separation medium. Different methods have been suggested for hydrophilisation of the surface of particles based on hydrophobic polymers:
WO 91/11241 relates to a method of producing a hydrophilic coating on a hydrophobic surface by which a compound comprising a hydrophobic and a hydrophilic domain is adsorbed on the surface. The draw backs with this method are several. The polymer to be adsorbed has a high molecular weight and therefore the polymer will not spread out evenly in all pores. The control of the pore size distribution is then lost and some pores may not even be coated at all. As the polymer coating is only adsorbed it may loosen from the surface at contacting with non-polar solvents. Therefore the coating must be cross-linked.
WO 95/23022 discloses a method of covalently bonding a hydrophilic coating on a hydrophobic surface. An unsaturated polymer coating is grafted to the surface via the unsaturated groups on the surface. Also with this method there is the same problem of obtaining the coating evenly distributed on the porous surface of the matrix.
Various uses of vinyl groups pending on vinyl benzene polymers have been reviewed during the priority year by Hubbard et al (Reactive Functional Polymers 36 (1998) 1-16 and 17-30). The use of pending vinyl groups for immobilizing a catalyst on a macroporous polystyrene resin has been described by Faber et al (Reactive Polymers 11 (1989) 117-126. Modifying chromatographic vinyl-benzene based supports by routes other than via residual vinyls has been described by Sun et al (J, Chromatog, 522 (1990) 95-105). Still another route has been described by Moberg et al (Reactive Polymers 15 (1991) 25-35).
OBJECTIVES OF THE INVENTION
The object of the present invention is to obtain improved coated polymer articles and improved methods of coating a polymer article to change the surface characteristics of the article without the draw backs of known methods.
A further object of the invention is to produce polymer particles with suitable surface characteristics for chromatographic use.
It is a further object of the invention to provide a coating which may be derivatized to produce a wide range of different functional groups for use in different types of chromatography. The intention is to be able to achieve a large variety in both hydrophobicity/hydrophilicity and selectivity and to reduce the amount of solvent used in the elution.
The demands on supports to be used in the synthesis of oligonucleotides and oligopeptides with respect to the balance between hydrophobicity and hydrophilicity are less critical than for chromatographic matrices, although it remains that maintaining open pores is important in order to maintain high capacity of a given porous support. The primary object in this aspect of the invention is to provide a simple well-defined way of introducing a handle in form of a primary or secondary amino group into a polymer support based on a hydrophobic polymer.
THE INVENTION
The objects of the invention are achieved by the polymer articles and methods defined in the claims. According to the invention a coated polymer article is obtained, which article is characterized in that the coating is covalently bound to the polymer surface via double bonds of the polymer. The article has the structure:
PLCH—CH
2
Y(R
2
)
p
X(R
1
)
p
where
P comprises the basic polymer structure of the article before coating and further groups
—L—CH(—X(R
1
)
p
)—CH
2
(—Y(R
2
)
p
);
L is a part of a pending group projecting from the basic polymer and comprising the double bonds utilized for introducing —X(R
1
)
p
and —Y(R
2
)
p
. It may be a single covalent link to the basic polymer or a benzene ring.
X and Y are independently selected from halogens, in particular Br, and N, S and O.R
1
is hydrogen, a straight, branched or cyclic alkyl or acyl group, such as C
1
-C
10
alkyl, C
1
-C
18
acyl, or R
2
when X is N, O or S with particular emphasis for X equals Y equals O.
R
2
is hydrogen, straight, branched or cyclic alkyl, such as C
1
-C
18
alkyl, —R
3
(—NH
2
)
q
, alkylaryl or arylalkyl in which the alkyl part may contain 1-18 carbon atoms,
—R
3
(—NH—CR
4
═O)
q
, —CR
4
═O, or poly lower alkyloxy groups that may have been terminally acylated or alkylated (e.g. —((CH
2
)
n
—O)
n
.OR′ where n is an integer 2, 3 or 4 and n′ is an integer 2-100 and an H in CH
2
may have been replaced with methyl and R′ may be any one of the expressly mentioned R
1
groups.
p=0 when Y=Br. p may be 1 when Y=O or S. p may be 2 when Y=N or S. p may be 3 for Y=N. In case there are more than one R
2
, they may be identical or different.
R
3
is a straight, cyclic or branched alkyl, —O—alkyl, hydroxyalkyl, phenylalkyl, with up to 18 carbon atoms in the alkyl part.
R
4
is a straight, branched or cyclic alkyl group, such as C
1
-C
18
alkyl.
q represents that one or more (1, 2, 3, 4 etc, i.e. 1-poly) hydrogens in a basic alkyl group R
3
may
Fonnum Geir
Hagen Steinar
Ringberg Rune
Amersham Pharmacia Biotech AB
Chisholm Robert F.
Kiliman L.
Ronning, Jr. Royal N.
Ryan Stephen G.
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