Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2001-08-15
2003-03-18
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S451000, C528S361000
Reexamination Certificate
active
06534599
ABSTRACT:
BACKGROUND OF INVENTION
i) Field of the Invention
This invention relates to macromers derived from the thermal degradation of poly(3-hydroxybutyrate), poly(3-hydroxyvalerate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); a process for their preparation, homopolymers and copolymers derived from the macromers the use of such homopolymers and copolymers to provide product having amphiphilic and biocompatible properties, for example, in drug delivery systems, polymer surfactants and biocompatible adjuvants.
ii) Description of Prior Art
Poly(3-hydroxybutyrate), PHB; poly(3-hydroxyvalerate), PHV; and poly(3-hydroxybutyrate-co-3-hydroxy-valerate), PHB/V, are aliphatic thermoplastic polyesters
[
1,2,3] of formulae I
a
, I
b
and I
c
, respectively:
Where n and m are integers indicating the number of repeat units, and p and q are mole % of each monomer randomly distributed
[
3]. Typically, n is an integer of 10 to 10,000,000, preferably 100 to 1,000,000; m is an integer of 10 to 200,000 preferably 60,000; p and q are each 0 to 100, and the summation p + q is 100.
PHB and PHB/V are poly(hydroxyalkanoates), PHAs, known as bacterial carbon and energy storage materials. They are biodegradable and biocompatible polymers produced by a large number of bacteria such as
Alcaligenes eutrophus
[
3,4,5], now called
Ralstonia eutropha
. PHB is brittle, which reduces its potential industrial applications, but the incorporation of 3-hydroxyvalerate repeat units has been shown to improve flexibility in the resulting copolymer by reducing crystallinity
[
3,6]. PHB and PHB/V are crystalline polymers, with melting points (T
m
) of ca. 180° C. for PHB and a range of 70 to ca 180° C. for the PHB/V copolymers
[
7,8].
PHB, PHV and PHB/V are &bgr;-polyesters, i.e. their &bgr;-carbons are substituted, which makes them thermally unstable at temperatures higher than their melting point
[
3].
SUMMARY OF THE INVENTION
It is an object of this invention to provide macromers derived from PHB, PHV and PHB/V, respectively.
It is a further object of this invention to provide a process for producing the aforementioned macromers.
It is another object of this invention to provide families of macromers which differ in end group functionality and/or in molecular weight.
It is still another object of this invention to provide macromers derived from the thermal degradation of poly(3-hydroxyalkanoate)s.
It is yet another object of this invention to provide homopolymers of the macromers.
It is still another object of this invention to provide copolymers of the macromers with one or more comonomers.
In accordance with one aspect of the invention, there is provided a macromer derived from thermal degradation of poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), or poly(3-hydroxybutyrate-co-3-hydroxyvalerate). In accordance with another aspect of the invention, there is provided a process of producing a macromer comprising thermally degrading poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), or poly(3-hydroxybutyrate-co-3-hydroxyvalerate).
In accordance with other aspects of the invention, there is provided a homopolymer of the macromer of the invention; a copolymer of the macromer of the invention and a comonomer; and a block copolymer of a macromer of the invention, and a block comonomer.
DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS
i) Production of Macromers
The present invention focuses on macromers of PHB, PHV and PHB/V, which are macromolecules of small size or length, typically between 1000 and 6000 g/mol, and their preparation by thermal degradation at a constant temperature.
Suitably, the thermal degradation is carried out at a temperature of 180° C. to 220° C.
In particular embodiments, PHB and copolymers of PHB/V having up to 21 mol% of hydroxyvalerate were treated at two different temperatures, 190-192° C. and 200-202° C., for a reaction time of 3.5 hrs, and then fractionated. The products obtained were then characterized by proton nuclear magnetic resonance spectroscopy (
1
H-NMR) and gel permeation chromatography (GPC). The copolymers were also degraded at 190+/−1° C. for reaction times of 3.5, 5, and 7 hrs, and the crude products were analysed by
1
H-NMR and GPC. The homopolymers PHB and PHV were analyzed also by positive fast atom bombardment mass spectrometry (FAB
+
-MS). The resulting macromers can be used as monomers for polymerization, for example, homopolymerization or copolymerization with one or more comonomers. Thermal degradation produces low molecular weight PHB and PHB/V containing one unsaturated end (Scheme
1
). At moderately high temperatures, the reaction proceeds by a random scission cis-elimination mechanism having a six-membered ring ester intermediate
[8,9,10]
, which is shown on Scheme
2
.
In Scheme
1
, the methyl sidegroup can be replaced by ethyl; the integer n is 10 to 10,000,000, preferably 100 to 1,000,000 when the terminal sidegroup is methyl.
The scale-up experiments were performed at 201° C. (average value), 3 hours and gave similar results to lab-scale reactions.
ii) Macromers
Polymer architecture is controlled by a wide variety of catalysts and synthesis strategies. The use of macromers of the invention to make architectures involving PHB, PHV and PHB/V blocks is enabled by the availability of alpha and omega functionally terminated low molecular weight poly(3-hydroxyalkanoates). The structure of the PHB polyester may be represented as:
where n is an integer indicating the number of repeat units. Suitably n is 10 to 10,000,000, preferably 100 to 1,000,000.
Specifically, the macromer can be used to make block and comb-like polymers and other architectures with amphiphilic and biocompatible properties for applications such as drug delivery, polymer surfactant, biocompatible adjuvant. The following molecular models A to E show some of the PHB macromers which can be produced:
The models A to E may be generally represented by formula II:
In formula II R′ is a PHB macromer end group providing a carboxyl or carboxylate alpha end; and R provides a propenyl omega end (Models A and B) or a beta hydroxyl or methoxide end (Models C, D and E). The designation
in formula II identifies repeating continuity of the PHB as shown in II above.
Various controlled chemical chain scissions and end group reactions can be used to create the above models A to E, including alkaline and acid hydrolysis as well as pyrolysis. Under certain conditions the reactions lead to narrow molecular weight macromers with yields of 70-90%.
Typically the macromers of the invention have a number average molecular weight of 1,000 to 6,000 g/mol.
Polymerization of Macromers and Block Copolymer Formation
Two major ways of polymerization from the macromers are possible, using the &bgr;-alkyl acrylate end group, or the carboxylic acid end group.
Polymerization by the unsaturated end group:
The particularity of the olefin end group is the &bgr;-substitution with a methyl, and its predominantly trans configuration.
The following equation represents the formation of a comb polymer from the &bgr;-methylacrylate macromer below by chemical linkage of macromers via a polymerization reaction at the double bond end, in which R is methyl as shown in models A and B but may also be ethyl, in the case of macromers from PHB/V or PHV or other terminal moiety as shown in models C, D and E. R
3
is the appropriate alpha moiety, such as indicated for formula II in the case of PHB.
The Group Transfer polymerization may be employed to polymerize the macromers. Ute et al. reported the polymerization of trans-methylcrotonate 1 via this method, using 1-methoxy-1-(trimethylsiloxy)-2-methyl-1-propene 2 with catalytic amounts of HgI
2
and (CH
3
)
3
SiI in CH
2
Cl
2
. [Ute et al.
Polymer Journal
1997, 29, 11, 957-958, also 1999, 31, 2, 177-183].
Polymerization by the carboxylic acid end group:
A possible approach involves the modification of the carboxylic acid end group to increase the reactivity of the macromers towa
Marchessault Robert H.
Nguyen Sophie
Yu Ga-Er
(Ogilvy Renault)
Asinovsky Olga
McGill University
Seidleck James J.
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