U.S. patent application number 09/885085 was filed with the patent office on 2002-03-07 for polymers and polymerization processes.
Invention is credited to Barnette, Deborah, Branham, Keith, English, James, Hall, Donna, Land, Reuben, Mink, Doug, Zhao, Zhong.
Application Number | 20020028911 09/885085 |
Document ID | / |
Family ID | 26911026 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028911 |
Kind Code |
A1 |
Barnette, Deborah ; et
al. |
March 7, 2002 |
Polymers and polymerization processes
Abstract
The present invention provides improved processes for purifying
polymer preparations by removing contaminants, such as metal
contaminants. The present invention also provides improved
processes for producing phosphopolymers, which can yield improved
polymers in terms of molecular weight, homogeneity, consistency and
purity. Polymers and polymer preparations also are provided. The
present invention is time, labor and energy efficient, and thus
marks an improvement over past approaches.
Inventors: |
Barnette, Deborah; (Ellicott
City, MD) ; English, James; (Chelsea, AL) ;
Branham, Keith; (Pelham, AL) ; Hall, Donna;
(Verbena, AL) ; Land, Reuben; (Huntingtown,
MD) ; Mink, Doug; (Baltimore, MD) ; Zhao,
Zhong; (Ellicott City, MD) |
Correspondence
Address: |
HELLER EHRMAN WHITE & MCAULIFFE
SUITE 300
1666 K STREET, N.W.
WASHINGTON
DC
20006
US
|
Family ID: |
26911026 |
Appl. No.: |
09/885085 |
Filed: |
June 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60228729 |
Aug 29, 2000 |
|
|
|
60216462 |
Jul 6, 2000 |
|
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Current U.S.
Class: |
528/400 ; 521/25;
528/354; 528/356; 528/398; 528/482; 528/486; 528/487; 528/495 |
Current CPC
Class: |
C08G 63/90 20130101;
C08G 63/692 20130101 |
Class at
Publication: |
528/400 ;
528/398; 528/354; 528/356; 528/482; 528/486; 528/487; 528/495;
521/25 |
International
Class: |
C08G 079/02; C08G
063/08; C08G 063/692; C08G 063/90 |
Claims
What is claimed is:
1. A method of producing a polyphosphoester, comprising: reacting a
prepolymer with an organophosphorous compound in the presence of at
least one acid scavenger until substantially all of the
organophosphorous compound has bound with the prepolymer to form a
polyphosphoester; and purifyng the polyphosphoester.
2. The method according to claim 1, wherein the reaction is
quenched with an alcohol prior to the purification.
3. The method according to claim 1, wherein the reaction is
performed at a warm temperature.
4. The method according to claim 1, wherein the reaction is
performed at a cold temperature.
5. The method according to claim 1, wherein the purification
employs at least one ion exchange resin.
6. The method according to claim 1, wherein the prepolymer is
formed from one or more selected from the group consisting of
D,L-lactide, trimethylene chloride, L-lactide, caproloactone,
dioxanone, propylene glycol, ethylene glycol, 1,6 hexanediol,
glycolide, 1,4-cyclohexane dimethanol, terephthaloyl chloride and
bis(hydroxyethyl) terephthalate.
7. The method according to claim 1, wherein the organophosphorous
compound is selected from the group consisting of alkyl
dichlorophosphates, alkyl dichlorophosphonates, alkyl
dichlorophosphites, aryl dichlorophosphates, aryl
dichlorophosphonates, aryl dichlorophosphites, alkylaryl
dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl
dichlorophosphites.
8. The method according to claim 7, wherein the organophosphorous
compound is selected from the group consisting of ethyl
dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate, and hexyl dichlorophosphonate.
9. The method according to claim 1, wherein the polyphosphoester is
biodegradable.
10. A polyphosphoester obtainable by: reacting a prepolymer with an
organophosphorous compound in the presence of at least one acid
scavenger until substantially all of the organophosphorous compound
has bound with the prepolymer to form a polyphosphoester; and
purifying the polyphosphoester.
11. The polyphosphoester according to claim 10, wherein the
reaction is quenched with an alcohol prior to the purification.
12. The polyphosphoester according to claim 10, wherein the
reaction is performed at a warm temperature.
13. The polyphosphoester according to claim 10, wherein the
reaction is performed at a cold temperature.
14. The polyphosphoester according to claim 10, wherein the
purification employs at least one ion exchange resin.
15. The polyphosphoester according to claim 10, wherein the
prepolymer is formed from one or more selected from the group
consisting of D,L-lactide, trimethylene chloride, L-lactide,
caproloactone, dioxanone, propylene glycol, ethylene glycol, 1,6
hexanediol, glycolide, 1,4-cyclohexane dimethanol, terephthaloyl
chloride and bis(hydroxyethyl) terephthalate.
16. The polyphosphoester according to claim 10, wherein the
organophosphorous compound is selected from the group consisting of
alkyl dichlorophosphates, alkyl dichlorophosphonates, alkyl
dichlorophosphites, aryl dichlorophosphates, aryl
dichlorophosphonates, aryl dichlorophosphites, alkylaryl
dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl
dichlorophosphites.
17. The polyphosphoester according to claim 10, wherein the
organophosphorous compound is selected from the group consisting of
ethyl dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate and hexyl dichlorophosphonate.
18. The polyphosphoester according to claim 10, wherein the
polyphosphoester is biodegradable.
19. A method of producing a polyphosphoester, comprising: reacting
a prepolymer with an organophosphorous compound in the presence of
at least one acid scavenger at a cold temperature until
substantially all of the organophosphorous compound has bound with
the prepolymer to form a polyphosphoester; stopping the reaction;
contacting the polyphosphoester with at least one ion exchange
resin; and removing the ion exchange resin to yield a purified
polyphosphoester.
20. The method according to claim 19, wherein the reaction is
stopped by quenching with an alcohol.
21. The method according to claim 19, wherein the polyphosphoester
is contacted with an acidic ion exchange resin and a basic ion
exchange resin.
22. The method according to claim 19, further comprising
concentrating the polyphosphoester; precipitating the
polyphosphoester; and drying the polyphosphoester.
23. The method according to claim 19, wherein the prepolymer is
formed from one or more selected from the group consisting of
D,L-lactide, trimethylene chloride, L-lactide, caproloactone,
dioxanone, propylene glycol, ethylene glycol, 1,6 hexanediol,
glycolide, 1,4-cyclohexane dimethanol, terephthaloyl chloride and
bis(hydroxyethyl) terephthalate.
24. The method according to claim 19, wherein the organophosphorous
compound is selected from the group consisting of alkyl
dichlorophosphates, alkyl dichlorophosphonates, alkyl
dichlorophosphites, aryl dichlorophosphates, aryl
dichlorophosphonates, aryl dichlorophosphites, alkylaryl
dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl
dichlorophosphites.
25. The method according to claim 24, wherein the organophosphorous
compound is selected from the group consisting of ethyl
dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate and hexyl dichlorophosphonate.
26. The method according to claim 19, wherein the at least 50% of
the contaminants are removed by the ion exchange resin.
27. The method according to claim 19, wherein the at least 70% of
the contaminants are removed by the ion exchange resin.
28. The method according to claim 19, wherein the at least 90% of
the contaminants are removed by the ion exchange resin.
29. The method according to claim 19, wherein the purified
polyphosphoester has a metal content of less than 20 ppm.
30. The method according to claim 19, wherein the purified
polyphosphoester has a metal content of less than 10 ppm.
31. The method according to claim 19, wherein the purified
polyphosphoester has a metal content of less than 5 ppm.
32. The method according to claim 19, wherein the polyphosphoester
is biodegradable.
33. A polyphosphoester obtainable by: reacting a prepolymer with an
organophosphorous compound in the presence of at least one acid
scavenger at a cold temperature until substantially all of the
organophosphorous compound has bound with the prepolymer to form a
polyphosphoester; stopping the reaction; contacting the
polyphosphoester with at least one ion exchange resin; and removing
the ion exchange resin.
34. The polyphosphoester according to claim 33, wherein the
polyphosphoester is contacted with an acidic ion exchange resin and
a basic ion exchange resin.
35. The polyphosphoester according to claim 33, further comprising
concentrating the polyphosphoester; precipitating the
polyphosphoester; and drying the polyphosphoester.
36. The polyphosphoester according to claim 33, wherein the
prepolymer is formed from one or more selected from the group
consisting of D,L-lactide, trimethylene chloride, L-lactide,
caproloactone, dioxanone, propylene glycol, ethylene glycol, 1,6
hexanediol, glycolide, 1 ,4-cyclohexane dimethanol, terephthaloyl
chloride and bis(hydroxyethyl) terephthalate.
37. The polyphosphoester according to claim 33, wherein the
organophosphorous compound is selected from the group consisting of
alkyl dichlorophosphates, alkyl dichlorophosphonates, alkyl
dichlorophosphites, aryl dichlorophosphates, aryl
dichlorophosphonates, aryl dichlorophosphites, alkylaryl
dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl
dichlorophosphites.
38. The polyphosphoester according to claim 33, wherein the
organophosphorous compound is selected from the group consisting of
ethyl dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate and hexyl dichlorophosphonate.
39. The polyphosphoester according to claim 33, wherein the
polyphosphoester has a metal content of less than 20 ppm.
40. The polyphosphoester according to claim 33, wherein the
polyphosphoester has a metal content of less than 10 ppm.
41. The polyphosphoester according to claim 33, wherein the
polyphosphoester has a metal content of less than 5 ppm.
42. The polyphosphoester according to claim 33, wherein the
polyphosphoester is biodegradable.
43. A method of producing a polyphosphoester, comprising: reacting
a prepolymer with an organophosphorous compound in the presence of
one or more acid scavengers until substantially all of the
organophosphorous compound has bound with the prepolymer to form a
polyphosphoester, wherein at least one of the acid scavengers is a
substituted aminopyridine; and purifying the polyphosphoester.
44. The method according to claim 43, wherein the reaction is
performed at a warm temperature.
45. The method according to claim 43, wherein the reaction is
performed at a cold temperature.
46. The method according to claim 43, wherein the purification
employs at least one ion exchange resin.
47. A polyphosphoester obtainable by: reacting a prepolymer with an
organophosphorous compound in the presence of one or more acid
scavengers until substantially all of the organophosphorous
compound has bound with the prepolymer to form a polyphosphoester,
wherein at least one of the acid scavengers is a substituted
aminopyridine; and purifying the polyphosphoester.
48. The polyphosphoester according to claim 47, wherein the
reaction is performed at a warm temperature.
49. The polyphosphoester according to claim 47, wherein the
reaction is performed at a cold temperature.
50. The polyphosphoester according to claim 47, wherein the
purification employs at least one ion exchange resin.
51. A method of purifying a polymer preparation, comprising
contacting the polymer preparation with at least one ion exchange
resin.
52. The method according to claim 51, wherein the polymer
preparation is contacted with an acidic resin and a basic
resin.
53. The method according to claim 51, wherein the acidic resin is a
strong acidic resin, and the basic resin is a weak basic resin.
54. The method according to claim 51, wherein the ion exchange
resin removes metal contaminants from the polymer preparation.
55. The method according to claim 54, wherein the metal
contaminants are selected from the group consisting of tin and
zinc.
56. The method according to claim 55, wherein the polymer has a
metal content of less than 20 ppm.
57. The method according to claim 55, wherein the polymer has a
metal content of less than 10 ppm.
58. The method according to claim 55, wherein the polymer has a
metal content of less than 5 ppm.
59. A polymer preparation having a reduced level of metal
contaminants, wherein the polymer preparation is obtainable by
contacting the polymer preparation with at least one ion exchange
resin.
60. The polymer preparation according to claim 59, wherein the
polymer preparation is contacted with an acidic resin and a basic
resin.
61. The polymer preparation according to claim 60, wherein the
acidic resin is a strong acidic resin, and the basic resin is a
weak basic resin.
62. The polymer preparation according to claim 59, wherein the
metal contaminants are selected from the group consisting of tin
and zinc.
63. The polymer according to claim 59, wherein the polymer has a
metal content of less than 20 ppm.
64. The method according to claim 59, wherein the polymer has a
metal content of less than 10 ppm.
65. The method according to claim 59, wherein the polymer has a
metal content of less than 5 ppm.
66. A method of producing a polyphosphoester, comprising: reacting
a prepolymer with an organophosphorous compound in the presence of
at least one acid scavenger at a cold temperature until
substantially all of the organophosphorous compound has bound with
the prepolymer to form a polyphosphoester; stopping the reaction;
contacting the polyphosphoester with an acidic ion exchange resin
and a basic ion exchange resin; and removing the acidic and basic
ion exchange resins to yield a purified polyphosphester that has a
reduced level of metal contaminants.
67. The method according to claim 66, wherein the metal
contaminants are selected from the group consisting of tin and
zinc.
68. A method of producing a polyphosphoester comprising reacting a
diol with an organophosphorus compound in the presence of at least
one acid scavenger until substantially all of the organophosphorus
compound has bound with the diol to form a polyphosphoester, and
purifying the polyphosphoester.
Description
[0001] This application claims priority to U.S. Ser. No.
60/228,729, filed Aug. 29, 2000, and U.S. Ser. No. 60/216,462,
filed Jul. 6, 2000.
[0002] The present invention relates to improved polymers and
polymerization processes, and are particularly suitable for
producing polymers for a variety of uses, including
pharmaceuticals, medical devices, food packaging materials and the
like. The improved polymers have reduced levels of contaminants as
compared to the commercial polymers currently available, as
demonstrated below, and thus are ideal for situations where the
polymer, or compositions in contact with the polymer, are injected
or inserted into, placed within or on, and/or ingested by a living
organism. The ability to reduce contaminant levels according to the
invention permits greater flexibility in terms of polymerization
reaction conditions, including types and amount of catalysts and
reactants, as well as expanding the fields of use for polymers and
polymer preparations. See U.S. Ser. No. 60/228,729, the entirety of
which is hereby incorporated by reference.
[0003] The present invention also relates to various polymers,
which include the phosphopolymers, which are polymers containing
phosphorous linkages. Phosphopolymers include the polyphosphoester
polymers ("polyphosphoesters"). These polymers are considered to be
biodegradeable polymers having phosphorous-based linkages.
[0004] Polyphosphoesters contain phosphate ester bonds, phosphonate
ester bonds and/or phosphite ester bonds. Certain polyphosphoesters
have hydrolyzable bonds, and as such are considered useful in in
vivo contexts because they are biodegradable/biocompatible--at
least in part by virtue of the labile phosphoester bond in the
polymer backbone. New and useful biodegradable phosphopolymers have
previously been produced. See U.S. Pat. Nos. 5,952,451 and
6,008,318; and PCT publications WO 98/44020, WO 98/44021, and WO
98/48859, which are hereby incorporated by reference in their
entirety.
[0005] Polyphosphoesters have been produced using bulk melt
polymerization processes, such as polymerizations using L-lactide,
ethylene glycol and ethyl phosphorodichloridate: 1
[0006] This example is Poly(L-lactide-co-ethyl phosphate), referred
to as Poly(LA-EG-EOP).
[0007] Similar approaches have been used to form
Poly(L-lactide-co-hexyl phosphate), referred to as Poly(LAEG-HOP),
except that hexyl phosphodichloridate (HOP) substitutes for ethyl
phosphorodichloridate (EOP). The polymer is depicted below: 2
[0008] Many previous production methodologies have been
comparatively energy and time consuming in terms of overall yield.
Accordingly, there is a desire to improve production methodologies
to provide greater efficiency and control over the polymerization
process. The invention disclosed herein provides improved
production methodologies, which result in more efficient
production, enhanced purity, better polymer properties, increased
yields and improved control over molecular weight and other
properties.
[0009] For convenience, before further description of the present
invention, certain terms employed in the specification, examples,
and appended claims are collected and explained here. These
definitions should be read in light of the remainder of the
disclosure and understood as by a person of skill in the art.
[0010] The terms "biocompatible polymer" and "biocompatibility," in
their various grammatical forms, when used in relation to polymers
are art-recognized. For example, biocompatible polymers include
polymers that are neither themselves toxic to the host (e.g., an
animal or human), nor degrade (if the polymer degrades) at a rate
that produces monomeric or oligomeric subunits or other byproducts
at toxic concentrations in the host. In certain embodiments of the
present invention, biodegradation generally involves degradation of
the polymer in an organism, e.g., into its monomeric subunits,
which may be known to be effectively non-toxic. Intermediate
oligomeric products resulting from such degradation may have
different toxicological properties in some instances, however, or
biodegradation may involve oxidation or other biochemical reactions
that generate molecules other than monomeric subunits of the
polymer. Consequently, it may be desired in some circumstances to
evaluate the toxicology of a biodegradable polymer intended for in
vivo use, such as implantation or injection into a patient, which
may be readily determined after one or more toxicity analyses. It
is not necessary that any subject composition have a purity of 100%
to be deemed biocompatible; indeed, it is only necessary that the
subject compositions be biocompatible as set forth above. Hence, a
subject composition may comprise a polymer comprising 99%, 98%,
97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible
polymers, e.g., including polymers and other materials and
excipients described herein, and still be biocompatible.
[0011] As mentioned above, to determine whether a polymer or other
material is biocompatible, it may be desirable to conduct a
toxicity analysis. Such assays are well known in the art, and are
performed routinely. One example of such an assay may be performed
with live carcinoma cells, such as GT3TKB tumor cells, in the
following manner: the sample is degraded in 1M NaOH at 37.degree.
C. until complete degradation is observed. The solution is then
neutralized with 1M HCl. About 200 .mu.L of various concentrations
of the degraded sample products are placed in 96-well tissue
culture plates and seeded with human gastric carcinoma cells
(GT3TKB) at 10.sup.4/well density. The degraded sample products are
incubated with the GT3TKB cells for 48 hours. The results of the
assay may be plotted as % relative growth vs. concentration of
degraded sample in the tissue-culture well. In addition, polymers
and formulations of the present invention may also be evaluated by
well-known in vivo tests, such as subcutaneous implantations in
rats to confirm that they hydrolyze without significant levels of
irritation or inflammation at the subcutaneous implantation
sites.
[0012] In certain embodiments, polymeric formulations of the
present invention biodegrade within a period that is acceptable in
the desired application. In certain embodiments, such as in vivo
therapy, such degradation occurs in a period usually less than
about five years, one year, six months, three months, one month,
fifteen days, five days, three days, or even one day on exposure to
a physiological solution with a pH between 6 and 8 having a
temperature of between 25 and 37.degree. C. In other embodiments,
the polymer degrades in a period of between about one hour and
several weeks, depending on the desired application.
[0013] The term "biodegradable," in its various grammatical forms,
is art-recognized, and includes polymers, compositions and
formulations, such as those described herein, that are intended to
degrade during use. Biodegradable polymers typically differ from
non-biodegradable polymers in that the former may be degraded
during use. In certain embodiments, such use involves in vivo use,
such as in vivo therapy, and in other certain embodiments, such use
involves in vitro use. In general, degradation attributable to
biodegradability involves the degradation of a biodegradable
polymer into its component subunits, or digestion, e.g., by a
biochemical process, of the polymer into smaller, non-polymeric
subunits. In certain embodiments, two different types of
biodegradation may generally be identified. For example, one type
of biodegradation may involve cleavage of bonds (whether covalent
or otherwise) in the polymer backbone. In such biodegradation,
monomers and oligomers typically result, and even more typically,
such biodegradation occurs by cleavage of a bond connecting one or
more of subunits of a polymer. In contrast, another type of
biodegradation may involve cleavage of a bond (whether covalent or
otherwise) internal to side chain or that connects a side chain to
the polymer backbone. For example, a therapeutic agent or other
chemical moiety attached as a side chain to the polymer backbone
may be released by biodegradation. In certain embodiments, one or
the other or both generally types of biodegradation may occur
during use of a polymer. As used herein, the term "biodegradation"
encompasses both general types of biodegradation.
[0014] The degradation rate of a biodegradable polymer often
depends in part on a variety of factors, including the chemical
identity of the linkage responsible for any degradation, the
molecular weight, crystallinity, biostability, and degree of
cross-linking of such polymer, the physical characteristics of the
implant, shape and size, and the mode and location of
administration. For example, the greater the molecular weight, the
higher the degree of crystallinity, and/or the greater the
biostability, the biodegradation of any biodegradable polymer is
usually slower. The term "biodegradable" is intended to cover
materials and processes also termed "bioerodible".
[0015] In certain embodiments, if the biodegradable polymer also
has a therapeutic agent or other material associated with it, the
biodegradation rate of such polymer may be characterized by a
release rate of such materials. In such circumstances, the
biodegradation rate may depend on not only the chemical identity
and physical characteristics of the polymer, but also on the
identity of any such material incorporated therein.
[0016] A variety of polymers may be used in the subject invention.
Both non-biodegradable and biodegradable polymers may be used in
the subject invention, although biodegradable polymers in certain
contexts are preferred. As discussed below, the choice of polymer
will depend in part on a variety of physical and chemical
characteristics of such polymer and the use to which such polymer
may be put.
[0017] In certain embodiments, polymers having phosphorus linkages
may be used in the subject invention. Exemplary phosphorus linkages
in such polymers include, without limitation, phosphonamidite,
phosphoramidite, phosphorodiamidate, phosphomonoester,
phosphodiester, phosphotriester, phosphonate, phosphonate ester,
phosphorothioate, thiophosphate ester, phosphinate or phosphite.
Any of the subject polymers may be provided as copolymers,
terpolymers, etc. Certain of such polymers may be biodegradable,
biocompatible or both.
[0018] The structure of certain of the foregoing polymers having
phosphorus linkages may be identified as follows. The term
"biodegradable polymer having phosphorous-based linkages" is used
herein to refer to polymers in which the following substructure is
present at least a multiplicity of times in the backbone of such
polymer: 3
[0019] wherein, independently for each occurrence of such
substructure:
[0020] X1, each independently, represents --O-- or --N(R5)--;
[0021] R5 represents --H, aryl, alkenyl or alkyl; and
[0022] R6 is any non-interfering substituent,
[0023] wherein such substructure is responsible in part for
biodegradability properties observed for such polymer in vitro or
in vivo. In certain embodiments, R6 may represent an alkyl,
aralkyl, alkoxy, alkylthio, or alkylamino group.
[0024] In certain embodiments, such a biodegradable polymer is
non-naturally occurring, i.e., a man-made product with no natural
source. In other embodiments, R6 is not --OH or halogen, e.g., is
an alkyl, aralkyl, aryl, alkoxyl, aryloxy, or aralkyloxy. In still
other embodiments, the two X1 moieties in such substructure are the
same. For general guidance, when reference is made to the "polymer
backbone chain" or the like of a polymer, with reference to the
above structure, such polymer backbone chain comprises the motif
[--X1--P--X1--]. In other polymers, the polymer backbone chain may
vary as recognized by one of skill in the art.
[0025] By way of example, but not limitation, a number of
representative polymers having phosphorus linkages are described in
greater detail below. In certain embodiments, a polymer includes
one or more monomeric units of Formula II: 4
[0026] wherein, independently for each occurrence of such unit:
[0027] X1, each independently, represents --O-- or --N(R7)--;
[0028] R7 represents --H, aryl, alkenyl or alkyl;
[0029] L1 is described below;
[0030] R8 represents, for example, --H, alkyl, --O-alkyl,
--O-cycloalkyl, aryl, --O-aryl, heterocycle, --O-heterocycle, --Cl,
--N(R9)R10 and other examples presented below;
[0031] R9 and R10, each independently, represent a hydrogen, an
alkyl, an alkenyl, --(CH.sub.2)n-R11, or R9 and R10, taken together
with the N atom to which they are attached complete a heterocycle
having from 4 to about 8 atoms in the ring structure; and
[0032] R11 represents --H, alkyl, aryl, cycloalkyl, cycloalkenyl,
heterocycle or polycycle.
[0033] L1 may be any chemical moiety as long as it does not
materially interfere with the polymerization or biodegradation (or
both) of the polymer, wherein a "material interference" or
"non-interfering substituent" is understood to mean, for synthesis
of the polymer by polymerization, an inability to prepare the
subject polymer by methods known in the art or taught herein, and
for biodegradation, a reduction in the biodegradation of the
subject polymer so as to make such polymer impracticable for
biodegradation.
[0034] In certain embodiments, L1 is an organic moiety, such as a
divalent branched or straight chain or cyclic aliphatic group or
divalent aryl group, with in certain embodiments, from 1 to about
20 carbon atoms. In certain embodiments, L1 represents a moiety
between about 2 and 20 atoms selected from carbon, oxygen, sulfur,
and nitrogen, wherein at least 60% of the atoms are carbon. In
certain embodiments, L1 may be an alkylene group, such as
methylene, ethylene, 1,2-dimethylethylene, n-propylene,
isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene,
n-heptylene; an alkenylene group such as ethenylene, propenylene,
2-(3-propenyl)-dodecylene; and an alkynylene group such as
ethynylene, proynylene, 1-(4-butynyl)-3-methyldecylene; and the
like. Such unsaturated aliphatic groups may be used to cross-link
certain embodiments of the present invention.
[0035] Further, L1 may be a cycloaliphatic group, such as
cyclopentylene, 2-methylcyclopentylene, cyclohexylene,
cyclohexylenedimethylene, cyclohexenylene and the like. L1 may also
be a divalent aryl group, such as phenylene, benzylene,
naphthalene, phenanthrenylene and the like. Further, L1 may be a
divalent heterocyclic group, such as pyrrolylene, furanylene,
thiophenylene, alkylyene-pyrrolylene-alkylene, pyridinylene,
pyrimidinylene and the like.
[0036] Other examples of L1 may include any of the polymers listed
above, including the biodegradable polymers listed above, and in
particular polylactide, polyglycolide, polycaprolactone,
polycarbonate, polyethylene terephthalate, polyanhydride and
polyorthoester, and polymers of ethylene glycol, propylene glycol
and the like. Embodiments containing such polymers for L1 may
impart a variety of desired physical and chemical properties.
[0037] The foregoing, as with other moieties described herein, may
be substituted with a non-interfering substituent, for example, a
hydroxy-, halogen-, or nitrogen-substituted moiety.
[0038] R8 represents hydrogen, alkyl, cycloakyl, --O-alkyl,
--O-cycloalkyl, aryl, --O-aryl, heterocycle, --O-heterocycle, or
--N(R9)R10. Examples of possible alkyl R8 groups include methyl,
ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, --C.sub.8H.sub.17
and the like groups; and alkyl substituted with a non-interfering
substituent, such as hydroxy, halogen, alkoxy or nitro;
corresponding alkoxy groups.
[0039] When R8 is aryl or the corresponding aryloxy group, it
typically contains from about 5 to about 14 carbon atoms, or about
5 to about 12 carbon atoms, and optionally, may contain one or more
rings that are fused to each other. Examples of particularly
suitable aromatic groups include phenyl, phenoxy, naphthyl,
anthracenyl, phenanthrenyl and the like.
[0040] When R8 is heterocyclic or heterocycloxy, it typically
contains from about 5 to about 14 ring atoms, alternatively from
about 5 to about 12 ring atoms, and one or more heteroatoms.
Examples of suitable heterocyclic groups include furan, thiophene,
pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole,
1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, isothiazole,
1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole,
1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole,
1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole,
1,2,5-oxatriazole, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone,
1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine,
pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine,
1,2,3-triazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, o-isoxazine,
p-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine,
1,4,2-oxadiazine, 1,3,5-oxadiazine, azepine, oxepin, thiepin,
indene, isoindene, benzofuran, isobenzofuran, thionaphthene,
isothionaphthene, indole, indolenine, 2-isobenzazole, isoindazole,
indoxazine, benzoxazole, anthranil, 1,2-benzopyran,
1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone,
quinoline, isoquinoline, 12,-benzodiazine, 1,3-benzodiazine,
naphthyridine, pyrido-[3,4-b]-pyridine, pyrido-[3,2-b]-pyridine,
pyrido-[4,3-b]-pyridine- , 1,3,2-benzoxazine, 1,4,2-benzoxazine,
2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine,
1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the
like. In certain embodiments, when R8 is heterocyclic or
heterocycloxy, it is selected from the group consisting of furan,
pyridine, N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene,
anthracene and purine rings.
[0041] In certain embodiments, R8 is an alkyl group, an alkoxy
group, a phenyl group, a phenoxy group, a heterocycloxy group, or
an ethoxy group.
[0042] In still other embodiments, R8, such as an alkyl, may be
conjugated to a bioactive substance to form a pendant drug delivery
system.
[0043] In certain embodiments, the number n in Formula II and other
subject formulas ranges over a wide range, e.g., from about 5 to
25,000 or more, but generally from about 100 to 5000, or 10,000.
Alternatively, in other embodiments, n may be about 10, 25, 50, 75,
100, 150, 200, 300 or 400.
[0044] In Formula II and other formulas herein, "*" represents
other monomeric units of the subject polymer, which may be the same
or different from the unit depicted in the formula in question, or
a chain terminating group, by which the polymer terminates.
Examples of such chain terminating groups include monofunctional
alcohols and amines.
[0045] In another aspect, the polymeric compositions of the present
invention include one or more recurring monomeric units represented
in general Formula III: 5
[0046] wherein Z1 and Z2, respectively, for each independent
occurrence is: 6
[0047] wherein, independently for each occurrence set forth
above:
[0048] Q1, Q2 . . . Qs, each independently, represent O or
N(R1);
[0049] X1, X2 . . . Xs, each independently, represent --O-- or
--N(R1);
[0050] the sum of t1, t2 . . . ts is an integer and at least one or
more;
[0051] Y1 represents --O--, --S-- or --N(R7)--;
[0052] x and y are each independently integers from 1 to about 1000
or more;
[0053] L1 and M1, M2 . . . Ms each independently, represent the
moieties discussed below; and
[0054] the other moieties are as defined above.
[0055] M1, M2 . . . Ms (collectively, M) in Formula III are each
independently any chemical moiety as long as it does not materially
interfere with the polymerization or biodegradation (or both) of
the polymer. For certain embodiments, M in the formula are each
independently: (i) a branched or straight chain aliphatic or aryl
group having from 1 to about 50 carbon atoms, or (ii) a branched or
straight chain, oxa-, thia-, or aza-aliphatic group having from 1
to about 50 carbon atoms. In certain embodiments, the number of
such carbon atoms does not exceed 20. In other embodiments, M may
be any divalent aliphatic moiety having from 1 to about 20 carbon
atoms, including therein from 1 to about 7 carbon atoms, that does
not cause any material interference with the polymerization or
biodegradation (or both) of the subject polymer.
[0056] M may include an aromatic or heteroaromatic moiety,
optionally with non-interfering substituents. In certain
embodiments, none of the atoms (usually but not always C) that form
the cyclic ring that gives rise to the aromatic moiety are part of
the polymer backbone chain.
[0057] Specifically, when M is a branched or straight chain
aliphatic group having from 1 to about 20 carbon atoms, it may be,
for example, an alkylene group such as methylene, ethylene,
1-methylethylene, 1,2-dimethylethylene, n-propylene, trimethylene,
isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene,
n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene,
n-dodecylene, and the like; an alkenylene group such as
n-propenylene, 2-vinylpropylene, n-butenylene, 3-thexylbutylene,
n-pentenylene, 4-(3-propenyl)hexylene, n-octenylene,
1-(4-butenyl)-3-methyldecylene, 2-(3-propenyl)dodecylene,
hexadecenylene and the like; an alkynylene group, such as
ethynylene, propynylene, 3-(2-ethynyl)pentylene, n-hexynylene,
2-(2-propynyl)decylene, and the like; or any alkylene, alkenylene
or alkynylene group, including those listed above, substituted with
a materially non-interfering substituent, for example, a hydroxy,
halogen or nitrogen group, such as 2-chloro-n-decylene,
1-hydroxy-3-ethenylbutylene, 2-propyl-6-nitro-10-dod- ecynylene,
and the like. Other M of the present invention include
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.5-- and
(CH.sub.2).sub.2OOCH.sub.2- --.
[0058] When M is a branched or straight chain oxaaliphatic group
having from 1 to about 20 carbon atoms, it may be, for example, a
divalent alkoxylene group, such as ethoxylene, 2-methylethoxylene,
propoxylene, butoxylene, pentoxylene, dodecyloxylene,
hexadecyloxylene, and the like. When M is a branched or straight
chain oxaaliphatic group, it may have the formula
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b-- wherein each of a and b,
independently, is about 1 to about 7.
[0059] When M is a branched or straight chain oxaaliphatic group
having from 1 to about 20 carbon atoms, it may also be, for
example, a dioxaalkylene group such as dioxymethylene,
dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene,
1,3-dioxy-2-methylpropy- lene, dioxy-n-pentylene,
dioxy-n-octadecylene, methoxylene-methoxylene,
ethoxylene-methoxylene, ethoxylene-ethoxylene,
ethoxylene-1-propoxylene, butoxylene-n-propoxylene,
pentadecyloxylene-methoxylene, and the like. When M is a branched
or straight chain, dioxyaliphatic group, it may have the formula
--(CH.sub.2).sub.a--O--(CH.sub.2).sub.b--O--(CH.sub.2)c--, wherein
each of a, b, and c is independently from 1 to about 7.
[0060] When M is a branched or straight chain thiaaliphatic group,
the group may be any of the preceding oxaaliphatic groups wherein
the oxygen atoms are replaced by sulfur atoms.
[0061] When M is a branched or straight chain, aza-aliphatic group
having from 1 to about 20 carbon atoms, it may be a divalent group
such as --CH.sub.2NHCH.sub.2--, --(CH.sub.2).sub.2NCH.sub.2--,
--CH.sub.2(C.sub.2H.sub.5)NCH.sub.2CH.sub.2--,
-n-C.sub.4H.sub.9NHCH.sub.- 2--,
-t-C.sub.4H.sub.9NHCH.sub.2CH.sub.2--,
--CH.sub.2(C.sub.3H.sub.7)N(CH- .sub.2).sub.4--,
--C.sub.2H.sub.5(C.sub.2H.sub.5)NCH.sub.2--,
--CH.sub.2(C.sub.8H.sub.17)NCH.sub.2CH.sub.2--, and the like. When
M is a branched or straight chain, amino-aliphatic group, it may
have the formula --(CH.sub.2).sub.aN(R1)(CH.sub.2).sub.b-- where R1
is --H, aryl, alkenyl or alkyl and each of a and b is independently
from about 1 to about 7.
[0062] x and y of Formula III each independently represent integers
in the range of about 1 to about 1000, e.g., about 1, about 10,
about 20, about 50, about 100, about 250, about 500, about 750,
about 1000, etc.
[0063] The molar ratio of n:(x or y) in Formula III may vary
greatly, typically between about 200:1 and 1:200. In certain
embodiments, the ratio n:(x or y) is from about 100:1 to about
1:100, from about 50:1 to about 1:50, and alternatively, from about
25:1 to about 1:25. In certain embodiments, the ratio of n:x to n:y
need not be the same. The molar ratio of x:y may also vary;
typically, such ratio is about 1. Other possible embodiments may
have ratios of 0.1, 0.25, 0.5, 0.75, 1.5, 2, 3, 4, 10 and the
like.
[0064] A number of different polymer structures are contemplated by
Formula III. For example, in certain polymers exemplified by
Formula III, when the sum of t1, t2 . . . ts equals one for each of
Z1 and Z2 and Q, M and X for each subunit ts are the same, then
Formula III becomes the following Formula IIIa: 7
[0065] In certain embodiments of Formula IIIa (and other subject
formulas), x and y may be even integers.
[0066] The above Formula III (and all of the subject formulae and
polymers) encompass a variety of different polymer structures,
including block copolymers, random copolymers, random terpolymers
and segmented block copolymers and terpolymers. Additional
structures for Z of subject monomeric units are set forth below,
which exemplify in part the variety of structures contemplated by
the present invention: 8
[0067] In Formula IIIb (and other formulas described below), there
may be more ts subunits depicted of the same molecular identity of
those depicted in the formulas. For example, in Formula IIIb,
subunits t.sub.1 and t.sub.2 may be repeated in a sequence, e.g.,
alternating, in blocks (which may themselves repeat), or in any
other pattern or random arrangement. Each subunit may repeat any
number of times, and one subunit (e.g., t.sub.1) may occur with
substantially the same frequency, more often, or less often than
another subunit (e.g., t.sub.2), such that both subunits may be
present in approximately the same amount, or in differing amounts,
which may differ slightly or be highly disparate, e.g., one subunit
is present nearly to the exclusion of the other. In certain
embodiments, the chiral centers of each subunit may be the same or
different and may be arranged in an orderly fashion or in a random
sequence in each of Z1 and Z2. 9
[0068] In certain embodiments of Formula IIIc, the sum of the
number of ts subunits in each of Z1 and Z2 is an even integer. As
in other examples of Z1 and Z2, such as described above for Formula
III, the ts subunits may be distributed randomly or in an ordered
arrangement in each of Z1 or Z2. 10
[0069] In Formula IIId, the subunit q1 is comprised of two ts
subunits, which may be repeated and arranged as described above for
Formula IIIb. In certain embodiments, q2 is an even integer, and in
other embodiments, the subunits q1 and q2 may be distributed
randomly or in an ordered pattern in each of Z1 and Z2. For
example, subunits q1 and q2 may be repeated in a sequence, e.g.,
alternating, in blocks (which may themselves repeat), or in any
other pattern or random arrangement. Each subunit may repeat any
number of times, and one subunit (e.g., ql) may occur with
substantially the same frequency, more often, or less often than
another subunit (e.g., q2), such that both subunits may be present
in approximately the same amount, or in differing amounts, which
may differ slightly or be highly disparate, e.g., one subunit is
present nearly to the exclusion of the other. 11
[0070] In certain embodiments of Formula IIIe, the sum of the ts
subunits for each of Z1 and Z2 is an even integer. In other
embodiments, the each of the subunits t.sub.1, t.sub.2, and t.sub.3
may be distributed randomly or in an ordered arrangement in each of
Z1 and Z2. For example, in Formula IIIe, subunits t.sub.1, t.sub.2,
and t.sub.3 may be repeated in a sequence, e.g., alternating, in
blocks (which may themselves repeat), or in any other pattern or
random arrangement. Each subunit may repeat any number of times,
and one subunit (e.g., t.sub.1) may occur with substantially the
same frequency, more often, or less often than another subunit
(e.g., t.sub.3), such that the three subunits may be present in
approximately the same amount, or in differing amounts, which may
differ slightly or be highly disparate, e.g., two subunits are
present nearly to the exclusion of the third.
[0071] In certain embodiments of Formula III, in which Q, M and X
for each subunit are the same, Q1 represents 0, M represents a
lower alkylene group, and X1 represents O or S, preferably O. For
example, M may represent --CH(CH.sub.3)-- to result in a polymer of
Formula III having a structure represented in Formula III; 12
[0072] In certain embodiments of Formula IIIf, as further described
in the Exemplification below, L1 represents a lower alkylene chain,
such as ethylene, propylene, etc. In certain embodiments, all Y1's
represent O. In certain embodiments, R8 represents --O-lower alkyl,
such as --OEt.
[0073] In certain embodiments of polymers depicted by Formula III,
the chirality of each subunit is identical, whereas in other
embodiments, the chirality is different. By way of example but not
limitation, in Formula IIIb above, if the chiral centers of all of
the subunits are D-enantiomers or L-enantiomers, then the monomeric
unit is effectively equivalent to D-lactic acid or L-lactic acid,
respectively, thereby giving rise to a region similar to
poly(D-lactic acid) or poly-(L-lactic acid), respectively.
Conversely, if the two subunits in Formula IIIb are comprised of
alternating D- and L-enantiomers (e.g., one unit of D-enantiomer,
one unit of L-enantiomer, etc.), then the resulting polymeric
region is analogous to poly(meso-lactic acid) (i.e., a polymer
formed by polymerization of meso-lactide).
[0074] Finally, in certain embodiments of the monomeric units set
forth in Formula III, in which the entire polymer may or may not be
composed of such units, the following moieties for Y1, L1, R8 Qs,
Xs and Ms may be used (with a variety of different x and y being
possible):
1 Abbreviation All Y1's L1 R8 P(LAEG-EOP) O --CH.sub.2CH.sub.2--
--OCH.sub.2CH.sub.3 P(LAEG-HOP) O --CH.sub.2CH.sub.2--
--O(CH.sub.2).sub.5CH.sub.3 P(D,L-AEG-EOP)* O --CH.sub.2CH.sub.2--
--OCH.sub.2CH.sub.3 P(D,L-APG-EOP)* O
--CH.sub.2(CH.sub.3)CH.sub.2-- --OCH.sub.2CH.sub.3 P(DAPG-EOP) O
--CH.sub.2(CH.sub.3)CH.sub.2-- --OCH.sub.2CH.sub.3 P(LAPG-EOP) O
--CH.sub.2(CH.sub.3)CH.sub.2-- --OCH.sub.2CH.sub.3 P(D,L-AHD-EOP)*
O 13 --OCH.sub.2CH.sub.3 P(D,L-APG-HOP)* O
--CH.sub.2(CH.sub.3)CH.sub.2-- --O(CH.sub.2).sub.5CH.sub.3
P(D,L-APG-EP)* O --CH.sub.2(CH.sub.3)CH.sub.2-- --CH.sub.2CH.sub.3
Abbreviation All Qs All Xs M1 M2 P(LAEG-EOP) O O --CH(CH.sub.3)--
(L) N/A P(LAEG-HOP) O O --CH(CH.sub.3)-- (L) N/A P(D,L-AEG-EOP)* O
O --CH(CH.sub.3)-- (L or D) --CH(CH.sub.3)-- (D or L)
P(D,L-APG-EOP)* O O --CH(CH.sub.3)-- (L or D) --CH(CH.sub.3)-- (D
or L) P(DAPG-EOP) O O --CH(CH.sub.3)-- (D) N/A P(LAPG-EOP) O O
--CH(CH.sub.3)-- (L) N/A P(D,L-AHD-EOP)* O O --CH(CH.sub.3)-- (L or
D) --CH(CH.sub.3)-- (L or D) P(D,L-APG-HOP)* O O --CH(CH.sub.3)--
(L or D) --CH(CH.sub.3)-- (L or D) P(D,L-APG-EP)* O O
--CH(CH.sub.3)-- (L or D) --CH(CH.sub.3)-- (L or D) *For
P(DAEG-EOP)-D/L* and P(DAPG-EOP)-D/L*, if the chiral carbon of M1
has configuration L, then M2 will have configuration D, and
vice-versa. The order of the chiral centers in each subunit M1 and
M2 for each Z1 and Z2 will be in random order.
[0075] In addition to the particular chiral version of the subject
polymers described in the above table, polymers in which the
chirality of Ms varies in each subunit M in the subject polymers
are also possible. For instance, referring to P(D,L-A-EG-EOP) by
example, a random order of D and L, in varying amounts, are
possible for this polymer. In contrast, the table sets forth one
such example in which a D and L chiral M are always adjacent, in
equal amounts, but that need not always be the case.
[0076] In another embodiment of the present invention, the
polymeric compositions of the present invention include one or more
recurring monomeric units represented in general Formula IV: 14
[0077] wherein, independently for each occurrence:
[0078] L2 is a divalent organic group as described in greater
detail below; and
[0079] the other moieties are as defined as above.
[0080] In Formula IV, L2 may be a divalent, branched or straight
chain aliphatic group, a cycloaliphatic group, or a group of the
formula: 15
[0081] Specific examples of particular divalent, branched or
straight chain aliphatic groups include an alkylene group with 1 to
7 carbon atoms, such as 2-methylpropylene or ethylene. Specific
examples of cycloaliphatic groups include cycloalkylene groups,
such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene and
2-chioro-cyclohexylene; cycloalkenylene groups, such as
cyclohexenylene; and cycloalkylene groups having fused or bridged
additional ring structures, such as tetralinylene, decalinylene and
norpinanylene; or the like.
[0082] In certain embodiments of the subject formulas, each of L1
independently may be an alkylene group, a divalent cycloaliphatic
group, a phenylene group or a divalent group of the formula: 16
[0083] wherein D is O, N or S and m is 0 to 3. Alternatively, L1 is
a branched or straight chain alkylene group having from 1 to 7
carbon atoms, such as a methylene, ethylene, n-propylene,
2-methylpropylene, 2,2'-dimethylpropylene group and the like.
[0084] In certain embodiments of the monomeric units set forth in
Formula IV, in which the entire polymer may or may not be composed
of such units, the following moieties for X1, L1 and R8 may be
used:
2 Abbreviation All X1 All L1 L2 R8 P(trans-CHDM/HOP) O --CH.sub.2--
17 --O(CH.sub.2).sub.5CH.sub.3 trans-1,4-cyclohexyl P(cis- and
trans- O --CH.sub.2-- mixture of trans-1,4-
--O(CH.sub.2).sub.5CH.sub.3 CHDM/HOP) cyclohexyl and 18
cis-1,4-cyclohexyl P(trans-CHDM/BOP) O --CH.sub.2--
trans-1,4-cyclohexyl --O(CH.sub.2).sub.3CH.sub.3 P(trans-CHDM/EOP)
O --CH.sub.2-- trans-1,4-cyclohexyl --OCH.sub.2CH.sub.3
[0085] In another embodiment of the present invention, the
polymeric compositions of the present invention include one or more
recurring monomeric units represented in general Formula V: 19
[0086] wherein, independently for each occurrence, d is equal to
one or more, and optionally two, and all of the other moieties are
as defined above.
[0087] In certain embodiments of the monomeric units set forth in
Formula V, in which the entire polymer may or may not be composed
of such units, the following moieties for X1, L1 and R8 may be used
(with a variety of different x possible for each example):
3 All Abbreviation X1 All L1 R8 P(BHET-EOP/TC) O --CH2CH2--
--OCH2CH3 P(BHDPT-EOP/TC) O --CH2CH(CH3)2CH2-- --OCH2CH3
P(BHDPT-HOP/TC) O --CH2CH(CH3)2CH2-- --OC6H13 P(BHPT-EOP/TC) O
--CH2CH2CH2-- --OCH2CH3 P(BHMPT-EOP/TC) O CH2CH2(CH3)CH2--
--OCH2CH3
[0088] In Formula V, the aryl groups represented therein may be
substituted with a non-interfering substituent, for example, a
hydroxy-, halogen-, or nitrogen-substituted moiety.
[0089] Other phosphorus-containing polymers which may be adapted
for use in the subject invention are described in the art,
including those described in U.S. Pat. Nos. 5,256,765 and
5,194,581; PCT publications WO 98/44020, WO 98/44021, and WO
98/48859; and U.S. application Ser. Nos. 09/053,649, 09/053,648 and
09/070,204. For all of the above-identified groups, non-interfering
substituents also may be present.
[0090] In certain embodiments, the polymers are comprised almost
entirely, if not entirely, of the same subunit. Alternatively, in
other embodiments, the polymers may be copolymers, in which
different subunits and/or other monomeric units are incorporated
into the polymer. In certain instances, the polymers are random
copolymers, in which the different subunits and/or other monomeric
units are distributed randomly throughout the polymer chain. For
example, a polymer having units of Formula II may consist of
effectively only one type of such subunit, or alternatively two or
more types of such subunits. In addition, a polymer may contain
monomeric units other than those subunits represented by Formula
II.
[0091] In other embodiments, the different types of monomeric
units, be they one or more subunits depicted by the subject
formulas or other monomeric units, are distributed randomly
throughout the chain. In part, the term "random" is intended to
refer to the situation in which the particular distribution or
incorporation of monomeric units in a polymer that has more than
one type of monomeric units is not directed or controlled directly
by the synthetic protocol, but instead results from features
inherent to the polymer system, such as the reactivity, amounts of
subunits and other characteristics of the synthetic reaction or
other methods of manufacture, processing or treatment.
[0092] In certain embodiments, the subject polymers may be
cross-linked. For example, substituents of the polymeric chain, may
be selected to permit additional inter-chain cross-linking by
covalent or electrostatic (including hydrogen-binding or the
formation of salt bridges), e.g., by the use of a organic residue
appropriately substituted.
[0093] The ratio of different subunits in any polymer as described
above may vary. For example, in certain embodiments, polymers may
be composed almost entirely, if not entirely, of a single monomeric
element, such as a subunit depicted in Formula II. Alternatively,
in other instances, the polymers are effectively composed of two
different subunits, in which the percentage of each subunit may
vary from less than 1:99 to more than 99:1, or alternatively 10:90,
15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85:15, 90:10 or the like.
For example, in some instances, a polymer may be composed of two
different subunits that may be both represented by the generic
Formula II, for example, but which differ in their chemical
identity. In certain embodiments, the polymers may have just a few
percent, or even less (for example, about 5, 2.5, 1, 0.5, 0.1%) of
the subunits having phosphorous-based linkages. In other
embodiments, in which three or more different monomeric units are
present, the present invention contemplates a range of mixtures
like those taught for the two-component systems.
[0094] In certain embodiments, the polymeric chains of the subject
compositions, e.g., which include repetitive elements shown in any
of the subject formulas, have molecular weights ranging from about
2000 or less to about 1,000,000 or more daltons, or alternatively
about 10,000, 20,000, 30,000, 40,000, or 50,000 daltons, more
particularly at least about 100,000 daltons, and even more
specifically at least about 250,000 daltons or even at least
500,000 daltons. Number-average molecular weight (Mn) may also vary
widely, but generally fall in the range of about 1,000 to about
200,000 daltons, preferably from about 1,000 to about 100,000
daltons and, even more preferably, from about 1,000 to about 50,000
daltons. Most preferably, Mn varies between about 8,000 and 45,000
daltons. Within a given sample of a subject polymer, a wide range
of molecular weights may be present. For example, molecules within
the sample may have molecular weights which differ by a factor of
2, 5, 10, 20, 50, 100, or more, or which differ from the average
molecular weight by a factor of 2, 5, 10, 20, 50, 100, or more.
[0095] One method to determine molecular weight, both number
average and weight average, is by gel permeation chromatography
("GPC"), e.g., through the use of mixed bed columns,
CH.sub.2Cl.sub.2 solvent, light scattering detector, and off-line
dn/dc. Polymer Laboratories and Waters. Laser light scattering
devices are available from Wyatt Laboratories.
[0096] Exemplary approaches are as follows: weight-Average MWs from
light scattering, Mw (LS), can be obtained using a system
incorporating a Waters 510 pump, two Polymer Labs "Mixed C" columns
in series, a Shimadzu CTO-10A column oven, a Waters 410
differential refractometer, and a MiniDawn multi-angle light
scattering detector (Wyatt Technologies). Data can be obtained and
analyzed on a PC using Astra software (Wyatt Technologies).
Weight-Average MWs and Number-Average MWs from conventional
calibration, Mw (CC) and Mn (CC) can be obtained using the system
described above through the Waters 410 differential refractometer
using a Polymer Labs data capture unit and Caliber software. A
calibration curves can be obtained using Polymer Laboratories
Easi-Cal PS-1 polystyrene standards. Data typically are reported in
daltons. Inherent Viscosities (IV) can be obtained using polymer
solutions of 0.45 to 0.55% w/v in a Canon-Fenske viscometer, size
25, at 30.degree. C. Such data typically are reported in dL/g.
Other methods are known in the art.
[0097] In certain embodiments, the intrinsic viscosities of the
polymers generally vary from about 0.01 to about 2.0 dL/g in
chloroform at 40.degree. C., alternatively from about 0.01 to about
1.0 dL/g and, occasionally, from about 0.01 to about 0.5 dL/g.
[0098] The glass transition temperature (T.sub.g) of the subject
polymers may vary widely, and depend on a variety of factors, such
as the degree of branching in the polymer components, the relative
proportion of phosphorous-containing monomer used to make the
polymer, and the like. When the article of the invention is a rigid
solid, the T.sub.g is often within the range of from about
-10.degree. C. to about 80.degree. C., particularly between about 0
and 50.degree. C. and, even more particularly between about
25.degree. C. to about 35.degree. C. In other embodiments, the
T.sub.g is preferably low enough to keep the composition of the
invention flowable at body temperature. Then, the glass transition
temperature of the polymer used in the invention is usually about 0
to about 37.degree. C., or alternatively from about 0 to about
25.degree. C.
[0099] In certain embodiments, substituents of the phosphorus atom,
such as R8 in the above formulas, and other components of the
subject polymers may permit additional inter-chain cross-linking by
covalent or electrostatic interactions (including, for example,
hydrogen-binding or the formation of salt bridges) by having a side
chain of either of them appropriately substituted as discussed in
greater detail below.
[0100] In other embodiments, the polymer composition of the
invention may be a flexible or flowable material. By "flowable" is
meant the ability to assume, over time, the shape of the space
containing it at body temperature. This includes, for example,
liquid compositions that are capable of being sprayed into a site;
injected with a manually operated syringe fitted with, for example,
a 23-gauge needle; or delivered through a catheter.
[0101] Also included by the term "flowable", are highly viscous,
"gel-like" materials at room temperature that may be delivered to
the desired site by pouring, squeezing from a tube, or being
injected with any one of the commercially available power injection
devices that provide injection pressures greater than would be
exerted by manual means alone for highly viscous, but still
flowable, materials. When the polymer used is itself flowable, the
polymer composition of the invention, even when viscous, need not
include a biocompatible solvent to be flowable, although trace or
residual amounts of biocompatible solvents may still be
present.
[0102] In certain embodiments, the subject polymers are soluble in
one or more common organic solvents for ease of fabrication and
processing. Common organic solvents include such solvents as
chloroform, dichloromethane, dichloroethane, 2-butanone, butyl
acetate, ethyl butyrate, acetone, ethyl acetate, dimethylacetamide,
N-methyl pyrrolidone, dimethylformamide, and dimethylsulfoxide.
[0103] The following chart provides an explanation of some of the
more frequently employed abbreviations in this application:
4 bis(hydroxyethyl) terephthalate BHET 1,4-cyclohexane dimethanol
CHDM 4-dimethylaminopyridine DMAP ethylene glycol BC ethyl
dichlorophosphate EOPCl.sub.2 ethyl dichlorophosphonate EPCl.sub.2
1,6 hexanediol HD hexyl dichlorophosphate HOPCl.sub.2
N-methylmorpholine NMM propylene glycol PG terephthaloyl chloride
TC Triethylamine TEA tetrahydrofuran THF trimethylene chloride
TMC
[0104] In view of the above definitions and explanations, the
present invention provides methods for producing polymers, such as
phosphopolymers (e.g., polyphosphoesters), and polymers, such as
phosphopolymers (e.g., polyphosphoesters), made by such
methods.
[0105] The present invention also provides methods of purifying a
polymer preparation. In accordance with one aspect of the
invention, purification methods comprising contacting the polymer
preparation with at least one ion exchange resin are provided.
Polymer preparations refer to a mass, collection, concentration or
aggregation of polymers, and can be in a solid form or in solution.
In purifying, the preparation can be contacted with an acidic resin
and a basic resin, such as a strong acidic resin and a weak basic
resin. The ion exchange resins can remove a variety of contaminants
from a polymer preparation, such as amines from the reaction and
metal contaminants arising from polymerization catalysts like tin
and zinc. Polymer preparations having a reduced level of metal
contaminants that are obtainable by these methodologies also are
provided. The polymer preparations can comprise phosphopolymers,
including polyphosphoesters.
[0106] In accordance with another aspect of the invention, methods
of producing a phosphopolymer, comprising reacting a reactive
prepolymer, preferably dissolved in an appropriate solvent with an
organophosphorous compound in the presence of at least one acid
scavenger, preferably until substantially all of the
organophosphorous compound has bound with the prepolymer to form a
phosphopolymer; and purifying the phosphopolymer. A reactive
prepolymer should have one or more, preferably at least two,
reactive end groups. The reactive end groups include, but are not
limited to, primary and secondary alcohol, amine, and thiol
groups.
[0107] The reaction can be stopped/quenched with an alcohol prior
to the purification. The reaction can performed at a warm
temperature or a cold temperature. The purification preferably
employs at least one ion exchange resin. The prepolymer can be
formed from one or more monomers selected from the group consisting
of D,L-lactide, trimethylene chloride, L-lactide, caproloactone,
dioxanone, propylene glycol, ethylene glycol, 1,6 hexanediol,
glycolide, 1,4-cyclohexane dimethanol, terephthaloyl chloride and
bis(hydroxyethyl) terephthalate, for example. The organophosphorous
compound can be selected from the group consisting of alkyl
dichlorophosphates, alkyl dichlorophosphonates, alkyl
dichlorophosphites, aryl dichlorophosphates, aryl
dichlorophosphonates, aryl dichlorophosphites, alkylaryl
dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl
dichlorophosphites. Exemplary organophosphorous compounds include
ethyl dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate and hexyl dichlorophosphonate, for example.
[0108] The prepolymer can be formed using a variety of catalysts,
including stannous catalysts and/or zinc catalysts, for example.
Appropriate acid scavengers include the tertiary amines, such as
triethylamine, and substituted aminopyridines, such as
4-dimethylaminopyridine, although other acid scavengers available
to the skilled person can be employed according to the teachings
contained herein, such as N,N,N-triethylamine,
N,N-dimethyl-n-phenyl amine; N-methylmorpholine, pyridine,
triethylenediamine, POLYDMAP (poly 4-dimethylaminopyridine), and
REILLEX 402. In many instances, the substituted aminopyridines,
such as DMAP, cause larger molecular weight polymers to form. See
Holfe et al., Angew. Chem. Int. Ed. Engl. 17: 569 (1978); Scriven,
Chem. Soc. Rev. 12:129 (1983). Phosphopolymers and phosphopolymer
preparations obtainable from these methodologies also are
provided.
[0109] In accordance with another aspect of the invention, there
are provided methods of producing phosphopolymers, comprising
reacting a prepolymer (as described above), preferably dissolved in
an appropriate solvent, with an organophosphorous compound (as
described above) in the presence of at least one acid scavenger (as
described above) at a cold temperature, preferably until
substantially all of the organophosphorous compound has bound with
the prepolymer to form a phosphopolymer; stopping/quenching the
reaction; contacting the phosphopolymer with at least one ion
exchange resin, which purifies the phosphopolymer; and removing the
ion exchange resin, which can be done via filtration. The reaction
can be stopped/quenched with an alcohol. The acidic ion exchange
resins and basic ion exchange resins can be contacted with the
phosphopolymer. An acidic resin exchanges cations, and a basic
resin exchanges anions. Resins can be considered strong or weak, as
is known in the field. Appropriate resins include Dowex MR3, MR3C,
HCR-S, M-43, DR-2030, MSC-1, Monosphere 66 and 77; Marathon C;
50WX4; Rohm & Haas Amberlyst 15 and A21; and Mitsubishi Diaion
WA30. Other resins available to the skilled person can be employed
in accordance with the teachings contained herein. The methods can
further comprise concentrating the phosphopolymer; precipitating
the phosphopolymer; and drying the phosphopolymer.
[0110] The prepolymer can be formed from one or more monomers
selected from the group consisting of D,L-lactide, trimethylene
carbonate, L-lactide, caproloactone, dioxanone, propylene glycol,
ethylene glycol, 1,6 hexanediol, glycolide, 1,4-cyclohexane
dimethanol, terephthaloyl chloride and bis(hydroxyethyl)
terephthalate, for example, and the organophosphorous compound can
be selected from the group consisting of alkyl dichlorophosphates,
alkyl dichlorophosphonates, alkyl dichlorophosphites, aryl
dichlorophosphates, aryl dichlorophosphonates, aryl
dichlorophosphites, alkylaryl dichlorophosphates, alkylaryl
dichlorophosphonates, and alkylaryl dichlorophosphites, for
example. Exemplary organophosphorous compounds include ethyl
dichlorophosphate, ethyl dichlorophosphonate, hexyl
dichlorophosphate and hexyl dichlorophosphonate. The prepolymner
can be formed using a stannous catalysts and/or zinc catalysts, for
example.
[0111] Appropriate acid scavengers include tertiary amines, such as
triethylamine, and substituted aminopyridines, such as
4-dimethylaminopyridine, although other acid scavengers available
to the skilled person can be employed according to the teachings
contained herein. Phosphopolymers and phosphopolymer preparations
obtainable from these methodologies also are provided.
[0112] In accordance with still another aspect of the invention,
there are provided methods of producing a polyphosphoesters
comprising (1) reacting at least one type of diol with at least one
type of organophosphorus compound in the presence of at least one
acid scavenger until substantially all of the organophosphorus
compound has bound with the diol to form a polyphosphoester and (2)
purifying the polyphosphoester. The diol can be a straight-chain
aliphatic diol, a branched aliphatic diol, a cycloaliphatic diol,
an aryl, and can be monomeric or polymeric. Illustrative diols
include cyclohexane dimethanol, ethylene glycol,
1,4-benzenedimethanol, 1,6 hexane diol, bis(hydroxyethyl
terephthalate) and propylene glycol. Polyethylene glycols of
various molecular weights, e.g., about 200 Da, about 500 Da, about
5000 Da or larger also can be employed according to the invention,
and such polyethylene glycols are readily obtained by the skilled
person. The diol can substitute for or be in addition to a
prepolymer. Preferably, the diol is present in stoiciometric
amounts to the organophosphate.
[0113] Appropriate acid scavengers include tertiary amines, such as
triethylamine, and substituted aminopyridines, such as
4-dimethylaminopyridine, although other acid scavengers available
to the skilled person can be employed according to the teachings
contained herein. Phosphopolymers and phosphopolymer preparations
obtainable from these methodologies also are provided.
[0114] In accordance with still another aspect of the invention,
there are provided methods of producing polyphosphoesters,
comprising: reacting a prepolymer with an organophosphorous
compound in the presence of at least one acid scavenger at a cold
temperature until substantially all of the organophosphorous
compound has bound with the prepolymer to form a polyphosphoester;
stopping the reaction; contacting the polyphosphoester with an
acidic ion exchange resin and a basic ion exchange resin; and
removing the acidic and basic ion exchange resins to yield a
purified polyphosphester that has a reduced level of metal
contaminants, such as tin and zinc. Polyphosphoesters and
polyphosphoester preparations obtainable by these methods also are
provided.
[0115] These and other aspects of the invention will become
apparent in view of the teachings, examples and data contained
herein.
[0116] Purification Methodologies
[0117] One aspect of the present invention advantageously employs
ion exchange resins ("IERs") to remove ionized and/or or ionizable
contaminants from any polymer process stream, and is particularly
useful for polymers to be used in pharmaceutical, medical device,
and food product settings. Preferably, at least 50% of the
contaminants are removed, more preferably at least 70% of the
contaminants are removed, and still more preferably at least 90% of
the contaminants are removed. For example, in the case of metal
contaminants, the metal concentration following purification is 20
ppm or lower, preferably 10 ppm or lower, and still more preferably
5 ppm or lower.
[0118] Typically, at a given stage of a process stream, a polymer
product is in the form of a solute. Alternatively, a solid polymer
preparation can be solubilized in an appropriate solvent. Whatever
the approach, post-polymerization polymers are contaminated with
process byproducts. In order to remove these contaminants, at an
appropriate stage of the process, the polymer solute is contacted
with one or more IERs to remove the contaminants. The polymer
solute/IER mixture is usually agitated in order to facilitate
contact between the solution and the IER, which maximizes
contaminant removal. Exemplary approaches for agitation include
mechanical shaking or spinning a vessel containing the polymer
solute/IER mixture, or internal stirring using a paddle, blade or
stir bar. The IER treatment can be from minutes to days, preferably
ranging about 2 to about 24 hours, and preferably is performed at
ambient temperature or below, depending upon the polymer and the
solvent. Exemplary temperatures include -78.degree. C. to
30.degree. C., preferably within about -10.degree. C. to 25.degree.
C., and more preferably within about -5.degree. C. to 20.degree.
C., although any temperature within or about the above intervals
are appropriate for use according to the invention. After an
appropriate contact period, the IER is removed, typically through
filtration and/or sedimentation.
[0119] Typical contaminants include cationic and anionic species
that exist in solution. Cationic contaminants include:
[0120] (1) Alkali metals, for example lithium and sodium;
[0121] (2) Alkali earth metals, for example magnesium and
calcium;
[0122] (3) Transition metals, for example iron, nickel and
zinc;
[0123] (4) Other main group metals, for example aluminum and
tin;
[0124] (5) Heavy metals, for example lead, cadmium and mercury;
and
[0125] (6) Ammonium cations and organic cationic species, for
example amines like protonated organic amines.
[0126] Other types of cationic species include electrically neutral
species like organic amines that can react with strong acid IERs in
protonated form to form cationic species, for example amine
hydrochloride. Thus, any cationic contaminant or neutral
contaminant that can be protonated to form a cationic species can
be removed with ER. In the context of polymers for pharmaceutical
and other medical uses, the need to remove tin and zinc is typical
because these metal contaminants come from commonly used
catalysts.
[0127] Anionic contaminants include:
[0128] (1) Halides, for example chlorides and bromides;
[0129] (2) Monoatomic main-group anions, for example sulfide and
selenide;
[0130] (3) Polyatomic anions, for example nitrate, sulfate and
phosphate; and
[0131] (4) Other organic anions, for example carboxylates,
organonitrates and
[0132] organophosphates.
[0133] Finally, electrically neutral species, like inorganic acids
(for example, hydrochloric acid and nitric acid), can react with
base IERs to form water and anionic species, which in turn can be
removed by the IERs.
[0134] Solvents, including mixtures thereof, that can be used to
dissolve the polymers include:
[0135] (1) Water;
[0136] (2) Alcohols, for example methanol and ethanol;
[0137] (3) Ketones, for example acetone and 2-butanone;
[0138] (4) Ethers, for example diethyl ether and
tetrahydrofuran;
[0139] (5) Esters, for example ethyl acetate;
[0140] (6) Halogenated hydrocarbons, for example carbon
tetrachloride, chloroform, dichloromethane, 1,2 dichloroethane and
methylene chloride;
[0141] (7) Hydrocarbons, for example toluene, benzene and hexane;
and
[0142] (8) Other organics, for example dimethlylsulfoxide.
[0143] The IERs to be employed must be compatible with the polymer
and the solvent in which the polymer is dissolved. Preferably, the
IER is wetted with the same solvent, or compatible solvent(s), used
to dissolve the polymer. Appropriate resins to be used according to
the invention include:
[0144] (1) Dowex MR3 and MR3C (mixed ion exchange resins containing
Marathon A (strong base) and Marathon C (strong acid) resins);
[0145] (2) Dowex HCR-S (strong acid--styrene-DVB, gel matrix with a
sulfonic acid functional group);
[0146] (3) Dowex M-43 (weak base resin (tertiary amine) made from
macroporous styrenic plastic beads);
[0147] (4) Dowex DR-2030 (strong acid resin--styrenic plastic bead
fuinctionalized with sulfonic acid groups, often referred to as a
catalyst);
[0148] (5) Dowex MSC-1 (Strong acid resin);
[0149] (6) Dowex Monosphere 66 and 77 (basic resins);
[0150] (7) Marathon C (strong acid);
[0151] (8) Marathon A (strong base);
[0152] (9) 50WX4 (Strong acid);
[0153] (10) Rohm & Haas Amberlyst 15 (Acidic resin);
[0154] (11) Rohm & Haas Amberlyst A21 (Basic resin); and
[0155] (12) Mitsubishi Diaion WA30 (Basic resin).
[0156] The above listing is exemplary, and thus is not exhaustive.
Other resins available to the skilled person can be employed
according to the teachings contained herein.
[0157] At least one ion exchange resin is employed according to one
aspect of the invention. Preferably, more than one ion exchange
resin is employed, for example a strong acid resin and a weak basic
resin are used to remove contaminants from a polymer.
[0158] The usefulness of IERs is demonstrated by the following,
non-limiting, examples.
EXAMPLE 1
[0159] Two batches of poly(lactide) were prepared using zinc
acetate as a catalyst Samples 1 and 2 were each prepared by mixing
10.0 g of DL-lactide, 0.084 g of 1-dodecanol, and 0.0050 g of zinc
acetate (in the form of 0.050 ml of solution of 0.1 g/ml zinc
acetate in DMSO) in 20 ml Teflon vials. The vials were suspended in
oil baths and heated to 145.degree. C. Vials were removed from the
oil baths, shaken vigorously, and then returned to the oil bath
every 15 minutes for 2.5 hours after the initial mixing. The vials
were allowed to stand in the oil bath for 16 hours, and then the
vials were allowed to cool to room temperature, where thereafter
the cylindrical polymer masses were removed from the vials.
[0160] The weight average molecular weights (Mw) were 54,400
daltons (sample 1) and 43,700 daltons (sample 2), as determined by
gel permeation chromatography. The polymer samples were dissolved
in chloroform to a concentration of 0.3 g/ml and placed in sealed
glass vessels. Samples were removed to conduct an analysis of zinc
content.
[0161] The solutions also were treated with 1.4 g of Dowex DR-2030
IER and 1.4 g of Dowex M-43 EER per gram of polymer. The IERs were
wetted with chloroform prior to use. The process conditions are set
forth below.
5 Sample g Polymer g DR-2030 g M-43 ml chloroform 1 6.35 8.89 8.89
21 2 5.55 7.77 7.77 19
[0162] The samples with the IER were shaken on a mechanical shaker
for 2 hours at ambient temperature (20-25.degree. C.). The IERs
then were removed by vacuum filtration. The resulting clear
solutions were then concentrated, and then the polymers were
precipitated in methanol. The solids were then isolated and vacuum
dried, which in turn were frozen in liquid nitrogen, ground to a
fine powder in a stainless steel blender, and then vacuum dried
again. A zinc analysis was then performed, which provided the
following results:
6 Sample Zinc before treatment (ppm) Zinc after treatment (ppm) 1
150 <16 2 480 <16
[0163] These results show the effectiveness of the IERs in removing
catalyst-originated zinc contaminants from polymer preparations to
yield reduced contaminant levels.
EXAMPLE 2
[0164] Thirty six samples of polyphosphoesters were produced using
tin catalysts. Samples 1 and 2 were prepared according to Example
8. Sample 4 was prepared according to Example 9. Sample 5 was
prepared according to Example 10.
[0165] Sample 3 was prepared as follows: A 14 g portion of
propylene glycol was weighed into a 500 ml 3-necked round bottom
flask. The flask was equipped with a gas joint, a stirrer
bearing/shaft/paddle assembly, and a Teflon-coated thermocouple.
The reaction apparatus was placed in a preheated oil bath at
130.degree. C. and purged with nitrogen for one minute. A 283 g
portion of D,L-Lactide was added using a powder addition funnel
over a period of 45 minutes. The reaction apparatus was then
immersed in the oil so that the oil level was at the bottom of the
ground glass joints. The mixture was stirred until all of the solid
monomer had melted and the internal temperature had reached
approximately 125.degree. C. At this time, a volume of solution of
stannous octoate in chloroform equivalent to approximately 200 ppm
(117 ppm Sn) was added to the melt using a syringe. The mixture was
allowed to stir for approximately 4 hours. The residual monomer was
then removed using vacuum for approximately 2 hours. The prepolymer
was left at ambient conditions under nitrogen overnight. Then, a
113 ml portion of chloroform was used to dissolve and transfer the
prepolymer to a pre-chilled reactor that contained 2.5 equivalents
(based on propylene glycol) of triethylamine and 0.5 equivalents of
4-dimethylaminopyridine dissolved in 400 ml of chloroform. The
reactor was equipped with a stirrer bearing/shaft/turbine assembly,
a gas joint, a tubing adapter, and a Teflon-coated thermocouple.
With stirring and chilled recirculation on the jacket, the solution
was cooled to below -15.degree. C. A solution of 1 equivalent
(based on propylene glycol, approximately 30 g) of distilled ethyl
dichlorophosphate (EOPCl.sub.2) in 95 ml chloroform was prepared in
a round bottom flask equipped with a tubing adapter and a gas
joint. The EOPCl.sub.2/chloroform solution was added over a period
of not less than 2.5 hours, maintaining the internal temperature at
approximately -10.degree. C. Tubing was connected to the gas joints
of the flask and reactor to equalize the pressure during the
addition. Following the addition, a 15 ml portion of chloroform was
added to rinse the flask, feed lines, and pump. The reaction
mixture was stirred for 1 hour at low temperature (0.degree. C.)
before the reaction was quenched with 20 ml of anhydrous methanol.
The polyphosphoester, already dissolved in chloroform, was then
ready for treatment with the IERs.
[0166] Samples 6-36 were prepared from propylene glycol,
D,L-lactide, and ethyl dichlorophosphate (EOPCl.sub.2). The
prepolymer polymerization time, the prepolymer polymerization
temperature, the stannous octoate level, the temperature of the
vacuum stripping process, and the duration of the vacuum stripping
process were varied in the ranges specified below. The processes
were as follows:
[0167] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas to ambient temperature. A 28.5 g portion of
D,L-lactide and 1.5 g of PG (molar ratio, 10:1) were weighed into a
250 ml 3-neck round bottom flask. The flask was equipped with a gas
joint and a stirrer bearing/shaft/paddle assembly. The mixture was
evacuated and filled with argon five times to remove residual air
and moisture. The reaction apparatus was immersed in a preheated
oil bath at 125.degree. C. to 160.degree. C., connected to an argon
source with an oil bubbler, and stirred at a moderate speed until
all of the solid monomer had melted.
[0168] Then, a volume of stock stannous octoate solution (about 130
mg/ml in toluene) equivalent to 100 ppm to 500 ppm stannous octoate
or 30 ppm to 150 ppm Sn was added to the melt using a syringe. The
reaction mixture was allowed to stir under a slight argon pressure
for approximately 4 to 24 hours. The oil bath temperature was then
reduced to between 105.degree. C. and 135.degree. C. and the
residual monomer was removed under vacuum. The upper parts of the
reaction assembly were heated gently with a heat gun to aid in the
monomer removal. The total time under vacuum was 1 to 4 hours.
[0169] The prepolymer was dissolved in 84 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent of distilled ethyl dichlorophosphate
(EOPCl.sub.2) in 10 ml of chloroform was prepared in a dropping
funnel. The solution in the funnel was added slowly to the reaction
mixture over a period of 0.5 hour. After the addition was complete,
the reaction mixture was allowed to stir at low temperature for 1
hour at -5.degree. C. The reaction was then quenched with 1 ml of
anhydrous methanol and stirred for another five minutes. The
polymer, already dissolved in chloroform, was then ready for
treatment with EERs.
[0170] Samples 1-36, dissolved in chloroform, were treated with
EERs, specifically Dowex DR-2030 (1 g of resin/g polymer) and Dowex
M-43 (1.2 g of resin/g polymer), which were pre-wetted with
chloroform. The polymer-resin mixture was stirred, and the IERs
were removed through filtration after various contact time at
various temperatures. The polymer solution was concentrated, and
then either precipitated with a non-solvent and vacuum dried or
just dried in a vacuum oven at ambient temperature. The solid
polymer was recovered and then tested for tin content. The results
are set forth below for various samples.
7 Temperature Sample (.degree. C.) Time (hours) Initial tin (ppm) %
Tin removal 1 0 16 35 49 2 0 16 35 >80 3 0 2.25 62 74 4 5 12 58
86 5 9 16 605 94 6 25 2 29 73 7 25 2 146 88 8 25 2 29 66 9 25 2 146
86 10 25 2 29 69 11 25 2 146 49 12 25 2 146 88 13 25 2 29 52 14 25
2 146 83 15 25 2 88 78 16 25 2 29 62 17 25 2 29 39 18 25 2 29 69 19
25 2 146 86 20 25 2 29 11 21 25 2 29 35 22 25 2 29 66 23 25 2 88 92
24 25 2 146 91 25 25 2 29 -2 26 25 2 29 59 27 25 2 146 91 28 25 2
146 82 29 25 2 146 81 30 25 2 146 84 31 25 2 29 42 32 25 2 88 67 33
25 2 29 59 34 25 2 29 25 35 25 2 88 65 36 25 2 29 59
[0171] In 35 of 36 tests, the use of IERs showed significant
reduction in metal contamination.
EXAMPLE 3
[0172] Using the approach of Example 2, polyphosphoesters were
treated and tested.
[0173] First, polymer samples 2 and 3 were prepared and treated
with IERs according to Example 11. Sample 1 was prepared from
propylene glycol, D,L-lactide, and ethyl dichlorophosphate
(EOPCl.sub.2) as follows: A 497.3 g portion of D,L-lactide and 25.2
g of PG molar ratio, 10:1) were weighed into a 1 liter jacketed
reactor. The reactor was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The reaction apparatus was
maintained at 100 to 110.degree. C. and stirred at a moderate speed
until all of the solid monomer had melted.
[0174] Then, a volume of stock stannous octoate solution equivalent
to 120 ppm stannous octoate was added to the melt using a syringe.
The reaction mixture was allowed to stir for approximately 19
hours. The oil bath temperature was then reduced to 100.degree. C.
and the residual monomer was removed under vacuum for 3 hours.
[0175] The prepolymer was then dissolved in 1400 ml of methylene
chloride with stirring and 2.5 equivalents of TEA and 0.5
equivalents of DMAP were added to the stirring reaction mixture
using a powder funnel. The reaction mixture was chilled to about
-5.degree. C. A solution of about 1 equivalent (54.5 g) of
distilled ethyl dichlorophosphate (EOPCl.sub.2) in 150 ml of
methylene chloride was prepared. The solution was added slowly to
the reaction mixture over a period of 4 hours. After the addition
was complete, the reaction mixture was allowed to stir at low
temperature for 12 hours at 1.degree. C. The reaction was then
quenched with 34 ml of anhydrous methanol and stirred for another
five minutes.
[0176] Next, the reaction mixture was filtered into a flask and
mixed with Dowex HCR-S and Dowex M-43, and stirred for 1 hour. The
resin was removed from the reaction mixture by vacuum filtration
through Whatman 4 filter paper. The resin was washed with about one
bed volume (i.e., a volume sufficient to submerge the resin) of
dichloromethane and the filtrate was concentrated. Ethyl ether was
added to the viscous filtrate. This was then poured into petroleum
ether to precipitate the polymer. The polymer mass was dried under
vacuum.
[0177] Differences in solvents and ion exchange resins used are
noted in the below table.
8 Initial Acidic Basic Temp. Time Tin % Tin Sample Solvent resin
resin (.degree. C.) (hours) (ppm) removal 1 Methylene Dowex Dowex
25 1 37 78 Chloride HCR-S M-43 2 51% Dowex Dowex -7 15 118 96
Chloroform DR-2030 M-43 and 49% Methylene Chloride 3 42% Dowex
Dowex 21 15 115 94 Chloroform DR-2030 M-43 and 58% Methylene
Chloride
[0178] Significant metal contaminant reduction was achieved even
when different solvents and ion exchange resins were employed.
EXAMPLE 4
[0179] Polyphosphoester samples produced using tin catalysts as
follows: a 100 g portion of propylene glycol was weighed into a
3000 ml 3-necked round bottom flask. The flask was equipped with a
gas joint, a stirrer bearing/shaft/paddle assembly, and a
Teflon-coated thermocouple. The reaction apparatus was placed in a
preheated oil bath at 130.degree. C. and purged with nitrogen for
one minute. A 2000 g portion of D,L-Lactide was added using a
powder addition funnel over a period of 45 minutes. The reaction
apparatus was then immersed in the oil so that the oil level was at
the bottom of the ground glass joints. The mixture was stirred
until all of the solid monomer had melted and the internal
temperature had reached approximately 125.degree. C. At this time,
a volume of solution of stannous octoate in chloroform equivalent
to approximately 400 ppm (117 ppm Sn) was added to the melt using a
syringe. The mixture was allowed to stir for approximately 2 hours.
The residual monomer was then removed using vacuum for
approximately 0.5 hour. A 2500 ml portion of chloroform was used to
dissolve and transfer the prepolymer to a pre-chilled, 20 liter
jacketed reactor, which contained 2.5 equivalents (based on
propylene glycol) of triethylamine and 0.5 equivalents of
4-dimethylaminopyridine dissolved in 3600 ml of chloroform. The
reactor was equipped with a stirrer bearing/shaft/turbine assembly,
a gas joint, a tubing adapter, and a Teflon-coated thermocouple.
With stirring and chilled recirculation on the jacket, the solution
was cooled to below -15.degree. C. A solution of 1 equivalent
(based on propylene glycol, approximately 215 g) of distilled ethyl
dichlorophosphate (EOPCl.sub.2) in 650 ml chloroform was prepared
in a 1000 ml 3-necked round bottom flask equipped with a tubing
adapter and a gas joint. The EOPCl.sub.2/chloroform solution was
added using a piston pump and Teflon tubing over a period of 60
minutes, maintaining the internal temperature at approximately
-10.degree. C. Tubing was connected to the gas joints of the flask
and reactor to equalize the pressure during the addition. Following
the addition, a 50 ml portion of chloroform was added to rinse the
flask, feed lines, and pump. The reaction mixture was stirred for 1
hour at low temperature (-8.degree. C. after 1 hour) before the
reaction was quenched with 140 ml of anhydrous methanol.
[0180] Aliquots of the polymer/chloroform solution (0.2 g/ml) were
treated with WERs (1.4 g of both acidic and basic resin per g
polymer). The IERs were wetted in about 2.5 ml methylene chloride
per gram of resin. The chilled polymer--resin mixture (at about
4.degree. C.) was stirred for about 15 hours. The IERs were then
removed by filtration. The polymer solution was concentrated by
vacuum oven at ambient temperature. The recovered solid polymer was
sampled for tin content. It was determined that the theoretical
maximum tin concentration was 117 ppm. The results are set forth in
the below table.
9 Final tin concentration Sample Acidic resin Basic resin (ppm) %
removal Control None None 90 0 1 Dowex MSC-1 Dowex 27 81 Monosphere
66 2 Dowex MSC-1 Dowex <9 >90 Monosphere 77 3 Dowex MSC-1
Mitsubishi <10 >89 Diaion WA30 4 Dowex MSC-1 Rohn & Haas
<9.2 >90 Amberlyst A21 5 Rohn & Haas Dowex <8.4 >91
Amberlyst 15 Monosphere 66 Dry 6 Rohn & Haas Dowex <10.2
>89 Amberlyst 15 Monosphere 77 Dry 7 Rohn & Haas Mitsubishi
<9 >90 Amberlyst 15 Diajon WA30 Dry 8 Rohn & Haas Romn
& Haas <9.4 >90 Amberlyst 15 Amberlyst A21 Dry 9 Dowex
DR- Dowex M-43 <9.6 >89 2030
[0181] These data show that other types of IERs, when employed
according to the invention, are effective at metal contaminant
removal to reduce overall contaminant levels.
EXAMPLE 5
[0182] The following study was performed using commercially
available MEDISORB polymers from Alkermes. A sample of the polymers
was dissolved in methylene chloride (0.25 g/ml). The dissolved
polymers were mixed with Dowex DR-2030 and Dowex M-43 resins at 1.4
grams of resin each per gram of polymer. The resins were wetted in
about 2.5 ml of methylene chloride per gram resin. The chilled
polymer--resin mixture (at about 4.degree. C.) was stirred for
about 16 hours. The IERs were then removed by filtration. The
polymer solution was concentrated by vacuum oven at ambient
temperature. The recovered solid polymer was sampled for tin
content. The results are set forth in the below table.
10 Initial Tin Final Tin % Tin Sample Polymer Content (ppm) Content
(ppm) Removal 1 5050 DL 92 <5 >95 Low IV (co-polymer of
d,1-lactide and glycolide) 2 6535 DL 98 16 84 High IV (co- polymer
of d,1- lactide and glycolide) 3 6535 DL 94 <5 >95 Low IV
(co-polymer of d,1-lactide and glycolide) 4 100 DL 73 8.9 88 Low IV
(polymer of d,1- lactide) 5 100 DL 75 5.3 93 High IV (polymer of
d,1- lactide) 6 5050 DL 2A 42 <5 >88 (co-polymer of
d,1-lactic acid and glycolic acid) 7 7525 DL 73 6.3 91 Low IV
(co-polymer of d,1-lactide and glycolide) 8 8515 DL 74 <5 >93
High IV (co-polymer of d,1-lactide and glycolide) 9 7525 DL 74 7.4
90 High IV (co-polymer of d,1-lactide and glycolide) 10 5050 DL 4A
77 <5 >94 (co-polymer of d,1-lactide and glycolide)
[0183] The above data demonstrate that IERs can be used to remove
contaminants from a wide range of polymer preparations, and thus a
polymer preparation treated according to the invention will have
reduced levels of contamination, such as metal contamination, as
compared to commercially available polymers.
[0184] Phosphopolymer Production Methodologies
[0185] The present invention also provides methods for producing
polymers, for example phosphopolymers. It also provides
phosphopolymers (for example, polyphosphoesters) made by such
methods. Various types of phosphopolymers that are amenable to
production according to the present invention are disclosed in U.S.
Pat. Nos. 5,952,451 and 6,008,318; and PCT publications WO
98/44020, WO 98/44021, and WO 98/48859.
[0186] The present invention includes, but is not limited to, warm
and cold reaction approaches, and many of the processes steps
recited therein can be jointly employed in either approach, such as
purification techniques described above, as will be recognized by
the skilled person in view of the teachings contained herein.
Suitable purification techniques can be employed to remove some or
all of the impurities, such as undesired contaminants or reaction
by-products, from the phosphopolymers or compositions containing
such phosphopolymers, such as the polyphosphoesters. The approaches
are described below, although the skilled person will recognize
that many process steps are interchangeable.
[0187] One approach for the production of polyphosphoesters is a
dehydrochlorination reaction between a phosphorodihalo compound, a
type of organophosphorous compound, and a diol. The overall
reaction can be described as follows: 20
[0188] As is apparent from the schematic, the reaction generates 2
moles of acid for every mole of the phosphorodihalo compound (in
the above case, reaction with a phosphorodichloro compound
generates the hydrochloric acid). Preferably, Halo is Br, Cl or I,
and R3 is H, alkyl, alkoxy, heterocyclic or heterocycloxy.
Preferably, X1, R8 and R' are defined as above in relation to
Formula II (note that R' is defined the same as L1 in formula
II).
[0189] Warm Approach for Production
[0190] Prepolymers can be synthesized using monomers such as one or
more of D,L-lactide, TMC, L-lactide, caproloactone, dioxanone,
propylene glycol, ethylene glycol, 1,6 hexanediol, glycolide,
1,4-cyclohexane dimethanol, terephthaloyl chloride and
bis(hydroxyethyl) terephthalate, for example, and other appropriate
monomers, such as those disclosed in U.S. Pat. Nos. 5,952,451 and
6,008,318; and PCT publications WO 98/44020, WO 98/44021, and WO
98/48859. The monomers are preferably melted by heating to an
appropriate temperature, such as 135.degree. C. The monomer(s) can
be polymerized to form the prepolymer using stannous catalysts,
such as stannous octoate. Monomers and reaction proportions are
selected depending upon the structure and properties desired in the
final product.
[0191] The prepolymer then can be dissolved in an appropriate
solvent, such as a halogenated organic solvent (for example,
chloroform, dichloromethane, carbon tetrachloride and 1,2
dichloroethane). Other appropriate solvents include
tetrahydofuiran, toluene, dimethoxyethane, N-methylpyrrolidone,
dimethylsulfoxide, dimethylformamide, 2-butanone and acetone, for
example. The solution containing the prepolymer also should contain
one or more acid scavengers, such as TEA and DMAP, to remove acid
generated by dehydrochlorination reactions, for example.
[0192] The prepolymer solution should then be chilled (for example,
by ice bath), and then an organophosphorphous compound is added to
the solution. The organophosphorous compound can be selected from
the group consisting of ethyl dichlorophosphate, ethyl
dichlorophosphonate, hexyl dichlorophosphate and other appropriate
organophosphorous compounds. The solution is then preferably warmed
to an ambient temperature or above. Appropriate temperatures range
from about 20.degree. C. to 50.degree. C. and any temperature
therebetween, more preferably about 25.degree. C. to 40.degree. C.,
although temperatures outside of these ranges also can be employed
in view of the present teachings.
[0193] Next, the solution is refluxed (and optionally heated) for
up to 48 hours, during which time the phosphopolymer is formed.
Optionally, the solution can then be concentrated to about 1/3 its
original volume, and then refluxed further, preferably for about 16
hours at about 100.degree. C. The temperature can then be raised,
for example to about 115.degree. C., and then permitted to
cool.
[0194] The solution is then diluted with an appropriate solvent,
such as a halogenated organic solvent (for example, methylene
chloride). Next, the solution can be extracted with an HCl solution
followed by extraction with an NaCl solution.
[0195] The organic layer containing the phosphopolymer then can be
isolated, and then dried over sodium sulphate or magnesium
sulphate, which later can be removed by filtration. The
phosphopolymer in solution can then by concentrated, followed by
precipitation. The phosphopolymer then can be dried under a
vacuum.
[0196] Cold Approach for Production
[0197] Prepolymers can be synthesized using monomers such as one or
more of D,L-lactide, TMC, L-lactide, caproloactone, dioxanone,
propylene glycol, ethylene glycol, 1,6 hexanediol, glycolide,
1,4-cyclohexane dimethanol, terephthaloyl chloride and
bis(hydroxyethyl) terephthalate, for example, and other appropriate
monomers, such as those disclosed in U.S. Pat. Nos. 5,952,451 and
6,008,318; and PCT publications WO 98/44020, WO 98/44021, and WO
98/48859. The monomers are preferably melted by heating to an
appropriate temperature, such as 135.degree. C. The monomer(s) can
be polymerized to form the prepolymer using stannous catalysts,
such as stannous octoate. Monomers and reaction proportions are
selected depending upon the structure and properties desired in the
final product.
[0198] The prepolymer can then be dissolved in an appropriate
solvent, such as a halogenated organic solvent (for example,
chloroform, dichloromethane, carbon tetrachloride and 1,2
dichloroethane). Other appropriate solvents include tetrahydofuran,
toluene, dimethoxyethane, N-methylpyrrolidone, dimethylsulfoxide,
dimethylformamide, 2-butanone and acetone, for example. The
solution containing the prepolymer also should contain on or more
acid scavengers, such as TEA and DMAP, to remove acid generated by
dehydrochlorination reactions, for example.
[0199] The prepolymer solution should then be chilled (for example,
by ice bath or refrigeration), and then a solution of an
organphosphorphous compound is added to the solution. The
organophosphorous compound can be selected from the group
consisting of ethyl dichlorophosphate, ethyl dichlorophosphonate,
hexyl dichlorophosphate and other appropriate organophosphorous
compounds. The reaction is maintained at a cold temperature, that
is, below ambient temperature, such as at any temperature within
the range of -15.degree. C. to less than 20.degree. C., preferably
at a temperature range of -10.degree. C. to 10.degree. C., and more
preferably at about 0.degree. C. to 5.degree. C., although
temperatures outside of these ranges also can be appropriate in
view of the present teachings. The reaction is allowed to continue
until substantially all of the organophosphorous compound has bound
with the prepolymer, preferably at least 80%, more preferably at
least 90%, still more preferably at least 95%, yet more preferably
at least 98%, and still more preferably at least 99% of the
organophosphorous compound has bound with the prepolymer to form
the phosphopolymer. By "substantially", as recognized by the
skilled person, it is meant in this and similar contexts that the
reaction yields a product that is sufficiently free of unbound
reactants to be suitable for its intended purpose. Also as
recognized by the skilled person, "bound" in its various
grammatical forms refers to the formation of chemical bonds,
including covalent bonds, ionic bounds, hydrogen bonds and Van der
Waals forces.
[0200] Typically, the reaction should be run for any time interval
within the range of about 0.5 to 18 hours, although reaction times
outside of this range also can be appropriate.
[0201] Once the reaction has progressed to the desired point, such
as when substantially all of the organophosphorous compound has
bound with the prepolymer, the reaction can then be
stopped/quenched with an alcohol, preferably an anhydrous alcohol
such as anhydrous methanol. Next, the quenched solution can be
contacted with acid and base ion exchange resins, as explained
above, which preferably have been wetted in an appropriate organic
solvent, such as chloroform, dichloromethane or an alcohol. The ion
exchange resins are useful for removing contaminates, including but
not limited to amines and metal contaminants, such as tin and zinc,
resulting from the metal catalysts used in the formation of the
polymers. The removal of metal contaminants is very desirable for
polymers to be used in medical settings, particularly where there
is to be long-term exposures to the polymer through, for example,
dosing for chronic diseases and ailments.
[0202] After an appropriate contact period, such as any time
interval within the range of about 1 to 20 hours or more, the ion
exchange resins can be removed by appropriate techniques, such as
filtration and/or sedimentation.
[0203] The organic layer containing the phosphopolymer then can be
isolated. The phosphopolymer in solution can then be concentrated,
followed by precipitation. The phosphopolymer then can be dried
under a vacuum.
[0204] The cold approach has advantages over other approaches at
least in terms of:
[0205] (1) fewer process steps (it can result in up to a three day
time savings, for example);
[0206] (2) a capability to making polymers having higher and more
homogeneous molecular weights;
[0207] (3) more consistent T.sub.g (glass transition
temperature);
[0208] (4) increased control over reaction parameters and molecular
weight of the final product;
[0209] (5) use of ion exchange resins and more efficient amine and
metal removal results in higher purity and permits better scale-up
as compared to other approaches, such as liquid extractions;
[0210] (6) higher yields;
[0211] (7) less energy consumption; and
[0212] (8) less labor intensive.
[0213] The invention is further described by the following
examples, which are illustrative of the various aspects of the
invention but do not limit the invention in any way or manner.
EXAMPLE 6
[0214] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
1,2 propanediol (molar ratio, 10:1) were weighed into a 250 mL
3-neck round bottom flask. The flask was equipped with a gas joint
and a stirrer bearing/shaft/paddle assembly. The mixture was
evacuated and pressurized with argon five times to remove residual
air and moisture. The reaction apparatus was immersed in a
preheated oil bath at 135.degree. C., connected to an argon source
with an oil bubbler, and stirred at a moderate speed until all of
the solid monomer had melted.
[0215] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene of chloroform) equivalent to 3.6 mg tin
(120 ppm stannous octoate or equivalent to 35 ppm tin based upon
weight of the prepolymer) was added to the melt using a 50 .mu.l
syringe. The reaction mixture was allowed to stir under a slight
argon pressure for approximately 16 hours. The oil bath temperature
was then reduced to about 110.degree. C. and the residual monomer
was removed under vacuum. The upper parts of the reaction assembly
were heated gently with a heat gun to aid in the monomer removal.
The total time under vacuum was 2-3 hours. A reflux condenser was
then inserted between the gas joint and the flask in the prepolymer
apparatus described above. The molten prepolymer was dissolved by
adding 100 mL of chloroform to the reaction flask with
stirring.
[0216] Next, 6.9 mL of TEA and 1.21 g of DMAP were added to the
stirring reaction mixture. The reaction mixture was then chilled to
about 4.degree. C. in an ice bath. A solution of approximately 2.5
mL of freshly distilled EOPCl.sub.2 in 25 mL of chloroform was
prepared in a dropping funnel. The solution in the funnel was added
drop wise to the reaction mixture over a period of about 30
minutes. After the addition was complete the reaction mixture was
allowed to continue stirring at about 4.degree. C. for 10 minutes
and then the ice bath was removed. The reaction mixture was allowed
to warm to room temperature over about 1 hour. At this time a
significant increase in viscosity of the clear solution was
observed. The reaction mixture was then heated to reflux using an
oil bath. Over the next hour the solution became cloudy. The
reaction mixture was allowed to reflux over two nights, about 38
hours total.
[0217] At this time, a Barret trap was inserted between the
condenser and the flask and 88 mL of solvent (2/3 of the total
volume) were distilled from the reaction mixture. The Barret trap
was removed and the reaction mixture was allowed to reflux for an
additional 16 hours with the oil bath temperature between
98-102.degree. C. Next, the oil bath temperature was increased to
115.degree. C. for 2 hours. After this time, the reaction mixture
was allowed to cool to room temperature, and 200 mL of
dichloromethane was added and transferred to a separatory funnel.
The reaction mixture was extracted twice with 100 mL of 0.1 M HCl
and twice with 100 mL of saturated sodium chloride solution. The
organic layer was isolated, dried overnight in the freezer at about
-15.degree. C. over 50 g of sodium sulfate, and filtered twice. The
resulting polymer solution was poured into 1500 mL of hexane plus
500 mL of ether. The resulting mass of polymer was dried under
vacuum. The Inherent Viscosity (IV) of this material was measure to
be 0.39 dL/g.
EXAMPLE 7
[0218] A polyphosphoester was prepared from PG, D,L-lactide, and
EOPCl.sub.2 as follows:
[0219] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. Each
time the polymerization vessel was evacuated to a pressure between
0.5 and 10 torr. The reaction apparatus was immersed in a preheated
oil bath at 125.degree. C., connected to an argon source with an
oil bubbler, and stirred at a moderate speed until all of the solid
monomer had melted. At this time, a volume of stock stannous
octoate solution (about 130 mg/ml in toluene) equivalent to 100 ppm
stannous octoate (29 ppm Sn) was added to the melt using a syringe.
The reaction mixture was allowed to stir under a slight argon
pressure for 3 hours. The oil bath temperature was then reduced to
about 105.degree. C. and the residual monomer was removed under
vacuum. The pressure was maintain as low as possible, typically
between 0.5 and 10 torr. The upper parts of the reaction assembly
were heated gently with a heat gun to aid in the monomer removal.
The total time under vacuum was 1 hour.
[0220] The prepolymer was cooled to room temperature under argon
gas and allowed to stand for 12-18 hours at ambient temperature.
The prepolymer was dissolved in 84 ml of chloroform with stirring
and 2.5 equivalents of TEA and 0.5 equivalents of DMAP were added
to the stirring reaction mixture using a powder funnel. The
reaction mixture was chilled to about -5.degree. C. A solution of
about 1 equivalent of distilled ethyl dichlorophosphate in 10 ml of
chloroform was prepared in a dropping funnel. The solution in the
funnel was added slowly to the reaction mixture over a period of
0.5 hour.
[0221] After the addition was complete, the reaction mixture was
allowed to stir at low temperature for 1 hour at -5.degree. C. The
reaction was then quenched with 1 ml of anhydrous methanol and
stirred for another five minutes. Next, the reaction mixture was
transferred to a 0.5 gallon vessel and mixed with 37 g of Dowex
DR-2030 and 30 g of Dowex M-43, and shaken on a mechanical shaker
for 2 hour to remove residual DMAP and TEA free base and salts (the
IERs had been washed with several bed volumes of methanol and
chloroform and dried under vacuum at ambient temperature for about
18 hours). The resin was removed from the reaction mixture by
vacuum filtration through Whatman 54 filter paper.
[0222] The resin was washed with about one bed volume of
dichloromethane and the filtrate was concentrated to approximately
50 ml. The viscous filtrate was poured into 200 ml of petroleum
ether to precipitate the polymer. The polymer mass was washed with
100 ml of petroleum ether and dried under vacuum. Molecular weights
of the polymers were obtained from Gel Permeation Chromatography
(GPC) using both differential refractive index detection and a
polystyrene calibration curve (CC) and by light scattering
detection. The molecular weight and IV data for the polymers
prepared by this process are listed in the table below.
11 Sample Mw (LS), daltons Mw (CC), daltons IV, dL/g 1 101,200
107,500 0.62 2 150,100 155,900 0.80 3 85,200 84,300 -- 4 92,600
89,900 --
EXAMPLE 8
[0223] A 2000 g of portion D,L-Lactide and 100 g of propylene
glycol were weighed into a 3000 ml 3-necked round bottom flask. The
flask was equipped with a gas joint, a stirrer bearing/shaft/paddle
assembly, and a Teflon-coated thermocouple. The flask was purged
with nitrogen for 1 minute. The reaction apparatus was immersed in
a preheated oil bath at 135.degree. C. so that the oil level was at
the bottom of the ground glass joints. The mixture was stirred
until all of the solid monomer had melted and the internal
temperature had reached 135.degree. C. At this time, a volume of
10% solution of stannous octoate in toluene equivalent to 120 ppm
(35 ppm Sn) was added to the melt using a syringe. Following a 1
minute nitrogen purge, the mixture was allowed to stir for a
minimum of 16 hours. The oil bath was then reduced to 115.degree.
C.
[0224] When the internal (prepolymer mixture) temperature reached
115.degree. C., the residual monomer was removed using vacuum for a
minimum of 3 hours. A 2000 ml portion of chloroform was used to
dissolve and transfer the prepolymer to a pre-chilled, 10 liter
jacketed reactor, which contained 2.5 equivalents (based on
propylene glycol) of triethylamine and 0.5 equivalents of
4-dimethylaminopyridine dissolved in 3600 ml of chloroform. The
reactor was equipped with a stirrer bearing/shaft/turbine assembly,
two gas joints, a tubing adapter, and a Teflon-coated thermocouple.
With stirring and chilled recirculation on the jacket, the solution
was cooled to below 5.degree. C.
[0225] A solution of 1 equivalent (based on propylene glycol,
approximately 215 g) of distilled ethyl dichlorophosphate in 645 ml
chloroform was prepared in a 1000 ml 3-necked round bottom flask
equipped with a tubing adapter and a gas joint. The
EOPCl.sub.2/chloroform solution was added using a piston pump and
Teflon tubing over a period of 2 hours, maintaining the internal
temperature at or below 5.degree. C. Tubing was connected to the
gas joints of the flask and reactor to equalize the pressure during
the addition. Following the addition, a 50 ml portion of chloroform
was added to rinse the flask, feed lines, and pump. The reaction
mixture was stirred at low temperature (0-5.degree. C.) for a
minimum of 12 hours before the reaction was quenched with an
addition of 140 ml of anhydrous methanol.
[0226] The reaction mixture was then diluted with the addition of
4-6 liters of chloroform. The reactor was then charged with 2 kg of
a sulfonic acid strong cation exchange resin and 2 kg of a
polyamine weak anion exchange resin. The polymer/resin mixture was
mixed at low temperature for a minimum of 3 hours, after which it
was transferred by vacuum to the stainless steel laboratory Nutsche
filter. The polymer solution was pulled into the reservoir leaving
the resin behind in the Nutsche. Approximately 2 liters of
chloroform were added to wash the reactor before being pulled into
the Nutsche, where the resin/solution were stirred for 15 minutes.
The solution was then filtered into the reservoir.
[0227] The polymer solution was transferred back to the reactor
with 1.5 kg of strong acid resin and 1 kg of weak base resin. The
secondary polymer/resin mixture was mixed at low temperature for
12-18 hours. The filtration step was repeated using 1-2 liters of
chloroform to rinse the reactor and resin. The polymer solution was
pulled by vacuum through the pressure filter into the concentrator
(a similar 10 liter jacketed reactor) where the solution was
concentrated with the aid of heated recirculation on the jacket.
After most of the chloroform had been removed, approximately 2-3
liters of a viscous solution remained. A portion of 3200 ml of
ethyl ether was added to redissolve the polymer. After draining the
polymer/ether mixture from the reactor, the polymer was
precipitated in 30 liters of petroleum ether. The polymer was then
spread out on a Teflon pan and placed in the vacuum oven for
initial drying. After a minimum of 16 hours in the oven under
vacuum, the polymer was ground into smaller pieces before being
returned to the oven for a minimum of 24 hours.
12 Yield composition Mw (LS) Tg Residual Residual Residual sample %
PG:La:EOP daltons .degree. C. TEA % DMAP, % Sn, ppm 1 81 1:10:1.0
41,000 42 <0.01 0.4 18 2 84 1:11:1.0 37,000 41 <0.01 0.4
14
EXAMPLE 9
[0228] A 2000 g portion of D,L-Lactide and 100 g portion of
propylene glycol were weighed into a 3000 ml 3-necked round bottom
flask. The flask was equipped with a gas joint, a stirrer
bearing/shaft/paddle assembly, and a Teflon-coated thermocouple.
The flask was purged with nitrogen for 1 minute. The reaction
apparatus was immersed in a preheated oil bath at 135.degree. C. so
that the oil level was at the bottom of the ground glass joints.
The mixture was stirred until all of the solid monomer had melted
and the internal temperature had reached approximately 130.degree.
C. (oil bath was re-set for 130.degree. C.).
[0229] At this time, a volume of solution of stannous octoate in
toluene equivalent to approximately 200 ppm (about 60 ppm Sn) was
added to the melt using a syringe. The mixture was allowed to stir
for approximately 3 hours. The residual monomer was then removed
using vacuum for approximately 1 hour. A 2000 ml portion of
chloroform was used to dissolve and transfer the prepolymer to a
pre-chilled, 10 liter jacketed reactor, which contained 2.5
equivalents (based on propylene glycol) of triethylamine and 0.5
equivalents of 4-dimethylaminopyridine dissolved in 3600 ml of
chloroform. The reactor was equipped with a stirrer
bearing/shaft/turbine assembly, two gas joints, a tubing adapter,
and a Teflon-coated thermocouple. With stirring and chilled
recirculation on the jacket, the solution was cooled to below
-5.degree. C.
[0230] A solution of 1 equivalent (based on propylene glycol,
approximately 215 g) of distilled EOPCl.sub.2 in 500 ml chloroform
was prepared in a 1000 ml 3-necked round bottom flask equipped with
a tubing adapter and a gas joint. The EOPCl.sub.2/chloroform
solution was added using a piston pump and Teflon tubing over a
period of 1 hour, maintaining the internal temperature at or below
0.degree. C. Tubing was connected to the gas joints of the flask
and reactor to equalize the pressure during the addition. Following
the addition, a 50 ml portion of chloroform was added to rinse the
flask, feed lines, and pump. The reaction mixture was stirred for 1
hour at low temperature (-5.degree. C. after 1 hour) before the
reaction was quenched with 140 ml of anhydrous methanol.
One-quarter of the reaction mixture was then removed to perform a
separate experiment.
[0231] The main cut was transferred to a 20 liter jacketed reactor
containing 2.5 kg of a sulfonic acid strong cation exchange resin
and 2.5 kg of a polyamine weak anion exchange resin, wetted with
approximately 5 liters of chloroform. The polymer/resin mixture was
mixed at low temperature for 14 hours, after which it was
transferred to the stainless steel laboratory Nutsche filter. The
polymer solution was then filtered into the reservoir. The reactor
was washed with 1 liter of chloroform, which was transferred to the
Nutsche. A portion of the polymer solution was pulled through the
pressure filter into the concentrator (a similar 10 liter jacketed
reactor). Approximately 4 liters of chloroform were added to the
Nutsche, and its contents were mixed for 30 minutes.
[0232] After 30 minutes, the remaining solution was transferred to
the concentrator where the solution was concentrated with the aid
of heated recirculation on the jacket. After most of the chloroform
had been removed, approximately 2 liters of a viscous solution
remained. A portion of 2400 ml of ethyl ether was then added to
redissolve the polymer. After draining the polymer/ether mixture
from the reactor, the polymer was precipitated in 25 liters of
petroleum ether. The polymer was then spread out on a Teflon pan
and placed in the vacuum oven at ambient temperature. After the
initial drying under vacuum, the polymer was ground into smaller
pieces before being returned to the oven.
13 yield composition Mw (LS) Tg Residual Residual Residual sample %
PG:La:EOP daltons .degree. C. TEA % DMAP % Sn ppm 1 71 1:10:09
32,000 40 0.1 0.05 8
EXAMPLE 10
[0233] A 100 g portion of propylene glycol was weighed into a 3000
ml 3-necked round bottom flask. The flask was equipped with a gas
joint, a stirrer bearing/shaft/paddle assembly, and a Teflon-coated
thermocouple. The reaction apparatus was partially immersed in a
preheated oil bath at 135.degree. C. and purged with nitrogen for
one minute. A 2000 g portion of D,L-Lactide was added incrementally
over period of approximately 1 hour. The reaction apparatus was
then immersed in the oil so that the oil level was at the bottom of
the ground glass joints. The mixture was stirred until all of the
solid monomer had melted and the internal temperature had reached
approximately 130.degree. C.
[0234] At this time, a volume of solution of stannous octoate in
toluene equivalent to approximately 2000 ppm (about 600 ppm Sn) was
added to the melt using a syringe. The mixture was allowed to stir
for approximately 16 hours. The residual monomer was then removed
using vacuum for approximately 1 hour. A 2000 ml portion of
chloroform was used to dissolve and transfer the prepolymer to a
pre-chilled, 10 liter jacketed reactor, which contained 2.5
equivalents (based on propylene glycol) of triethylamine and 0.5
equivalents of 4-dimethylaminopyridine dissolved in 3600 ml of
chloroform. The reactor was equipped with a stirrer
bearing/shaft/turbine assembly, two gas joints, a tubing adapter,
and a Teflon-coated thermocouple.
[0235] With stirring and chilled recirculation on the jacket, the
solution was cooled to below -15.degree. C. A solution of 1
equivalent (based on propylene glycol, approximately 215 g) of
distilled EOPCl.sub.2 in 500 ml chloroform was prepared in a 1000
ml 3-necked round bottom flask equipped with a tubing adapter and a
gas joint. The EOPCl.sub.2/chloroform solution was added using a
piston pump and Teflon tubing over a period of 1 hour, maintaining
the internal temperature at approximately -5.degree. C. Tubing was
connected to the gas joints of the flask and reactor to equalize
the pressure during the addition.
[0236] Following the addition, a 50 ml portion of chloroform was
added to rinse the flask, feed lines, and pump. The reaction
mixture was stirred for 1 hour at low temperature (-15.degree. C.
after 1 hour) before the reaction was quenched with an addition of
140 ml of anhydrous methanol. The reaction mixture was then diluted
with approximately 5 liters of chloroform and transferred to a 20
liter jacketed reactor. The reactor was then charged with 3 kg of a
sulfonic acid strong cation exchange resin and 3 kg of a polyamine
weak anion exchange resin. The polymer/resin mixture was mixed at
low temperature for 20 hours, after which it was transferred by
vacuum to the stainless steel laboratory Nutsche filter. With the
resin being filtered off in the Nutsche, the polymer solution was
pulled through the pressure filter into the concentrator (a similar
10 liter jacketed reactor) where the solution was concentrated with
the aid of heated recirculation on the jacket.
[0237] The 20 liter reactor and the resin in Nutsche were washed
with 4 liters of chloroform, which were subsequently transferred to
the concentrator. After most of the chloroform had been removed,
approximately 2-3 liters of a viscous solution remained. The
polymer was left under vacuum at ambient temperature for 16 hours.
Approximately 1.5 liters of methylene chloride were then added to
redissolve the mostly solid polymer. A portion of 3200 ml of ethyl
ether was then added to the polymer solution. The mixture was mixed
until homogenous and split into two equal cuts.
[0238] The first cut (1) was poured into a Teflon pan and placed in
the vacuum oven at ambient temperature. The second cut (2) was
precipitated in 25 liters of petroleum ether. The polymer was then
spread out on a Teflon pan and placed in the vacuum oven at ambient
temperature. After approximately 1.5 weeks in the oven under
vacuum, the polymer was ground into smaller pieces before being
returned to the oven for approximately 2 days.
14 Yield composition Mw (LS) Tg Residual Residual Residual sample %
PG:La:EOP daltons .degree. C. TEA % DMAP, % Sn, ppm 1 55 1:10:1.0
59,000 37 N.D. 0.12 36 2 102 1:10:1.0 56,000 43 <0.01 0.13 37
Note: Total % Yield (both cuts): 78.5%
EXAMPLE 11
[0239] A 100 g portion of propylene glycol was weighed into a 3000
ml 3-necked round bottom flask. The flask was equipped with a gas
joint, a stirrer bearing/shaft/paddle assembly, and a Teflon-coated
thermocouple. The reaction apparatus was placed in a preheated oil
bath at 130.degree. C. and purged with nitrogen for one minute. A
2000 g portion of D,L-Lactide was added using a powder addition
funnel over a period of 45 minutes. The reaction apparatus was then
immersed in the oil so that the oil level was at the bottom of the
ground glass joints. The mixture was stirred until all of the solid
monomer had melted and the internal temperature had reached
approximately 125.degree. C.
[0240] At this time, a volume of solution of stannous octoate in
chloroform equivalent to approximately 400 ppm (about 117 ppm Sn)
was added to the melt using a syringe. The mixture was allowed to
stir for approximately 16 hours (the oil set point was decreased to
approximately 125.degree. C. The residual monomer was then removed
using vacuum for approximately 1 hour. A 2500 ml portion of
chloroform was used to dissolve and transfer the prepolymer to a
pre-chilled, 20 liter jacketed reactor, which contained 2.5
equivalents (based on propylene glycol) of triethylamine and 0.5
equivalents of 4-dimethylaminopyridine dissolved in 3600 ml of
chloroform. The reactor was equipped with a stirrer
bearing/shaft/turbine assembly, a gas joint, a tubing adapter, and
a Teflon-coated thermocouple.
[0241] With stirring and chilled recirculation on the jacket, the
solution was cooled to below -15.degree. C. A solution of 1
equivalent (based on propylene glycol, approximately 215 g) of
distilled EOPCl.sub.2 in 650 ml chloroform was prepared in a 1000
ml 3-necked round bottom flask equipped with a tubing adapter and a
gas joint. The EOPCl.sub.2/chloroform solution was added using a
piston pump and Teflon tubing over a period of 50 minutes,
maintaining the internal temperature at approximately -10.degree.
C. Tubing was connected to the gas joints of the flask and reactor
to equalize the pressure during the addition. Following the
addition, a 50 ml portion of chloroform was added to rinse the
flask, feed lines, and pump. The reaction mixture was stirred for 1
hour at low temperature (-8.degree. C. after 1 hour) before the
reaction was quenched with 140 ml of anhydrous methanol.
[0242] The reactor was then charged with 3 kg of a sulfonic acid
strong cation exchange resin and 3 kg of a polyamine weak anion
exchange resin wetted with approximately 6.5 liters of methylene
chloride. The polymer/resin mixture was mixed at low temperature
for 15 hours, after which it was transferred by vacuum to the
stainless steel laboratory Nutsche filter. With the resin being
filtered off in the Nutsche, the polymer solution was pulled
through the in-line cartridge filter into the concentrator (a
similar 10 liter jacketed reactor) where the solution was
concentrated with the aid of heated recirculating fluid on the
jacket.
[0243] The 20 liter reactor and the resin in Nutsche were washed
with 5 liters of methylene chloride, which were transferred to the
concentrator after being stirred for 1 hour. An additional 5 liters
of methylene chloride were added to the resin in the Nutsche and
added to the concentrator when the solution had been reduced down
to approximately 6 liters. Concentration of the polymer solution
continued until approximately 4-5 liters of a viscous solution
remained. A portion of 1500 ml of ethyl acetate was then added to
the polymer solution.
[0244] The mixture was mixed until homogenous and precipitated in
approximately 10 liters of petroleum ether. After the precipitation
mixture was stirred for approximately 5 minutes, the supernatant
liquid was decanted. The polymer was then washed with S liters of
petroleum ether. After the mixture was stirred for 5 minutes. The
liquid was again decanted. The polymer was poured into a
Teflon-coated pan and placed in the vacuum oven at ambient
temperature. After drying for 3 days, the polymer was ground into
smaller pieces.
15 yield composition Mw (LS) Tg Residual Residual Residual sample %
PG:La:EOP daltons .degree. C. TEA % DMAP, % Sn ppm 1 82 1:10:0.9
62,000 N.D. 0.14 4
EXAMPLE 12
[0245] A phosphopolymer was prepared from 1,2 propanediol, PG,
D,L-lactide, and ethyl dichlorophosphate (EOPCl.sub.2) as
follows:
[0246] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0247] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 3.6 mg time (120 ppm
stannous octoate, equivalent to 35 ppm tin) was added to the melt
using a 50 .mu.l syringe. The reaction mixture was allowed to stir
under a slight argon pressure for approximately 16 hours. The oil
bath temperature was then reduced to about 110.degree. C. and the
residual monomer was removed under vacuum. The upper parts of the
reaction assembly were heated gently with a heat gun to aid in the
monomer removal. The total time under vacuum was 2-3 hours.
[0248] The molten prepolymer was dissolved in 100 ml of chloroform
with stirring and 2. 5 equivalents of TEA and equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The funnel was rinsed with 10 ml of chloroform. The reaction
mixture was chilled to about 4.degree. C. in a cold bath A solution
of about 1 equivalent of distilled EOPCl.sub.2 in 27.5 ml of
chloroform was prepared in a dropping funnel. The solution in the
funnel was added slowly to the reaction mixture over a period of 1
hour.
[0249] After the addition was complete, the reaction mixture was
allowed to stir at low temperature for another hour and then the
cold bath was removed. The reaction mixture was allowed to warm to
room temperature and stirred for 2 to 18 hours. After 2 hours a
significant increase in viscosity of the clear solution was
observed. The reaction was then quenched with 800 .mu.l of
anhydrous methanol and stirred for another five minutes.
[0250] Next, Dowex MR-3C ion exchange resin (IER) was added to the
reaction mixture and stirring was continued for another hour to
remove residual DMAP and TEA free base and salts (the Dowex resin
had been washed with several bed volumes of methanol and dried
under vacuum at ambient temperature for about 18 hours). The resin
was removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 100 ml. The viscous filtrate (now a somewhat cloudy
solution) was poured into 1000 ml of hexane to precipitate the
polymer. The polymer mass was washed with 2.times.200 ml of hexane
and dried under vacuum. The resulting polymer was dissolved in 50
mL of dichloromethane and precipitated into 1 L of methanol and
dried under vacuum.
[0251] The yield of dried polymer was 17.9 g. The weight-average
molecular weight for the polymer obtained using a differential
refractive index detector and a polystyrene calibration curve (Mw
CC) was 61,900 daltons. The weight-average Mw for the polymer
obtained using a light scattering detector (Mw LS) was 131,800
daltons. The values for inherent viscosity (IV) was 0.77 dL/g. The
.sup.1H and .sup.31P {.sup.1H} NMR spectra of this polymer are
consistent with the presumed structure.
EXAMPLE 13
[0252] A phosphopolymer was prepared from propylene glycol,
D,L-lactide, and EOPCl.sub.2 as follows:
[0253] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 100.0 g portion of D,L-lactide and 5.3 g
of PG (molar ratio, 10:1) were weighed into a 1000 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0254] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 110.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2-3 hours.
[0255] The molten prepolymer was dissolved in 350 ml of chloroform
with stirring and equivalents of TEA and equivalents of DMAP were
added to the stirring reaction mixture using a powder funnel. The
reaction mixture was chilled to about -5.degree. C. A solution of
about 1 equivalent of distilled EOPCl.sub.2 in 97 ml of chloroform
was prepared in a dropping funnel. The solution in the funnel was
added slowly to the reaction mixture over a period of 2 hours.
After the addition was complete, the reaction mixture was allowed
to stir at low temperature for 45 minutes at -5.degree. C. After 2
hours a significant increase in viscosity of the clear solution was
observed. The reaction was then quenched with 6.8 ml of anhydrous
methanol and stirred for another five minutes.
[0256] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 87 g of Dowex HCR-S and 104 g of Dowex M-43,
and shaken on a mechanical shaker for 1 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and dried under vacuum at ambient
temperature for about 18 hours). The resin was removed from the
reaction mixture by vacuum filtration through Whatman 54 filter
paper. The resin was washed with about one bed volume of
dichloromethane and the filtrate was concentrated to approximately
150 ml. The viscous filtrate was poured into 2000 ml of hexane to
precipitate the polymer. The polymer mass was washed with
2.times.200 ml of hexane and dried under vacuum. The molecular
weights were determined by GPC were 39,000 for Mw (LS) and 35,300
for Mw (CC). The value for IV was 0.30 dL/g.
EXAMPLE 14
[0257] A phosphopolymer was prepared from ethylene glycol (EG),
D,L-lactide, and ethyl dichlorophosphate as follows:
[0258] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 100.0 g portion of D,L-lactide and 4.3 g
of EG (molar ratio, 10:1) were weighed into a 1000 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0259] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 110.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2-3 hours.
[0260] The molten prepolymer was dissolved in 350 ml of chloroform
with stirring and equivalents of TEA and equivalents of DMAP were
added to the stirring reaction mixture using a powder funnel. The
reaction mixture was chilled to about -5.degree. C. A solution of
about 1 equivalent of distilled ethyl dichlorophosphate in 97 ml of
chloroform was prepared in a dropping funnel. The solution in the
funnel was added slowly to the reaction mixture over a period of 2
hours. After the addition was complete, the reaction mixture was
allowed to stir at low temperature for 45 minutes at -5.degree. C.
After 2 hours a significant increase in viscosity of the clear
solution was observed. The reaction was then quenched with 6.8 ml
of anhydrous methanol and stirred for another five minutes.
[0261] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 87 g of Dowex HCR-S and 104 g of Dowex M-43,
and shaken on a mechanical shaker for 1 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and dried under vacuum at ambient
temperature for about 18 hours). The resin was removed from the
reaction mixture by vacuum filtration through Whatman 54 filter
paper. The resin was washed with about one bed volume of
dichloromethane and the filtrate was concentrated to approximately
150 ml. The viscous filtrate was poured into 2000 ml of hexane to
precipitate the polymer. The polymer mass was washed with
2.times.200 ml of hexane and dried under vacuum. The molecular
weights were determined by GPC were 40,400 for Mw (LS) and 42,000
for Mw (CC).
EXAMPLE 15
[0262] A phosphopolymer was prepared from 1,6 hexanediol (HD),
D,L-lactide, and ethyl dichlorophosphate (EOPCl.sub.2) as
follows:
[0263] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 100.0 g portion of D,L-lactide and 8.2 g
of HD (molar ratio, 10:1) were weighed into a 1000 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0264] At this time, a volume of stock stannous octoate solution
equivalent (about 130 mg/ml in toluene) to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 110.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2-3 hours.
[0265] The molten prepolymer was dissolved in 350 ml of chloroform
with stirring and equivalents of TEA and equivalents of DMAP were
added to the stirring reaction mixture using a powder funnel. The
reaction mixture was chilled to about -5.degree. C. A solution of
about 1 equivalent of distilled ethyl dichlorophosphate
(EOPCl.sub.2) in 97 ml of chloroform was prepared in a dropping
funnel. The solution in the funnel was added slowly to the reaction
mixture over a period of 2 hours. After the addition was complete,
the reaction mixture was allowed to stir at low temperature for 45
minutes at -5.degree. C. After 2 hours a significant increase in
viscosity of the clear solution was observed. The reaction was then
quenched with 6.8 ml of anhydrous methanol and stirred for another
five minutes.
[0266] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 87 g of Dowex HCR-S and 104 g of Dowex M-43,
and shaken on a mechanical shaker for 1 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and dried under vacuum at ambient
temperature for about 18 hours). The resin was removed from the
reaction mixture by vacuum filtration through Whatman 54 filter
paper. The resin was washed with about one bed volume of
dichloromethane and the filtrate was concentrated to approximately
150 ml. The viscous filtrate was poured into 2000 ml of hexane to
precipitate the polymer. The polymer mass was washed with
2.times.200 ml of hexane and dried under vacuum. The molecular
weights were determined by GPC were 36,700 for Mw (LS) and 34,100
for Mw (CC). The value for IV was 0.33 dL/g.
EXAMPLE 16
[0267] A polyphosphoester was prepared from propylene glycol,
D,L-lactide, and EOPCl.sub.2 as follows:
[0268] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
130.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0269] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 to 18 hours. The oil bath temperature was then
reduced to about 115.degree. C. and the residual monomer was
removed under vacuum. The upper parts of the reaction assembly were
heated gently with a heat gun to aid in the monomer removal. The
total time under vacuum was 2 hours.
[0270] The prepolymer was dissolved in 84 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent of distilled EOPCl.sub.2 in 10 ml of
chloroform was prepared in a dropping funnel. The solution in the
funnel was added slowly to the reaction mixture over a period of
0.5 hour. After the addition was complete, the reaction mixture was
allowed to stir at low temperature for 1 hour at -5.degree. C. The
reaction was then quenched with 1 ml of anhydrous methanol and
stirred for another five minutes.
[0271] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 37 g of Dowex DR-2030 and 30 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the EERs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weight data for the polymers prepared by this process are
listed in the table below.
16 Sample Mw (LS), daltons Mw (CC), daltons 1 67,300 72,600 2
65,400 72,900 3 62,800 72,600
EXAMPLE 17
[0272] A phosphopolymer was prepared from propylene glycol,
D,L-lactide, and EOPCl.sub.2 as follows:
[0273] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 3.0 g of
PG (molar ratio, 5:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
145.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0274] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 115.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2 hours.
[0275] The prepolymer was dissolved in 88 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent based on PG (6.5 g) of distilled ethyl
dichlorophosphate (EOPCl.sub.2) in 20 ml of chloroform was prepared
in a dropping funnel. The solution in the funnel was added slowly
to the reaction mixture over a period of 0.5 hour. After the
addition was complete, the reaction mixture was allowed to stir at
low temperature for 1 hour at -5.degree. C. The reaction was then
quenched with 1 ml of anhydrous methanol and stirred for another
five minutes.
[0276] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 74 g of Dowex DR-2030 and 59 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weights were determined by GPC were 49,500 for Mw (LS)
and 49,600 for Mw (CC). The value for IV was 0.46 dL/g.
EXAMPLE 18
[0277] A phosphopolymer was prepared from propylene glycol,
D,L-lactide, and ethyl dichlorophosphate as follows:
[0278] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.0 g of
PG (molar ratio, 15:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
145.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0279] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 115.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2 hours.
[0280] The prepolymer was dissolved in 83 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent based on PG (2.2 g) of distilled ethyl
dichlorophosphate (EOPCl.sub.2) in 7 ml of chloroform was prepared
in a dropping funnel. The solution in the funnel was added slowly
to the reaction mixture over a period of 0.5 hour. After the
addition was complete, the reaction mixture was allowed to stir at
low temperature for 1 hour at -5.degree. C. The reaction was then
quenched with 1 ml of anhydrous methanol and stirred for another
five minutes.
[0281] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 25 g of Dowex DR-2030 and 20 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weights were determined by GPC were 36,900 for Mw (LS)
and 39,400 for Mw (CC). The value for IV was 0.37 dL/g.
EXAMPLE 19
[0282] A polyphosphoester was prepared from propylene glycol,
D,L-lactide, and ethyl dichlorophosphate as follows:
[0283] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 0.75 g
of PG (molar ratio, 20:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
145.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0284] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 115.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2 hours.
[0285] The prepolymer was dissolved in 82 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent based on PG (1.6 g) of distilled ethyl
dichlorophosphate in 5 ml of chloroform was prepared in a dropping
funnel. The solution in the funnel was added slowly to the reaction
mixture over a period of 0.5 hour. After the addition was complete,
the reaction mixture was allowed to stir at low temperature for 1
hour at -5.degree. C. The reaction was then quenched with 1 ml of
anhydrous methanol and stirred for another five minutes.
[0286] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 19 g of Dowex DR-2030 and 15 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the IERs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weights were determined by GPC were 47,100 for Mw (LS)
and 53,000 for Mw (CC). The value for IV was 0.44 dL/g.
EXAMPLE 20
[0287] A was prepared from propylene glycol, D,L-lactide, and
EOPCl.sub.2 as follows:
[0288] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 0.4 g of
PG (molar ratio, 40:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
145.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0289] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for
approximately 16 hours. The oil bath temperature was then reduced
to about 115.degree. C. and the residual monomer was removed under
vacuum. The upper parts of the reaction assembly were heated gently
with a heat gun to aid in the monomer removal. The total time under
vacuum was 2 hours.
[0290] The prepolymer was dissolved in 81 ml of chloroform with
stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about -5.degree. C. A solution
of about 1 equivalent based on PG (0.8 g) of distilled ethyl
dichlorophosphate (EOPCl.sub.2) in 2 ml of chloroform was prepared
in a dropping funnel. The solution in the funnel was added slowly
to the reaction mixture over a period of 0.5 hour. After the
addition was complete, the reaction mixture was allowed to stir at
low temperature for 1 hour at -5.degree. C. The reaction was then
quenched with 1 ml of anhydrous methanol and stirred for another
five minutes.
[0291] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 9 g of Dowex DR-2030 and 7 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the EERs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weights were determined by GPC were 12,200 for Mw (LS)
and 14,800 for Mw (CC). The value for IV was 0.19 dL/g.
EXAMPLE 21
[0292] A was prepared from propylene glycol, D,L-lactide,
glycolide, and ethyl dichlorophosphate as follows:
[0293] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly and a 125 ml dropping funnel
containing 4.6 g of glycolide. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0294] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 3.6 mg tin (120 ppm
stannous octoate or 35 ppm tin) was added to the melt using a 50
.mu.l syringe. The reaction mixture was allowed to stir under a
slight argon pressure for approximately 16 hours. At this time the
glycolide was melted using a heat gun and added to the polymer melt
in the flask. The melt was stirred for an additional 2 hours. The
oil bath temperature was then reduced to about 115.degree. C. and
the residual monomer was removed under vacuum. The upper parts of
the reaction assembly were heated gently with a heat gun to aid in
the monomer removal. The total time under vacuum was 2 hours.
[0295] The molten prepolymer was suspended in 84 ml of chloroform
with stirring and 2. 5 equivalents of TEA and equivalents of DMAP
were added to the stirring reaction mixture using a powder funnel.
The reaction mixture was chilled to about 4.degree. C. in a cold
bath. A solution of about 1 equivalent of distilled EOPCl.sub.2 in
27.5 ml of chloroform was prepared in a dropping funnel. The
solution in the funnel was added slowly to the reaction mixture
over a period of 1 hour. After the addition was complete, the
reaction mixture was allowed to stir at low temperature for another
1.75 hours and then the cold bath was removed. The reaction mixture
was allowed to warm to room temperature and stirred for 2 to 18
hours. After 2 hours a significant increase in viscosity of the
clear solution was observed. The reaction was then quenched with 1
ml of anhydrous methanol and stirred for another five minutes.
[0296] Next, 37 g of dry Dowex HCR-S and 30 g of dry Dowex M-43
were added to the reaction mixture and stirring was continued for
another hour to remove residual DMAP and TEA free base and salts.
The IERs were removed from the reaction mixture by vacuum
filtration through Whatman 54 filter paper. The resin was washed
with about one bed volume of dichloromethane and the filtrate was
concentrated to approximately 50 ml. The viscous filtrate was
poured into 700 ml of petroleum ether to precipitate the polymer
and dried under vacuum. The molecular weights determined by GPC
were 12,900 for Mw (LS) and 14,300 for Mw (CC). The value for IV
was 0.11 dL/g.
EXAMPLE 22
[0297] A was prepared from propylene glycol, D,L-lactide, and hexyl
dichlorophosphate (HOPCl.sub.2) as follows:
[0298] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
135.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0299] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 3.6 mg tin (120 ppm
stannous octoate or 35 ppm tin) was added to the melt using a 50
.mu.l syringe. The reaction mixture was allowed to stir under a
slight argon pressure for approximately 16 hours. The oil bath
temperature was then reduced to about 110.degree. C. and the
residual monomer was removed under vacuum. The upper parts of the
reaction assembly were heated gently with a heat gun to aid in the
monomer removal. The total time under vacuum was 2-3 hours.
[0300] The molten prepolymer was dissolved in 100 ml of chloroform
with stirring and TEA and DMAP were added to the stirring reaction
mixture using a powder funnel. The funnel was rinsed with 10 ml of
chloroform. The reaction mixture was chilled to about 4.degree. C.
in a cold bath. A solution of about 1 equivalent of distilled
HOPCl.sub.2 in 27.5 ml of chloroform was prepared in a dropping
funnel. The solution in the funnel was added slowly to the reaction
mixture over a period of 1 hour. After the addition was complete,
the reaction mixture was allowed to stir at low temperature for
another hour and then the cold bath was removed. The reaction
mixture was allowed to warm to room temperature and stirred for 2
to 18 hours. After 2 hours a significant increase in viscosity of
the clear solution was observed. The reaction was then quenched
with 800 gl of anhydrous methanol and stirred for another five
minutes.
[0301] Next, Dowex MR-3C ion exchange resin was added to the
reaction mixture and stirring was continued for another hour to
remove residual DMAP and TEA free base and salts (the Dowex resin
had been washed with several bed volumes of methanol and dried
under vacuum at ambient temperature for about 18 hours). The resin
was removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 100 ml. The viscous filtrate (now a somewhat cloudy
solution) was poured into 1000 ml of hexane to precipitate the
polymer. The polymer mass was washed with 2.times.200 ml of hexane
and dried under vacuum. The molecular weight and IV data for the
polymers prepared by this process are listed in the table
below.
17 Sample Mw (LS), daltons Mw (CC), daltons IV, dL/g 1 64,200
58,000 0.48 2 68,000 62,700 0.43
EXAMPLE 23
[0302] A was prepared from propylene glycol, D,L-lactide, and ethyl
dichlorophosphonate (EPCl.sub.2) as follows:
[0303] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of
PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
130.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0304] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate
or 35 ppm Sn was added to the melt using a syringe. The reaction
mixture was allowed to stir under a slight argon pressure for 4
hours. The oil bath temperature was then reduced to about
110.degree. C. and the residual monomer was removed under vacuum.
The upper parts of the reaction assembly were heated gently with a
heat gun to aid in the monomer removal. The total time under vacuum
was 2 hours.
[0305] The molten prepolymer was dissolved in 84 ml of chloroform
with stirring and 2.5 equivalents of TEA and 0.5 equivalents of
DMAP were added to the stirring reaction mixture using a powder
funnel. The reaction mixture was chilled to about -5.degree. C. A
solution of about 1 equivalent of distilled EPCl.sub.2 in 9 ml of
chloroform was prepared in a dropping funnel. The solution in the
funnel was added slowly to the reaction mixture over a period of
0.5 hour. After the addition was complete, the viscosity of the
solution had increased significantly and the reaction mixture was
allowed to stir at low temperature for 1 hour at -5.degree. C. The
reaction was then quenched with 1 ml of anhydrous methanol and
stirred for another five minutes.
[0306] Next, the reaction mixture was transferred to a 0.5 gallon
vessel and mixed with 37 g of Dowex DR-2030 and 30 g of Dowex M-43,
and shaken on a mechanical shaker for 2 hour to remove residual
DMAP and TEA free base and salts (the Rs had been washed with
several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to
approximately 50 ml. The viscous filtrate was poured into 200 ml of
petroleum ether to precipitate the polymer. The polymer mass was
washed with 100 ml of petroleum ether and dried under vacuum. The
molecular weight data for the polymers prepared by this process are
listed in the table below.
18 Sample Mw (LS), daltons Mw (CC), daltons 1 339,900 327,600 2
369,800 360,900
EXAMPLE 24
[0307] A was prepared from propylene glycol, D,L-lactide, and ethyl
dichlorophosphonate (EPCl.sub.2) as follows:
[0308] All glassware was dried for a minimum of 2 hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A 190.0 g portion of D,L-lactide and 10.0 g
of PG (molar ratio, 10:1) were weighed into a 2000 ml 3-neck round
bottom flask. The flask was equipped with a gas joint and a stirrer
bearing/shaft/paddle assembly. The mixture was evacuated and filled
with argon five times to remove residual air and moisture. The
reaction apparatus was immersed in a preheated oil bath at
130.degree. C., connected to an argon source with an oil bubbler,
and stirred at a moderate speed until all of the solid monomer had
melted.
[0309] At this time, a volume of stock stannous octoate solution
(about 130 mg/ml in toluene) equivalent to 200 ppm stannous octoate
was added to the melt using a syringe. The reaction mixture was
allowed to stir under a slight argon pressure for 4 hours. The oil
bath temperature was then reduced to about 110.degree. C. and the
residual monomer was removed under vacuum. The upper parts of the
reaction assembly were heated gently with a heat gun to aid in the
monomer removal. The total time under vacuum was 2 hours.
[0310] The molten prepolymer was dissolved in 560 ml of chloroform
with stirring and 2.5 equivalents of TEA, 0.5 equivalents of DMAP
and 433 .mu.l of anhydrous methanol (7.5 mole % based on PG) were
added to the stirring reaction mixture. The reaction mixture was
chilled to about -5.degree. C. A solution of about 1 equivalent of
distilled EPCl.sub.2 in 60 ml of chloroform was prepared in a
dropping funnel. The solution in the funnel was added slowly to the
reaction mixture over a period of 0.5 hour. After the addition was
complete, the viscosity of the solution had increased significantly
and the reaction mixture was allowed to stir at low temperature for
1 hour at -5.degree. C. The reaction was then quenched with 1 ml of
anhydrous methanol and stirred for another five minutes.
[0311] Next, the reaction mixture was transferred to a 1 gallon
vessel and mixed with 248 g of Dowex DR-2030 and 198 g of Dowex
M-43, and shaken on a mechanical shaker for 2 hour to remove
residual DMAP and TEA free base and salts (the IERs had been washed
with several bed volumes of methanol and chloroform and dried under
vacuum at ambient temperature for about 18 hours). The resin was
removed from the reaction mixture by vacuum filtration through
Whatman 54 filter paper. The resin was washed with about one bed
volume of dichloromethane and the filtrate was concentrated to less
than approximately 500 ml. The viscous filtrate was poured into
1500 ml of petroleum ether to precipitate the polymer. The polymer
mass was washed with 200 ml of petroleum ether and dried under
vacuum. The molecular weights were determined by GPC were 31,300
for Mw (LS) and 41,800 for Mw (CC).
EXAMPLE 25
[0312] A was prepared from 1,4-cyclohexane dimethanol (CHDM) and
hexyl dichlorophosphate (HOPCl.sub.2) as follows:
[0313] All glassware was dried for a minimum of two hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A reaction assembly consisting of a 1 L
three neck round bottom flask equipped with a gas joint, a stirrer
bearing/shaft/paddle and a dropping funnel. A solution of 20.0 g of
CHDM was prepared in 75 ml of anhydrous tetrahydrofuran (THF) and
transferred to the reaction vessel. The beaker was rinsed with 25
ml of THF and the wash was transferred to the reaction vessel.
[0314] Next, 29.0 ml of N-methyhnorpholine (NMM) and 1.61 g of DMAP
were added to the reaction mixture through a powder funnel. A
solution of 28.86 g of HOPCl.sub.2 in 30 ml of THF was prepared
under argon and transferred to the dropping funnel while the
reaction mixture was cooled to 4.degree. C. in a cold bath. The
solution in the funnel was added to the reaction mixture over a
period of one hour. With 5 to 10 minutes after the start of
addition, a white precipitate, presumably the hydrochloride salts
of NMM and DMAP, began to form. After the addition was complete the
funnel was rinsed with 30 ml of THF. The reaction mixture was
stirred for 1 hour at 4.degree. C. and then for either 2 or 18
hours at ambient temperature.
[0315] At the prescribed time, the precipitate was removed from
reaction mixture by vacuum filtration. The filtrate was diluted
with 100 ml of dichloromethane, transferred to a half gallon jar
and 86.5 of dried Dowex HCR-S and 103.8 g of dried Dowex M-43 were
added to the filtrate. The jar was sealed with a Teflon lined lid
and the mixture was agitated on a mechanical shaker for two
hours.
[0316] At this time, the IERs were removed by vacuum filtration and
the filtrate was concentrated to approximately 100 ml under vacuum.
The polymer solution was poured in 2 L of hexane and the resulting
fluid material that precipitated was isolated and transferred to a
Teflon lined glass dish. The polymer was dried under vacuum to
yield a sticky, free flowing viscous liquid. The Mw (LS) data for
the polymers prepared by this process are listed in the table
below.
19 Sample Mw (LS), daltons Mw (CC), daltons IV, dL/g 1 4400 5500
0.14 2 5000 6500 0.11 3 4000 4600 0.10
Example 26
[0317] A phosphopolymer (BHET/EOP) was prepared from
bis(hydroxyethyl) terephthalate (BHET) and EOPCl.sub.2 as
follows:
[0318] All glassware was dried for a minimum of two hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A reaction assembly consisting of a 500 ml
three neck round bottom flask equipped with a gas joint, a stirrer
bearing/shaft/paddle and a dropping funnel. First, 30.0 g of BHET
and 28.83 g of DMAP were added to the reaction vessel using a
powder funnel and mixed with 81 ml of THF. The solids were
dissolved with stirring and gentle heating using a heat gun.
[0319] After all solids had dissolved, the reaction mixture was
cooled to 4.degree. C. in a cold bath. A solution of 19.2 g of
EOPCl.sub.2 in 24 ml of THF was prepared in a 125 ml addition
funnel. The solution in the funnel was added to the solution in the
flask over a period of 1 hour. Shortly after the addition had
begun, a white precipitate, presumably DMAP hydrochloride, began to
precipitate from the reaction mixture. After all of the solution in
the funnel had been added, the stirrer shaft/paddle became
entrapped in a thick, stiff precipitate and stirring ceased. It
appears the polymer that had formed at this time was insoluble in
the reaction mixture.
[0320] Next, 125 ml of dichloromethane were added and the reaction
mixture was swirled by hand until mechanical stirring could be
resumed. The reaction mixture was now a homogenous solution
containing a white free flowing powder. The reaction mixture was
stirred at 4.degree. C. for one hour. The cold bath was removed and
the reaction mixture was allowed to warm to ambient temperature and
stirred for 16 hours. At this time, the white precipitate was
removed from the reaction mixture by vacuum filtration and the
filter cake was washed with 100 ml of dichloromethane.
[0321] The resulting filtrate was transferred to half gallon jar
and treated with 156.92 g of undried Dowex HCR-S and 160.92 g of
undried Dowex M-43. The resins were washed with 2 bed volumes of
methanol and 2 bed volumes of dichloromethane prior to use. The jar
was sealed with a Teflon lined lid and shaken on a mechanical
shaker for two hours. The resin was removed by vacuum filtration
and the filtrate, about 600 ml, was concentrated to about 150 ml.
The clear solution was poured into 1.2 L of hexane. The thick oil
that precipitated was washed with 400 ml of hexane and transferred
to a Teflon lined glass dish, dried under vacuum. The molecular
weights were determined by GPC were 2200 for Mw (LS) and 2100 for
Mw (CC). The value obtained for IV was 0.10 dL/g.
EXAMPLE 27
[0322] A phosphopolymer (BHET/EOP/TC) was prepared from BHET,
EOPCl.sub.2, and terephthaloyl chloride (TC) as follows:
[0323] All glassware was dried for a minimum of two hours at
105.degree. C. and allowed to cool in a desiccator or cooled under
a stream of argon gas. A reaction assembly consisting of a 500 ml
three neck round bottom flask equipped with a gas joint, a stirrer
bearing/shaft/paddle and a dropping funnel. First, 30.0 g of BHET
and 28.83 g of DMAP were added to the reaction vessel using a
powder funnel and mixed with 81 ml of THF and 125 ml of
dichloromethane.
[0324] The solids were dissolved with stirring and gentle heating
using a heat gun. After all solids had dissolved, the reaction
mixture was cooled to 4.degree. C. in a cold bath. A solution of
19.2 g of EOPCl.sub.2 in 24 ml of THF was prepared in a 125 ml
addition funnel. The solution in the funnel was added to the
solution in the flask over a period of 1 hour. Shortly after the
addition had begun, a white precipitate, presumably DMAP
hydrochloride, began to precipitate from the reaction mixture. The
reaction mixture was stirred at 4.degree. C. for one hour. Next, a
solution of 4.79 g of TC in 18 ml of THF was prepared in the
addition funnel and added to the solution in the flask over a 30
minute period. The reaction mixture was stirred for one hour at
4.degree. C.
[0325] At this time the cold bath was removed and the reaction was
allowed to warm to room temperature and stir for another 20 hours.
At this time, the white precipitate was removed from the reaction
mixture by vacuum filtration. The resulting filtrate was
transferred to half gallon jar and treated with 88.5 g of dried
Dowex HCR-S and 73.8 g of dried Dowex M-43. The jar was sealed with
a Teflon lined lid and shaken on a mechanical shaker for two hours.
The resin was removed by vacuum filtration and the filtrate was
concentrated to 100 ml. The clear solution was poured into 2 L of
hexane. The thick oil that precipitated was transferred to a Teflon
lined glass dish, dried under vacuum. The molecular weights were
determined by GPC were 7200 for Mw (LS) and 4000 for Mw (CC). The
value obtained for IV was 0.09 dL/g.
[0326] It is to be understood that the description, specific
examples and data, while indicating exemplary embodiments, are
given by way of illustration and are not intended to limit the
present invention. Various changes and modifications within the
present invention will become apparent to the skilled artisan from
the discussion, disclosure and data contained herein, and thus are
considered part of the invention.
* * * * *