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BACKGROUND OF THE INVENTION
This invention relates to novel polylactide compositions e.g., to polymers
containing segments of poly(R-lactides) interlocked with segments
poly(S-lactides) and to their preparation in various forms.
The optionally active enantiomers L-lactic acid (S-lactic acid) and
D-lactic acid (R-lactic acid), and the corresponding cyclic diesters
thereof. L- and D-(S- and L-)lactides, are known as are methods of
polymerizing the enantiomeric acids or, preferably for high molecular
weight, their lactides, to the enantiomeric open-chain polymers herein
referred to as poly(R-lactide) and poly(S-lactide), respectively, using
mainly cationic initiators, e.g. by compounds of tin, antimony, lead,
zinc. C. Lavallee et al., Proc. Int. Symp. on Adv. in Polymer Syn., Aug.
26-31, 1984, Plenum 1985, pp 441-461 discuss preparation and properties of
racemic and optically active substituted poly(beta-propiolactones). Blends
of these poly-R- and poly-S-lactones (1:1) were reported to form a
"stereocomplex" having a crystalline melting point of 203.degree. C. as
compared to 164.degree. C. for the individual isotactic enantiomers, and a
different crystal structure and morphology. Binary mixtures containing an
excess of either enantiomer also contained the high-melting phase. The
authors describe poly(L-lactide) and poly(D-lactide) as being highly
crystalline, melting at about 180.degree. C., whereas poly(D,L-lactide) is
amorphous. Blends of the individual poly(lactide)enantiomers were not
mentioned. Racemic polylactides, prepared from racemic monomers by these
methods, are either amorphous or somewhat crystalline, melting at about
130.degree. to 140.degree. C., while the polymers prepared from pure
enantiomeric monomers are optically active, isotactic and crystalline,
melting in the range of about 145.degree. to 215.degree. C. Copolymers of
the enantiomeric lactides are reportedly crystalline only when over 90% of
one enantiomer is present; melting point decreases from about 173.degree.
to 124.degree. C. as composition changes from pure enantiomer to 8%
comonomer (opposite enantiomer). Polylactide enantiomers are used in
various surgical and pharmaceutical applications, including sutures and
other prosthetic parts, and as controlled-release encapsulants for
biologically active materials such as anticancer agents and other drugs.
B. Kalb et al., Polymer 21, 607 (1980) describe the crystallization
behavior of poly(L-lactide) prepared by cationic ring-opening
polymerization of the dilactide. The polymer, described as bioabsorbable,
biodegradable and biocompatible, was found to have an equilibrium melting
point of about 215.degree. C., a Tg of about 55.degree. C. and a viscosity
average molecular weight of about 550,000 measured in chloroform.
Precipitation of poly(L-lactide) from chloroform solution with a mixture
of glycerol and ethanol produced porous fibers having pores of 0.1 to 0.6
micron diameter.
D. L. Wise et al. in "Drug Carriers in Biology and Medicine", Ed. G.
Gregoriadis; Acad, Press, N.Y., 237-270 (1979) discusses the
polymerization of D- and L-lactic acids and the dilactides thereof, the
former providing only low molecular weight polymers. Preparation of high
molecular weight polymers from D-, L- and D,L-lactides using
organometallic catalysts such as alkyl zinc, aluminum or tin is described.
Polymers from the individual enantiomeric lactides are preferred over
those from the racemate because sutures prepared therefrom by melt or
solution spinning exhibit less shrinkage. Copolymers of dilactide and
glycolide and their use in various biomedical applications are also
described.
U.S. Pat. No. 4,471,077 discloses that microporous powders can be prepared
from a polymer of D,L-lactic acid, D(-)lactic acid, L(+)lactic acid, or a
copolymer thereof with another hydroxycarboxylic acid. Porous powder is
prepared by cooling a solution of polymer (poly-D-lactide is exemplified)
in hot xylene, filtering off the precipitated polymer and vacuum-drying.
The exemplified powder had "interconnecting pores". 55% pore volume, and
particle sizes largely in the range 100-400 microns. The powders can be
formulated with medicants, nutrients, plant growth regulators, fragrances
and the like, for controlled dispensation. Although the patent teaches
that the polymers can be mixed, no examples or advantages are ascribed to
the mixtures in any proportions.
Ring-opening polymerizations of other lactones or heterocyclic monomers,
e.g. of beta-propiolactones, alkylene oxides and alkylene sulfides, are
known, initiated by ionic or coordination compounds some of which are
stereoselective and, in certain cases, avoid racemization of optically
active monomers during polymerization. Certain polymers prepared from
racemic monomers using stereoselective initiation are reportedly optically
active, indicating polymerization of only one enantiomer. D. Grenier et
al. J. Poly. Sci. Poly. Phys. Ed., 22, 577 (1984); ibid. 19, 1781 (1981);
Macromolecules, 16, 302 (1983) disclose the preparation of D-(R+) and
L-(S-)enantiomers of poly(alpha-methyl-alpha-ethyl-beta-propiolactone) by
ring-opening polymerization of the corresponding enantiomeric, and
preparation of the racemic polymer from the racemic lactone. Blends of the
polymeric enantiomers were prepared in solution and blend properties were
compared with those of the individual polymers. The latter each had a
crystalline melting point of about 160.degree. C., while approximately 1:1
(ee equal or less than 0.5) blends all melted at about 202.degree. C.
Blends having higher enantiomeric excesses showed two melting points at
about 202.degree. and 160.degree. C. respectively. The so-called higher
melting complex was shown to have a different morphology and different
physical properties to the individual polymeric enantiomers.
K. Hatada et al. Polymer J., 13 (8), 811 (1981) disclose 1:1 blends of R-
and S-enantiomers of poly(methylbenzyl methacrylate) which were distinctly
crystalline, melting at 228.degree.-230.degree. C.; the individual
enantiomeric polymers had little or no crystallinity and liquified below
about 160.degree. C.
H. Matsubayashi et al., Macromolecules 10, 996 (1977); P. Sumas et al., Die
Makromol. Chem., 156, 55 (1972) disclose preparation of optically active
and racemic poly(t-butylethylene sulfide) by polymerization of optically
active and racemic monomers, respectively, using a stereospecific
initiator. The racemic and active polymers had crystalline melting points
of 210.degree. C. and 162.degree. C. respectively, and different crystal
structures and morphology.
H. Sakakihara et al., Macromolecules 2, (5), 515 (1969) disclose
preparation of racemic and optically active poly(propylene sulfides), the
former by sterospecific initiation. X-ray diffraction studies led to the
conclusion that the crystal structures of both racemic and optically
active polymers were the same.
It is known that the melting points of enantiomers of a given compound are
the same and that progressive addition of one enantiomer to the other
generally causes a drop in melting point. Usually a minimum (eutectic)
melting point is reached, the melting point rising with further addition
of the second enantiomer. In some instances, including the classical case
of D- and L-tartaric acids, a maximum melt point is reached at
approximately the 1:1 composition. This maximum may be higher or lower
than that of the individual enantiomers, and in either case is thought to
reflect a new crystalline phase ("molecular compound" of the D- and
L-forms). In other instances no maximum is obtained. There is no reliable
way to predict the behavior of enantiomeric pairs in non-polymers let
alone in polymers whose crystalline phases, if any, are more complex.
The art discloses preparation of selected enantiomeric poly(alkylene
sulfides), poly(alkylene oxides), poly(methylbenzylmethacrylates), and
beta-propiolactones. Poly(methylethylene sulfides) prepared from racemic
monomer or from an enantiomer by stereoselective coordination
polymerization both melt at about 60.degree. C. but enantiomeric and
racemic polymers of t-butylethylene sulfide, prepared with the same
catalyst are both crystalline, melting at about 160.degree. and
205.degree. C. respectively. The high-melting racemic polymers reportedly
are mixtures of D- and L-enantiomers. Racemic poly(t-butylethylene
sulfide) prepared from racemic monomer with ionic catalysts is amorphous.
Enantiomers of poly(methylbenzyl methacrylates) prepared from enantiomeric
monomers are essentially amorphous, but 1:1 blends of the polymeric
enantiomers form a highly crystalline "complex" melting at
228.degree.-230.degree. C.
Ring-opening polymerization of beta-propiolactones, especially beta methyl-
or trifluoromethyl beta-propiolactone, has been studied in detail.
Coordination polymerization of enantiomeric monomers produces isotactic,
enantiomeric polymers melting at 164.degree. C. Blends (1:1) of these
enantiomers melt at about 203.degree. C. and differ in crystal morphology
and structure from the component polymers. Moreover, the new phase
persists in blends containing enantiomeric excesses of as high as 1:45.
Formation of a (high melting) complex is reportedly not always the result
of mixing isotactic enantiomeric polymers; equimolar mixtures of isotactic
enantiomeric polymers of beta-butyrolactam, propylene oxide or
methylthiirane (methyl ethylene sulfide) show the same thermal properties
and crystalline structure as the corresponding individual polymers.
U.S. Pat. No. 3,797,499 (1974) discloses absorbable surgical sutures
prepared from poly(L-lactide) or copolymers of L-lactide and glycolide of
high tensile strength and hydrolytic behavior and absorbability. The
poly-L-enantiomer is preferred because of availability and higher melting
point.
D. K. Gilding et al. Polymer 20, 1459 (1979) report the preparation of
poly(L-lactide), poly(D,L-lactide) and copolymers of glycolide and lactide
using antimony, zinc, lead or tin catalysts, preferably stannous
octanoate. Poly(L-lactide) was about 37% crystalline and the
poly(D,L-lactide) was amorphous. U.S. Pat. No. 4,279,249 discloses
bioabsorbable prosthesis (osteosynthisis) parts preparable from poly-D- or
poly-L-lactic acid having enantiomeric purity of over 90%. The latter had
a crystalline melting point of 175.degree. C.
U.S. Pat. No. 4,419,340 discloses controlled release of anticancer agents
from biodegradable polymers including polymers of L(+)-, D(-)- and
D,L-lactic acids and copolymers thereof. U.S. Pat. No. 3,636,956 discloses
absorbable sutures prepared from enantiomeric poly(lactides),
poly(D,L-lactide) and copolymers. Melting point, tensile strength are
reported higher from the individual enantiomeric poly(lactides). D. L.
Wise et al., J. Pharm. Pharmac., 30, 686 (1978) describe sustained release
of antimalarial drugs from poly-L(+)lactide or copolymers thereof with
D,L-lactide or glycolide.
The preparation of high molecular weight poly-D- and poly-L-lactides and
mixtures thereof in the proportions 1-99 to 99-1, formation of a
high-melting phase in the blends, and various medical uses, including
surgical thread, artificial ligaments and the like, are disclosed in
Japanese Unexamined Application J61/036-321.
As discussed hereinabove, poly(lactides) have many desirable properties for
biological applications, but use of even the crystalline enantiomeric
poly(lactides) is limited by melting point, hydrolysis rate, sensitivity
to solvents, polymeric strength and the like which, while superior to the
racemic polylactide, are marginal or inadequate for many applications.
M. Goodman et al., Polymer Letters 5, 515 (1967) describe synthesis of
optically active, highly crystalline poly(lactide) from optically pure
S(+)lactic acid via the lactide. Solution properties of the polymer
dissolved in chloroform, acetonitrile, trifluoroethanol and
trifluoroacetic acid were studied.
Fieser & Fieser "Organic Chemistry", 3rd Ed. Reinhold 1956, pp 267-269
describe non-polymeric optically active compounds and the melting behavior
of mixtures of opposite enantiomers, including the formation of a
"D,L-compound" which may melt higher or lower than the individual
enantiomers, depending on their chemical nature, but always higher than
the eutectic melting point formed by adding one enantiomer to its opposite
enantiomer.
SUMMARY OF THE INVENTION
The invention comprises compositions wherein segments of poly(R-lactide)
interlock or interact with segments of poly(S-lactide). The segments can
be present in mono- or copolymers including random, block and graft
copolymers so long as the segments are arranged to permit at least some
interlocking or interacting. The segments can be present in the molar
ratio of 99:1 to 1:99, preferably about 1:9 to about 9:1, more preferably
about 1:1. Compositions comprising at least one homopoly(lactide) are
preferred. Epsilon-caprolactone is a preferred comonomer. The segmental
interlocking can produce a novel crystalline phase which has a crystalline
melting point higher than that of either component. In preferred
compositions this phase accounts for most of the total crystallinity.
Compositions in the form of gels, porous structures, composits, shaped
articles, solutions, coatings and coated substrates are within the perview
of the present invention.
The present invention includes processes for preparing the above described
compositions e.g., by mixing and combining the previously-prepared
polymeric components in a suitable solvent or in the molten state, and
processes for preparing gels and porous structures of the compositions.
The invention can be employed to prepare absorbable stitching threads used
in vivo, bone plates, artificial tendons, artificial ligaments, artificial
blood vessels, time release carriers for medication, films used in
cultivation in agriculture, fibers, ropes, time release carriers for
agrichemicals, and separatory films for industrial use.
DETAILED DESCRIPTION OF THE INVENTION
Optically active R- and S-enantiomers of lactic acid and of the lactides
are commercially available and can be homopolymerized or copolymerized by
known methods such as bulk (co)polymerization usually in a dry, inert
atmosphere with an ionic catalyst such as stannous octanoate. The
resultant enantiomeric poly(lactides), after purification e.g., by
precipitation from solution in a suitable solvent such as methylene
chloride or chloroform by addition of a non-solvent such as diethyl ether,
have crystalline melting points of 173.degree. to 177.degree. C. Lactide
copolymers will generally have lower crystalline melting points, depending
on lactide content but may be amorphous. It should be understood that the
term "copolymers" as used herein includes polymers prepared from mixtures
of R- and S-lactide as well as from R- or S-lactide and at least one
non-lactide comonomer. Examples of suitable non-lactide comonomers include
those capable of condensation polymerization with lactide or lactic acid,
i.e., lactones such as epsilon-caprolactone, beta-propiolactone,
alpha,alpha-dimethyl-beta-propiolactone, delta-valerolactone, alpha-,
beta- or gamma-methyl-epsilon-caprolactone,
3,3,5-trimethyl-epsilon-caprolactone, dodecanolactone; lactams; other
hydroxy acids such as glycolic acid; amino acids and the like. Operable
copolymers will in general contain blocks of lactide of sufficient length
such that the copolymer exhibits a crystalline melting transition
characteristic of lactide, although enantiomerically balanced compositions
of certain amorphous lactide copolymers may also exhibit a crystalline
melting transition, reflecting the novel phase. Especially useful
thermoplastic elastomeric compositions are comprised of two block
copolymers containing, respectively, lactide blocks of opposite
enantiomeric configuration and "soft" blocks of polyether, polyester or
other similar polymer. The present composition can contain non-lactide
polymers, fillers and other known additives.
The segments of poly(R-lactide) in the polymers of this invention are
interlocked with segments of poly(S-lactide). Interlocked or interlocking
as used herein means the mutual restraint of independent motion exerted by
one of the polylactide segments on the oppositely configured segment. In
this sense, the segments interact or can be considered interacting, but
not so tightly bound as compared to polymer chains which are cross-linked.
X-ray diffraction indicates that when interlocked the interchain distance
of the interlocked portion of the poly(lactide) chain or segment is less
than the interchain distance of the separate (unlocked) poly(lactide)
chains. Only a portion of the polymer segments need be interlocked to
realize the benefits of the present invention, i.e., the poly(R-lactide)
and/or the poly(S-lactide) can be part of a block copolymer or be present
as recurring segments in a random copolymer it being understood that the
level of interlocking will significantly decrease in later case at least
because the (R- and S-) units are less likely to coincide and thereby
provide sites for potential interlocking or interaction. Branching may
also interfere with interlocking. The interlocking is evidenced for
example by the creation of a high melting phase and a distinctive X-ray
diffraction i.e., a reduced layer line spacing consistent with a tighter
helix and altered cell dimensions relative to the individual unlocked
segments.
Compositions of the invention can be prepared by several methods including
dissolving appropriate pairs of enantiomeric homopolymers and/or
copolymers in the desired enantiomeric ratio in a suitable solvent such as
methylene chloride or chloroform at a concentration of at least about 1
wt%, preferably about 10 wt% to about 20 wt%, with agitation, at a
temperature within the liquid or fluid range of the solvent e.g.,
-100.degree. to 300.degree. C., preferably 10.degree.-100.degree. C., at
sub to superatmospheric pressures, followed by evaporation of the solvent.
Preferably the individual enantiomers are dissolved separately and the
solutions mixed together with agitation until homogeneous. Suitable
solvents for preparing the compositions of the invention include
chlorinated solvents such as chloroform, methylene chloride and
chlorinated ethanes, sulfolane, N-methylpyrrolidone, dimethylformamide,
tetrahydrofuran, butyrolactone, trioxane and hexafluoroisopropanol.
Alternatively, the enantiomeric lactide polymers may be mixed in the molten
state. The molten composition can be extended and quenched into molding
powder of usual dimensions or processed into finished objects by methods
known in the art e.g., by injection molding. More particularly, the
dissolved or molten compositions can be cast or extruded onto a suitable
substrate or mold and recovered as film, shaped object, or (from solution)
a gel.
Gels may form spontaneously from a solution containing at least 1 wt% of
blended poly(lactide) enantiomers, preferably at least 5 wt%, on stirring
at about 15.degree. to about 30.degree. C., preferably room temperature.
The lower concentration limit for gelation depends on the solvent
employed. The rate of formation of gel generally increases with increasing
polymer concentration, polymer molecular weight, agitation rate and
decreasing enantiomeric excess. Temperatures significantly above
30.degree. C. or below the 15.degree. C. may reduce the gelation rate. Gel
formation is believed to reflect reduced solubility of the high-melting
cyrstalline phase. The gels can be re-dissolved in high-boiling solvents
at temperatures above about 80.degree., indicating that they are not
covalently cross-linked.
Interlocked homopoly(lactides) normally exhibit two crystalline melting
transitions in differential scanning calorimetry (DSC) while those
containing one or more copolymers may exhibit three or more crystalline
melting transitions. The lower-melting transitions occur at temperatures
essentially equivalent to melting transitions in the individual component
polymers, and reflect lower-melting crystalline phases characteristic of
the component polymers. The high-melting transition, which occurs at about
40.degree. to about 60.degree. above the highest of the lower transitions,
reflects the aforementioned novel high-melting crystalline phase, also
herein referred to as "high-melting phase", and which is further
characterized by a unique X-ray diffraction pattern and physical
properties.
The relative amounts of high- and low-melting phases present in the
invention compositions are determined, in part, by lactide enantiomeric
balance, i.e. the relative molar amounts of R- and S-lactide segments
present, and, in part by the thermal history of the compositions. The
proportions of high- and low-melting phases can be estimated from the
areas under the respective DSC endotherms. Brief melting of the invention
compositions, followed by quenching to below room temperature, results in
an increase of the proportion of high-melting phase present. In
compositions wherein the opposite enantiomeric lactide segments are
approximately balanced, i.e. the relative molar amounts of R- and
S-lactide segments are approximately equal, this thermal treatment can
result in the high-melting phase accounting for essentially all of the
crystallinity present.
The proportion of high-melting phase can be reduced by heating the
compositions for extended periods e.g., several hours at a temperature of
about 10.degree. to about 30.degree. above the highest crystalline melting
point, followed by slow cooling to room temperature. Rapid quenching from
the molten state can also result in an increased amount of amorphous
polymer that exhibits no crystalline melting transition. By careful
selection of enantiomeric balance and thermal treatment, desired
proportions of high- and low-melting crystalline phases and amorphous
content can be "tailored" to achieve a desired balance of properties for
selected uses. Compositions wherein the crystallinity is derived mainly
from the high-melting phase, such as those prepared via gelation, are
preferred. In view of the foregoing, it should now be apparent that some
of the conditions employed in melt-processing can significantly alter the
proportion of high-melting phase.
It has also been found that the polymers in the composition can differ in
molecular weight by a factor of at least 3 without departing from the
present invention.
As previously mentioned and as demonstrated in the examples, the presence
of high-melting crystalline phase substantially increases certain physical
properties such as tensile strength, toughness, tensile elongation,
hydrolytic stability and thermal stability while desirable biochemical
properties and biocompatibility are retained. These applications, which
are well described in the art, frequently require tough, durable, strong
polymer, for example in prosthetic devices, and accordingly benefit from
the present compositions wherein these properties are substantially
enhanced. Alternatively, the present high-melting, higher-performance
compositions permit greater dilution with lower-cost compatible polymers
such as poly(glycolic acid) without expressive compromise in desired
physical properties.
Lactide-containing polymer gels of the invention can be converted to porous
structures of low density (foams) by removing solvent under conditions
which prevent foam collapse. Foams having excellent structural integrity
can be prepared by successively extracting gel, prepared as described
above, with two or more liquids of progressively lower surface tension,
followed by air-drying. The foams are insoluble below about 80.degree. C.
and essentially unswollen by solvents in which component enantiomers
readily dissolve.
The following examples are presented to illustrate but not to restrict the
present invention. Parts and percentages are by weight and temperatures
are in degrees Celsius unless otherwise specified. Thermal transitions in
the exemplified compositions were determined by differential scanning
calorimetry (DSC). Weight- and number-average molecular weights (Mw and
Mn) were determined by gel permeation chromatography (GPC). Polymer
polydispersity (D) is defined by the ratio Mw/Mn. "Enantiomeric excess"
(ee) is given as a percentage by the formula
% ee=100(E1-E2)/(E1+E2)
where E1 and E2 are the number of moles, respectively, of the more abundant
enantiomer and the opposite, less abundant enantiomer. Inherent viscosity
(.eta..sub.inh) is defined by the following equation:
72 .sub.inh =1n.eta..sub.rel /C
wherein .eta..sub.rel represents the relative viscosity and C represents a
concentration in the range of 0.2 to 1.5 g of polymer in 100 g of solvent.
The relative viscosity (.eta..sub.rel) is determined by dividing the flow
time in a capillary viscometer for a solution of concentration C by the
flow time for the pure solvent, measured at 60.degree. C.
[.alpha.].sub.D.sup.25 represents the optical rotation of sodium D light
in a solution of 1 g of polymer in 100 mL of benzene at 25.degree. C.
Tensile properties of fibers and films were measured using ASTM methods:
fibers (single filaments) D-2101; films, ASTM D-882 on an Instron tester
(Instron Engineering Corp., Canton, Mass.). Density was determined by
means of ASTM method D-1505, except for foams; foam density was estimated
by immersing a weighed portion of foam in mercury and measuring the weight
of mercury displaced at 25.degree. C., from which volume is calculated.
Pore volume of foam was determined by the well-known BET (Brunauer, Emmett
and Teller) nitrogen adsorption method. Pores over about 600 A in diameter
are not "counted" by the BET method and are measured by the known method
of mercury intrusion porosimetry; see, for example, Winslow, J. Colloid
and Interface Science, 67, No. 1, 42 (1978).
The poly(R-lactide) and poly(S-lactide) used in the Examples were prepared
according to the following general procedure. The monomers R-lactide and
S-lactide were recrystallized from toluene and dried in vacuo before
polymerization.
Approximately 372 g. of R- or S-lactide was charged to a 500 ml resin
kettle fitted with a mechanical stirrer, a serum stopper, and a gas inlet
through which a dry nitrogen atmosphere was maintained. The resin kettle
was placed in an oil bath maintained at 200.degree. C. and the lactide was
rapidly stirred until completely melted (approx. 5 minutes). Stannous
octanoate (0.160 g.) and 1-dodecanol (0.085 g.) were then added via
syringe and the contents of the kettle were maintained at 200.degree. C.
for 40 minutes with constant stirring during the first 30 minutes. After
30 minutes the contents became too viscous to stir. The kettle was removed
from the oil bath and allowed to cool to room temperature following which
the reaction mixture was removed from the kettle and dissolved in approx.
2000 mL of methylene chloride. The resulting solution was filtered, then
slowly added to a Waring blender operating at high speed and containing a
volume of methanol equal to three times the volume of the methylene
chloride solution. The resulting precipitated poly-S-lactide was isolated
via filtration and dried overnight in vacuo at ambient temperature. The
polymer exhibited an inherent viscosity of 0.977 (chloroform), a melting
point of 171.degree. C., [.alpha.].sub.D.sup.25 =-193.degree., M.sub.w of
198,000 (gpc) and a density of 1.2739 g/cc. Following the above procedure,
similar quantity of poly(R-lactide) was prepared which exhibited an
inherent viscosity of 1.029 (chloroform), a melting point of 166.degree.
C., [.alpha.].sub.D.sup.25 =+191.degree., M.sub.w of 205,000 (gpc) and a
density of 1.2739 g/cc.
EXAMPLE 1
Poly(lactide) films containing varying ratios of poly-R-/poly-S segments
i.e., 1/0 (Comparative), 3/1, 1/1, 1/3, 0/1 (Comparative) were prepared by
dissolving 0.5 g total poly(lactide) in 50 mL methylene chloride with
rapid stirring for 48 hours at room temperature. The methylene chloride
was then evaporated under reduced pressure leaving a tough, transparent
film in the vessel which was shown by DSC to have melting transitions at
about 174.degree. C. and 220.degree. C. except for the film containing
only one enantiomer; the latter showed only one melting transition at
about 174.degree. C. On repeated melting followed by quenching to below
room temperature, the low and high-melting transitions in the
mixed-enantiomer compositions shifted to lower temperature
(2.degree.-3.degree. C. for samples heated to 240.degree. C.,
10.degree.-15.degree. C. for samples heated to 270.degree. C. and more for
samples melted above 270.degree. C.), and the low-melting transition
generally disappeared leaving only the high-melting transition. The
results demonstrate that compositions containing poly-R segments
interlocked with segments of poly-S-lactide form a new crystalline phase
having a melting point about 45.degree. C. higher than the melting point
of either component.
Films prepared as above containing poly-R segments/poly-S segments ratios
of 10/90 and 1/99 also exhibited two melting transitions, the lower at
about 177.degree. and the higher at about 214.degree. and 218.degree. C.
respectively.
EXAMPLE 2
Compositions of optically active polylactides of differing molecular weight
(A-H) were prepared by mixing equal volumes of 10% w/v chloroform
solutions of the appropriate R- and S-lactides and then allowing the
solvent to slowly evaporate at ambient temperature. DSC melting points of
these materials, shown in Table 1 below, indicate that the high-melting
crystalline phase can form even when the respective molecular weights of
the poly-R-(Ar-HR) and poly-S-lactides (AS-HS) are unmatched.
TABLE I
______________________________________
Composition Mw/1000 MP (.degree.C.)
______________________________________
A R- 231 225/233
S- 232
B R- 270 223
S- 280
C R- 133 233
S- 113
D R- 270 230
S- 113
E R- 280 230
S- 133
F R- 231 232
S- 113
G R- 133 230
S- 232
H R- 231 220
S- 280
______________________________________
EXAMPLE 3
Chloroform solutions of poly-R- and poly-S-lactide (10% w/w) were mixed at
room temperature and stirred until homogeneous. The solutions were cast
onto glass plates and allowed to dry for several days. The films were then
annealed for 1 hour at 70.degree. C. and cut with a razor blade into
strips. The tensile properties were set forth in Table II.
TABLE II
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Composition
Mole ratio
Stress- Tensile-
poly(R-lactide)
to-Break
Modulus Elongation-
Toughness
poly(S-lactide)
Kpsi(MPa/6.9)
Kpsi(MPa/6.9)
at-Break(%)
Kpsi(MPa/6.9)
__________________________________________________________________________
Comparative 1:0
4.5 .+-. 2.0
265 .+-. 20
3 .+-. 1
0.1 .+-. 0.05
3:3 5.3 .+-. 0.2
281 .+-. 8
10 .+-. 5
1:1 7.3 .+-. 0.9
340 .+-. 40
12 .+-. 3
0.6 .+-. 0.3
Comparative 0:1
4.3 .+-. 0.2
259 .+-. 25
3 .+-. 1
__________________________________________________________________________
The stress-to break is about 60% higher for films prepared from the 50/50
composition, compared to the pure enantiomers. The tensile modulus
elongation-at-break and toughness are similarly improved in the blends.
Samples of polylactide film prepared as above including the comparatives
and the composition of this invention (1:1) were heated to 230.degree. C.
for 210 minutes, and the weight loss was monitored. The results which are
set forth in Table III show that 1:1 films are more thermally stable than
films of pure enantiomer.
TABLE III
______________________________________
Comparatives
Time (min) 1:1 1/0 0/1
______________________________________
7 96.8 97.3 98.3
57 96.5 95.5 96.7
107 96.4 93.9 94.3
157 96.3 92.4 91.6
217 96.2 90.5 88.7
______________________________________
In addition to singlet loss the samples of polylactide showed some loss in
weight average molecular weight after heating for 210 minutes compared to
the starting polymers, with the 1:1 interlocked poly(R- and S-lactide)
being the most resistant as shown in Table IV.
TABLE IV
______________________________________
Sample M.sub.w (initial)/1000
M.sub.w (after)/1000
______________________________________
1:1 237 204
1/0 (Comparative)
220 102
0/1 (Comparative)
239 95
______________________________________
Polylactide films were prepared from poly-R-lactide and from a 1:1 blend of
poly-R- and poly-S-lactide as described above. The latter contained a
high-melting phase. Samples (200 mg) of the films were incubated at
37.degree. C. in 45 mL of a 2M phosphate buffer solution of pH 10 and the
amount of soluble lactide was periodically monitored by standard enzymatic
assay (H. V. Bergmeyer, Methods of Enzymatic Analysis, 3rd edit., Verlag
Chemie 6, 588 (1984)) and expressed as percent polymer converted to
soluble lactide. The results are shown in Table V.
TABLE V
______________________________________
Soluble Lactide (%)
Days 1:1 Poly(R-lactide)
______________________________________
0 0.00 0.00
14 0.05 0.46
28 0.28 0.90
42 0.28 1.13
72 0.56 3.06
87 0.62 3.86
120 0.84 7.67
127 1.07 9.01
137 1.41 10.6
142 1.86 11.4
145 2.37 11.8
148 2.65 12.6
______________________________________
The results show that the 1:1 films containing high-melting phase are about
6 times more resistant to hydrolysis than films containing only one
enantiomer.
EXAMPLE 4
Solutions of poly-R- and poly-S-lactide (10%) were mixed in equal amounts
and stirred at room temperature until homogeneous. The resultant solution
was charged to a syringe and then ejected through a 20 gauge needle into
methanol. The polylactide formed thin fibers which were removed from the
solution and dried overnight at room temperature under tension. The fibers
exhibited a tenacity of 4.1 Kpsi(Mpa/6.9), an elongation of 72%, a modulus
of 306 Kpsi(MPa/6.9) and a toughness of 2.7 Kpsi(MPa/6.9).
EXAMPLE 5
Samples of a poly(lactide) composition containing equal molar amounts of R-
and S-enantiomers were melted on a hot bar at different temperatures and
drawn into fibers. The results are shown in Table VI.
TABLE VI
______________________________________
Strain-
Tenacity at- Modulus Toughness
Sam- Kpsi Maximum Kpsi Kpsi Temp.
ple (MPa/6.9) Draw (MPa/6.9)
(MPa/6.9)
(.degree.C.)
______________________________________
A 9.6 37% 366 2.6 241
B 4.5 2 138 0.05 255
C 3.0 6 247 0.07 238
D 2.3 <1 298 0.01 267
______________________________________
EXAMPLE 6
A 1:1 composition of poly-R- and poly-S-lactide was prepared by mixing
chloroform solutions of the pure enantiomers and precipitating the thereby
interlocked polymer in methanol. The polymer was air-dried and then
vacuum-dried overnight at 100.degree. C. The polymer was formed into a
plug by compression molding at 150.degree. C. for 3 minutes at 5000 psi
(34.5 MPa) and spun through a capillary (0.30 mm diameter, 0.69 mm length)
at 230.degree. C. with a spin stretch of 2X.
The as-spun fiber was drawn over a hot shoe positioned between two
"Grapham" drives, and at 90.degree. C., a maximum draw of 9.8X was
obtained. Tensile properties, which varied with the thermal treatment and
the draw ratio, are set forth in Table VII.
TABLE VII
______________________________________
Fiber Draw Ratio and
Tenacity Elongation
Modulus
Sample
Temperature (.degree.C.)
(MPa) (%) (MPa)
______________________________________
A As-spun 42.8 1.4 3374
B 2.times. at 75
146 54 4837
C 2.5.times. at 75
214 97 4837
D 2.times. at 75 then
315 57 5175
2.times. at 25
E 4.times. at 75
111 58 4499
F 4.times. at 90
180 55 4727
G 9.4.times. at 90
525 23 7424
H 9.4.times. at 90,
191 29 5175
heat set
at 215
______________________________________
As-spun fibers prepared as set forth above show a glass transition (Tg) at
62.degree. C., a crystallizing transition at 96.degree.-100.degree. C.,
and melting transitions corresponding to the low- and high-melting phases.
The Tg and crystallizing transitions indicate some amorphous phase. X-ray
diffraction measurements indicate both low- and high-melting phases in all
of the fibers except those prepared by heat-setting at 215.degree. C. The
latter contained only high-melting crystalline phase.
EXAMPLE 7
A firm gel was obtained by mixing and dissolving equimolar amounts of solid
poly-R- and poly-S-lactides in chloroform (15% w/w, total polylactide) and
stirring for several hours at room temperature. The gel could be cut with
a spatula into smaller pieces which did not collapse or liquify after
diluting to 10% (w/w) and stirring for another 48 hours.
EXAMPLE 8
Separate solutions of 10.0 g of poly-R-lactide in 50 ml of chloroform and
10.0 g of poly-S-lactide in 50 ml of chloroform were prepared. The
solutions were thoroughly mixed, sealed and allowed to stand at ambient
temperature for two weeks after which the solution had set to a waxy gel
which could be cut into pieces with a spatula and removed from the flask.
The gel was shown to be soluble in hexafluoroisopropanol. A similar gel
dissolved in 1,1,2,2-tetrachloroethane (TCE) when heated to about
140.degree. C. and then reformed on cooling to room temperature. These
tests suggest that the gels are not irreversibly cross-linked. Additional
tests suggest that shear rate is important for initiating and controlling
the gelling process and that the time required to set to a firm gel was
varied inversely with the stirring period.
EXAMPLE 9
Separate solutions of poly-S-lactide and poly-R-lactide were prepared by
mixing 30 g of TCE with 3 g of polylactide and then heating and stirring
at 95.degree. C. (9% w/w). The two solutions were cooled to room
temperature, and 5 g of each solution were mixed and stirred. The solution
remained fluid for at least 24 hours but turned to a solid, homogeneous
gel within 48 hours.
The gel dissolved near the boiling point of TCE (149.degree. C.) to give a
visually clear solution. On cooling to 25.degree. C., the liquid
resolidified to a clear gel.
Gels of 1:1 compositions of poly-R- and poly-S-lactide were similarly
prepared in dimethylformamide and N-methylpyrrolidone at polymer
concentrations above about 1%.
EXAMPLE 10
Separate stock solutions of poly-R- and poly-S-lactides were prepared by
dissolving 10 g polymer in 56.67 g of chloroform. The solutions were mixed
in ratios (R/S) of 2:1, 1:1, 1:2 (w/w) to give 15% w/w solutions which
contained 33% ee poly-R-, 0% ee, and 33% ee poly-S-lactide, respectively.
The solutions were stirred for seven minutes at room temperature; gelation
occurred almost immediately.
EXAMPLE 11
poly(lactide) gel was prepared from a chloroform solution (12) containing
20 g total poly(lactide) 1:1 (R/S) in 100 ml solvent according to the
general procedure as described in Example 8, and extracted with carbon
tetrachloride in a soxhlet apparatus for 24 hours. The solvent was then
changed to 1,2-dichloro-1,1,2,2-tetrafluoroethane and extraction was
continued for another 24 hours. The extracted pieces of gel were air-dried
for 3 hours, and then placed under vacuum (50 torr) for 24 hours. The
resulting porous, solvent-free material exhibited a surface area of 152
m.sup.2 /g, a pore volume of 0.42 ml/g, and an average pore diameter of
111 A as measured by BET nitrogen absorption. The maximum cell-size (SEM)
and estimated density of the foam were, respectively, about 1 micron and
<0.51 g/ml.
Gel prepared from chloroform solution (10%) according to the general
procedure of Example 8, was successively extracted four times with carbon
tetrachloride and then four times with
1,2-dichloro-1,1,2,2-tetrafluoroethane. The gel had a firm, rubbery
consistency. On air-drying, substantial shrinkage occurred. The estimated
density of the foam was <0.54 g/ml. BET analysis showed a narrow pore-size
distribution centered near 80-90 A with 90% of the pore volume derived
from pores with diameters between 40 A and 120 A. The maximum cell-size
was about 0.5 micron (SEM).
This example demonstrates that the large pores (100 A to 1000 A) collapse
selectively when the solvent extraction is terminated after
1,2-dichloro-1,1,2,2-tetrafluoroethane. Terminating the extraction process
with a solvent of higher surface tension than
1,2-dichloro-1,1,2,2-tetrafluoroethane can shift the maximum of the
pore-sizes distribution to smaller pore-size and narrow the distribution
of pore-sizes about the maximum. The opposite effect is expected for
solvents with surface tensions less than
1,2-dichloro-1,1,2,2-tetrafluoroethane.
The estimated density of foam prepared from 10% gel in chloroform after
washing in perfluorohexane was <0.28 g/ml.
EXAMPLE 12
Gel prepared from 9% TCE solution as described in Example 9 was immersed in
carbon tetrachloride and allowed to stand for 24 hours. The resultant gel
was translucent, firm and rubbery. The gel was successively washed with
carbon tetrachloride (4 washes), with
1,2-dichloro-1,1,2,2-tetrafluoroethane (5.times.) and then air-dried to
constant weight. On drying, the gel shrank, indicating partial collapse of
the porous structure. When the dried gel was resolvated with carbon
tetrachloride it approached its original dimensions. The washing procedure
was repeated with 1,2-dichloro-1,1,2,2-tetrafluoroethane, followed by
perfluorohexane (2.times.), then air-drying to constant weight. The foam
showed little visible shrinkage, had an estimated density of 0.49 g/ml, a
surface area of 182 ml/g, pore volume of 1.05 ml/g, average pore diameter
of 230.7 A (BET absorption), and a maximum cell-size (SEM) of about 0.75
micron.
EXAMPLE 13
Gels prepared from a 5% sulfolane solution (Example 10) were immersed in
heptane (gel to heptane ratio was 1:5 w/w) for 24 hours at room
temperature. One-third of the heptane was then replaced with diethyl ether
and allowed to equilibrate for 24 hours. The solvent was then totally
replaced with pure diethyl ether and allowed to equilibrate for 24 hours;
this process was repeated 3 times. Diethyl ether was then exchanged for
1,2-dichloro-1,1,2,2-tetrafluoroethane 4 times with a 24 hour
equilibration period after each exchange. Finally,
1,2-dichloro-1,1,2,2-tetrafluoroethane was exchanged for perfluorohexane 4
times, again with 24 hour equilibration periods after each exchange. When
air-dried to constant weight, the solvated gel exhibited a density <0.1
g/ml. Characterization by SEM revealed an open, microcellular structure,
with a maximum cell size of about 1 micron. BET analysis showed a surface
area of 138.5 m.sup.2 /g, pore volume of 0.53 ml/g, and an average pore
diameter of 151.7 A.
Very similar results were obtained when the sulfolane gel was initially
immersed in hexane, pentane or cyclehexane instead of heptane.
Foams were also prepared from gels formed in trioxane, NMP and
dimethylformamide. In each case, low density, highly porous structures
were obtained with minimal shrinkage provided solvent extraction was
terminated with a low-surface tension solvent such as perfluorohexane.
EXAMPLE 14
The polylactide gel from Example 10 (10% solution) was successively washed
in carbon tetrachloride (5.times.), 1,2-dichloro-1,1,2,2-tetrafluoroethane
(5.times.) and perfluorohexane (7.times.) fol | | |
