Journal of Environmental Polymer Degradation, Vol. 5, No.

3, 1997

Poly(aspartic Acid): Synthesis, Biodegradation, and Current

Applications

S. Roweton, 1 S. J. H u a n g , 1'3 and G. Swift 2

Poly(aspartic acid) is a biodegradable, water-soluble polymer that is valuable in numerous indus-

trial applications. A variety of synthetic methods can be utilized to prepare poly(aspartic acid) and
related polymeric materials with a range of tailored physical and chemical characteristics. This
review of current investigative and patent literature describes methods of synthesis, biodegradative
studies, and important current and potential applications of both poly(aspartic acid) homopolymers
and copolymers.
KEY WORDS: Poly(aspartic acid); biodegradation; water-soluble polymers; N-carboxyanhydrides; polysuc-
cinimides

INTRODUCTION The unique characteristics of poly(aspartic acid)

Poly(aspartic acid) has several unique characteris-
tics that can be exploited for a range of uses. A variety
of methods for the synthesis of poly(aspartic acid) ex-
ists, facilitating the production of poly(aspartic acid) and
related materials with a range of physical and chemical
characteristics. Because it is a biodegradable, water-
soluble polymer, poly(aspartic acid) has been studied as
a replacement for polycarboxylate components in deter-
gents [1]. This polymer has proven to be adsorptive on
sewage sludge, which is also a key factor in determining
its usefulness as a polymeric detergent component. A
current need for new biodegradable materials for use as
scaffolding for tissue growth, drug delivery, and other
biomedical applications has also fostered interest in
poly(aspartic acid) and related polymers. In biomedical
implants, products of polymer degradation can be toxic
[2]. Because poly(amino acids), such as poly(aspartic
acid), comprise naturally occurring components, the
possibility of associated toxicity may be reduced.
Polymer Science Program, Institute of Materials Science, University
of Connecticut, 97 North Eagleville Road, Storrs, Connecticut
06269.
2Rohm and Haas Company, Spring House, Pennsylvania 19477.
3To whom correspondence should be addressed.
and other poly(amino acids) have motivated the study
of these polymers for a variety of applications. Indus-
trial applications include the use of poly(aspartic acid)
for water treatment, paper processing, and paint addi-
tives. Poly(aspartic acid) has potential biomedical ap-
plications including use as a material component in di-
alysis membranes, artificial skin, drug delivery systems,
and orthopedic implants [2, 3]. A review of current in-
vestigative and patent literature on poly(aspartic acid)
materials has revealed various methods of synthesis,
studies concerning the biodegradation of poly(aspartic
acid) and related copolymers, and a range of current and
potential applications for this class of polymeric mate-
rials.
SYNTHESIS OF POLY(ASPARTIC ACID)
The structures of poly(c~-L-aspartic acid) and
poly(~-L-aspartic acid) are shown in Fig. 1. Several
methods are available for synthesizing poly(aspartic
acid) including condensation reactions and the thermal
polymerization of maleamic acid.
The most common method for synthesizing
poly(aspartic acid) (PAA) and other poly(amino acid)s
involves the polycondensation of the appropriate N-car-

175
1064-7546/97/0700-0175512.50/0 9 1997 PlenumPublishingCorporation
176
c ,coo t coo
poly(~-L-asparticacid) poly(~-L-asparticacid)
Fig. 1. Structures of poly(~-L-asparticacid) and poly(fl-L-aspartic
acid) [41.
boxyanhydride or activated ester. The synthesis of
poly(aspartic acid) by this method has been well repre-
sented in the literature [3, 5-7]. N-Carboxyanhydrides
(NCAs) are monomers of a-amino acids that are blocked
at one carboxyl and activated for polymerization at the
other. One method of NCA preparation, used by Hay-
ashi and Iwatsuki (1990), involves the phosgenation of
the corresponding ~x-amino acids in tetrahydrofuran and
subsequent purification via multiple recrystallizations.
Poly(aspartic acid) is then prepared by this method using
a solution of the resulting fl-benzyl-L-aspartate (fl-BLA)
NCA in dioxane and/or methylene chloride and an amine
initiator (such as triethylamine or benzylamine).
Following polymerization, the protected carboxyl
is deblocked. One example of this deblocking procedure
involves the debenzylation of fl-BLA by a treatment
using anhydrous HBr in trifluoracetic acid [3-7]. A side
reaction can result in fl-aspartyl linkages through the
opening of an intermediary cyclic imide (Fig. 2).
Until recently, it was commonly believed that syn-
thesis of poly(aspartic acid) by the procedure described
above resulted in a polymer with one type of peptide
bond. As a trifunctional monomer, aspartic acid may be
linked in poly(aspartic acid) by an ~-peptide, a r-pep-
tide, or an imide bond. Using chemical degradation
methods, 13C-NMR spectroscopy, potentiometric titra-
tion, and other methods, it has been shown that PAA
samples, commercially supplied as being poly(c~-L-
aspartic acid) only, often contain up to 45 % fl-peptide
linkages [4, 6-8]. Determination of the nature of the
CO--N bonds present in poly(aspartic acid) is important
in determining the conformation of the resulting poly-
mer. Knowledge of the secondary molecular structure is
essential for modeling and other applications (Fig. 3).
0 0
f~-~_CH2CrHs ~..(a),
r --,.
o o
Fig. 2. Schematicrepresentationof the deprotectionof benzylgroups resultingin the formationof fl-aspartyl
linkages [4].
Roweton, Huang, and Swift
j, IcH ) cooH l ,m-
COOH (CH2)H---C
I II IlI
n=lor2
Fig. 3. Representativea-peptide (I), fl-peptide(II), and imide (III)
bonds [6].
A method has been developed that facilitates the
synthesis of PAA in pure c~-linkage form [4]. This
method involves the use of a-amino NCA monomers
and a dialkyl aspartate as the primary amine initiator.
Use of this initiator results in an end group that is an
additional aspartate unit.
In addition to methods involving the use of NCAs,
poly(aspartic acid) homopolymers can be synthesizing
using other condensation reactions. A method using
thermal polymerization for the synthesis of poly(aspartic
acid) is described in patents assigned to the Donlar Cor-
poration [9-11] and others [12, 13]. The Donlar Cor-
poration patents detail the synthesis of poly(aspartic
acid) using a technique that facilitates control of poly-
mer molecular weight and produces relatively high con-
version of L-aspartic acid to polysuccinimide and
poly(aspartic acid) with respect to other methods of syn-
thesis. This method involves heating powdered L-aspar-
tic acid to at least 370~ to initiate a condensation re-
action. Subsequently, the L-aspartic acid is heated to
higher than 440 oF, where the temperature is maintained
until at least 80 % conversion of L-aspartic acid to poly-
succinimide is achieved. Hydrolysis of the polysuccini-
mide produces poly(aspartic acid). The poly(aspartic
acid) produced using this method is characterized by a
molecular weight of 1000 to 5000. Related patents de-
scribe thermal polycondensation reactions facilitated by
acid catalysts [14] and continuous, relatively fast meth-
ods for the thermal polymerization of polysuccinimides
[15].
Poly(aspartic acid) has been synthesized on a large
scale using dry L-aspartic acid using a thermal poly-
O O
o o
(a)a-peptide (b)~-peptide
Poly(aspartic Acid)
merization method similar to the method described
above [16]. Polymerization yields a polysuccinimide,
which can be hydrolyzed in the presence of base to form
PAA. The overall process has been shown to yield up
to 99 % conversion of aspartic acid to polyaspartate. The
resulting thermal polyaspartate (TPA) was shown to be
a copolymer having 70% of the amide bonds formed
from 3-carboxyl groups and 30% from a-carboxyl
groups.
Another method for the thermal polymerization of
aspartic acid has been described in which poly(alkylene
glycol) is used as a dispersion medium [17, 18]. Aspar-
tic acid and poly(alkylene glycol) are heated to an ele-
vated temperature in the range from 120 to 300~ and
maintained at this temperature to form a polysuccinim-
ide. Poly(amino acid)s can then be produced by the hy-
drolysis of the polysuccinimides.
A third method for the synthesis of poly(aspartic
acid) homopolymers involves the polymerization of ma-
leamic acid obtained from the reaction of maleic anhy-
dride and ammonia. The preparation of high molec-
ular weight polysuccinimides and, subsequently,
poly(aspartic acid) using this method has been described
[19-22]. For example, Boehmke describes a process in
which maleic anhydride is melted and heated to 75~
Subsequently, 1 mol of 25% NHgOH is added to the
solution and then the solution is dried under vacuum.
The resultant maleic acid is reacted with ammonia at a
molar ratio of 1 : 1-1.5 at 120-150~ This reaction is
followed by the optional neutralization of the pendant
acid groups and isolation of the resultant salts.
A patent outlining a similar method for the prepa-
ration of the salt of poly(aspartic acid) is assigned to
SRchem Incorporated [23-25]. The process outlined in
this patent involves reacting maleic acid and ammonia
at a molar ratio of 1 : 1-2 at 190-350~ for a period of
up to 4 h. The resultant polymer can then be converted
to a salt by adding an alkaline-earth or alkali metal hy-
droxide or ammonium hydroxide.
SYNTHESIS OF POLY(ASPARTIC ACID)-
CONTAINING COPOLYMERS
Various types of amino acid-containing copoly-
mers have been synthesized including copolymers con-
taining aspartic acid. Copolymers of L-aspartic acid and
L-glutamic acid have been used to investigate the rate of
simulated in vivo degradation of these materials as a
function of copolymer composition [3, 5]. In this study,
copolypeptides were prepared using the NCA mono-
mers of 3-benzyl-L-aspartate (3-BLA) and "y-benzyl-L-
177
glutamate (3,-BLG). The NCA monomers were formed
as previously described by the phosgenation of the cor-
responding or-amino acids in tetrahydrofuran. Solutions
(0.1 M) of the 3-BLA and "y-BLG were prepared in both
dioxane and in a 1 : 3 (v/v) mixture of dioxane and meth-
ylene chloride. The two NCA monomer solutions were
mixed in varying proportions and the copolymerization
was initiated using triethylamine. The monomer-to-ini-
tiator ratio used was 50. Following the copolymeriza-
tion, the copolypeptides formed were precipitated at 4~
by adding four times the amount of methanol by vol-
ume. The methanol included 5 vol% of 0.1 N HCI. The
precipitate was washed in pure methanol and dried un-
der reduced pressure at 50~ Anhydrous HBr treatment
was employed for the debenzylation of 3-BLA and
3,-BLG residues. Fianlly, the debenzylated material was
dialyzed thoroughly against distilled water, filtered, and
freeze-dried.
Another method for the preparation of a PAA-con-
taining copolymer involves the use of NCAs. This
method was used to synthesize amphiphiles with poly(u-
aspartic acid) head groups [26]. These amphiphiles are
double-chain alkyl compounds with hydrophilic poly(u-
aspartic acid) head groups. First, L-glutamic acid dido-
decylamide (L-GAD) is obtained. The structure of the
L-GAD cation is shown in Fig. 4. The L-GAD is ob-
tained by coupling N-benzyloxycarbonyl-u-glutamic
acid with dodecylamine using a method described by
Ihara et al. [26]. The L-GAD amine shown in Fig. 4 is
then used as an initiator in the polymerization of poly(3-
benzyl-g-aspartate). The polymerization is accom-
plished as previously described, using the NCA 3-ben-
zyl-u-aspartate monomer. The structure of the resulting
amphiphile following deprotection is shown in Fig. 5.
The common method of polypeptide synthesis de-
scribed previously, involving the use of NCAs, is an
effective yet time-consuming approach. It requires prep-
aration of the appropriate NCA prior to polymeriza-
tions. This method can be applied only to the polymer-
ization of a-amino acids. An alternative method for
polypeptide synthesis has been described by Nishi et al.
and involves the use of dipbenylphosphoryl azide
(DPPA) and an adequate tertiary amine [27, 28]. This
method can be used to prepare poly(ot-amino acid)s and
sequential polypeptides by direct polycondensation of
peptides. In general, this method of polypeptide synthe-
CH3(CH2)11---NHCO-'~H-NH3 +
~H~ X_
CH2(CH2)ll--NHCO-CH2
Fig. 4. Structureof the L-GAD[26].
178
CH3(CH2)ll---NHCO-~H-NH--(CO--CH--NH)n--H
I
~H 2 CH2COOH
CH2(CH2)ll--NHCO-CH 2
n = 4, 7, and 13
Fig. 5. A representative amphiphile with a poly(L-aspartic acid)
headgroup [26].
sis involves 1.3 mol of DPPA and 2.3 mol of trieth-
ylamine per mol of amino acid. A solvent, such as di-
methyl sulfoxide, N,N-dimethylformamide, 1,4-
dioxane, or pyridine, is also required. This method often
eliminates the likelihood of racemization during synthe-
sis.
Copoly(amino acid)s have also been synthesized by
direct polycondensation using the method described by
Nishi et al. [29-31]. DPPA was used as a condensation
agent for the synthesis of these polymers. The random
copolymers produced were characterized by bimodal
molecular weight distributions. The effects of monomer
concentration, reaction time, solvents used, and tem-
perature on molecular weight were investigated. Bulk
polymerization proved most effective in producing
poly(amino acid)s with relatively high molecular
weights. DPPA has also been used to synthesize random
copolymers consisting of a-amino acid and nylon units
via direct copolycondensation [29-31].
Poly(amino acid)s, including fl-benzyl-L-aspartate
(BLA), have been grafted onto a polystyrene copolymer
[32]. To accomplish this, a copolymer of styrene and
1,4-divinylbenzene (DVB) is initially prepared. This is
accomplished via a radical copolymerization of DVB
and styrene at 45 ~ using 2,2'-azobis(2,4-dimethylval-
eronitrile) as an initiator. Benzene is used as the solvent.
After the reaction is complete, the polymer is precipi-
tated in petroleum ether and subsequently redissolved in
benzene. Lyophilization is then used to isolate the poly-
mer product.
Once the styrene/DVB copolymer has been synthe-
sized, the poly(/3-benzyl-L-aspartate) can be radically
grafted onto it. This reaction is initiated by mixing a
THF solution of BLA/NCA with a dichloromethane so-
lution of the styrene/DVB copolymer at 35~ The re-
action is complete after several days. The polymer prod-
uct is precipitated in petroleum ether and then filtered
and dried thoroughly.
In addition to the examples described above, a va-
riety of additional novel aspartic acid copolymers has
been synthesized for a range of uses. Examples include
poly(aspartic acid)/citric acid and poly(aspartic acid)/
succinic acid copolymers useful in water treatment ap-
Roweton, Huang, and Swift
plications [24, 25]. The existence of such a variety high-
lights the versatility of poly(aspartic acid)-containing
polymers.
BIODEGRADATION
The biodegradation of poly(aspartic acid) and as-
sociated materials has been investigated. Recently,
characterization of the biodegradation of poly(aspartic
acid) has been reported by Swift et al. [1] and Alford et
al. [33]. Swift et al. describe the preparation of sodium
salts of poly(aspartic acid) from initial thermal poly-
merization of aspartic acid alone or with an acid catalyst
or from the thermal polymerization of maleamic acid.
The resulting polysuccinimides were subsequently hy-
drolyzed to form the sodium salts of poly(aspartic acid).
Semicontinuous activated sludge (SCAS) testing and
subsequent CO2 evolution testing were used to evaluate
the rate and degree of biodegradation of the aspartic acid
polymers. It was determined that the acid-catalyzed
poly(aspartic acid) materials were significantly more
biodegradable than the poly(aspartic acid) materials pre-
pared via thermal polymerization without an acid cata-
lyst or those samples prepared from maleic anhydride
and ammonia. Swift et al. report that a linear polyamide
backbone is essential for polyaspartates to be totally
biodegradable.
Alford et al. [33] studied the biodegradation of
thermally synthesized polyaspartate prepared via a dry
thermal polymerization. Such a polymerization requires
no reagents other than aspartic acid. This type of poly-
merization is convenient for large-scale production and
is characterized by the fact that its only significant prod-
ucts are the polymer and the water produced by conden-
sation reactions. As described previously, the conden-
sation polymerization produces a polysuccinimide that
is subsequently hydrolyzed with base to form a polyam-
ide. A racemic mixture of aspartic acid as well as co-
polymer with amide bonds can be formed from both the
a- and the/3-carboxyl groups. Alford et al. investigated
the biodegradation of poly(aspartic acid) prepared via
dry thermal polymerization using biochemical oxygen
demand (BOD) analysis, SCAS and CO2 evolution test-
ing, TLC and GPC analysis, and adsorption assays in-
volving various particulate adsorbents. Adsorbents in-
cluded calcium carbonate, acid-washed kaolin, activated
sludge, and subsoil.
From this investigation, Alford et al. concluded
that polyaspartate synthesized using thermal methods,
referred to as thermal polyaspartate (TPA), has a desir-
able degradative character and would essentially be ad-
Poly(aspartic Acid)
sorbed and at least partially mineralized when subjected
to the environment of a typical wastewater treatment
plant. The mechanism of TPA hydrolysis has not been
definitively determined but could potentially involve
both exo- and endopeptidase activity. Enzymatic activ-
ity associated with TPA is unique due to the fact that
TPA does not have the structure of a typical protein.
Unlike other polypeptides, poly(aspartic acid) com-
prises only one amino acid. Racemization during poly-
merization may also affect the degradative profile of the
polymer as well as side reactions occurring during poly-
merization. It is possible that such side reactions could
produce structures resistant to degradation.
The in vitro biodegradation of copoly(L-aspartic
acid/L-glutamic acid) has been studied [3, 5]. Copoly-
mers of L-aspartic acid and L-glutamic acid were pre-
pared to investigate the influence of molar composition
on the rate of degradation in vivo. To simulate this deg-
radation in vitro, the copolymers were treated with pa-
pain in a pseudo-extracellular fluid solution at a tem-
perature of 37 ~ and at pH levels of 4.75 and 7.40. This
study showed that the copolymers under investigation
degraded by random-chain scission with papain. Also,
the degradation profile was consistent with Michaelis-
Menten kinetics. The side chain structure of the co-
polymers was found significantly to influence the rate of
degradation.
APPLICATIONS
One important area of application for polyaspar-
tates is the use of these polymer,,~as a totally biodegrad-
able water-soluble component in detergents and other
cleaning products [1, 34-36]. Poly(ct, /~-DL-aspartate)s
have been shown to adsorb on sewage sludge and have
proven to be degradable by organisms present in munic-
ipal treatment plants. Rhone-Poulenc Chimie holds a
patent concerning imidated polymers prepared by poly-
condensation of aspartic acid and/or glutamic acid that
can be used as builders in laundry and dishwashing de-
tergents [36]. These imidated polymers are stable in de-
tergent compounds and are biodegradable. Poly(aspartic
acid) and its copolymers are also important in other
water-related applications [13, 14, 24, 25, 37]. These
materials are known to inhibit the scale deposition and,
therefore, valuable water treatment agents in a range of
capacities.
Superabsorbant materials ahve been produced from
poly(amino acid)s, including poly(aspartic acid) [38,
39]. These materials have a higher absorption ability
179
than similar products that are currently available and can
be used as agricultural, sanitary, and building materials.
The superabsorbant is made when poly(anhydroaspartic
acid) is hydrolyzed at a pH of 10 and 60~ to form
poly(aspartic acid), which is subsequently combined
with L-aspartic acid and lysine-HC1. Heating at 220~
for 24 h under a nitrogen environment produces a su-
perabsorbant material.
Polyaspartates and other poly(amino acid)-contain-
ing materials have current and potential applications as
biomedical materials including the use of these mate-
dais as selective membranes [32]. One example of this
is the use of poly(L-aspartic acid) as a pH-sensitive
transmembrane domain in a synthetic polymer mem-
brane [40]. A natural biomembrane comprises a contin-
uous nonpolar hydrocarbon matrix that is impenetrable
to most polar substances. Incorporated in the biological
phospholipid bilayer are protein molecules that are able
to bind substrates reversibly and transport them across
the cell membrane, irrespective of the concentration
gradient. Such protein molecules are capable of revers-
ible conformation changes that facilitate the creation of
channels in the biomembrane. Synthetic biomembrane
models must have analogous pathways for facilitated
transport of otherwise impermeable molecules.
Poly(aspartic acid) can be used in the preparation of
pathway protein analogs.
Vinyl polymers that have domains of poly(amino
acid) are similar to those vinyl polymers that have
grafted poly(amino acid) branches [32]. A butyl meth-
acrylate-L-aspartic acid graft copolymer was prepared
and hydrolyzed in the form of a membrane to produce
a synthetic biomembrane material [40]. Experiments
monitoring Na + ion transport through the synthetic
biomembrane indicated that the polyaspartate domain
does facilitate ion transport via a pH-dependent revers-
ible conformational change.
Other research has been done on poly(aspartic
acid)-containing membranes [26]. As discussed previ-
ously, amphiphiles with poly(L-aspartic acid) head-
groups have been prepared. These amphiphiles were
dispersed via ultrasound in aqueous media and the mor-
phologies of the resulting membranes in dilute solution
were studied using electron microscopy. Characteriza-
tion of the amphiphilic bilayers revealed the ability of
these structures to self-assemble in dilute aqueous so-
lutions to form helices. These helices are capable of dra-
matic morphological changes such as a change from a
globular structure to a twisted filament, double helix, or
twisted ribbon. The superstructures formed were in-
duced by the interaction of two or more microfilaments
formed from bilayer membranes. Use of amphiphiles
180
with poly(L-aspartic acid) headgroups may facilitate the
modeling of organism morphogenesis [26].
Block copolymers of poly(ethylene oxide) (PEO)
and poly(/~-benzyl-L-aspartate) (PBLA) have also been
prepared as membrane materials [41]. Hydrophilic PEO
domains facilitate permeation, while hydrophobic PBLA
domains impart mechanical strength to these novel
membrane materials. Varying the lengths of the PEO
and PBLA segments permits control of the water con-
tent of these copolymers. The permeability of these
membranes was studied for several solutes including
myoglobin and vitamin B12, and it was determined that
permeability through these materials is highly depen-
dent on the solute molecular weight. For this reason,
these materials have potential applications for devices
which require permeability to species with a limited
range of molecular weights.
Currently, much of the medical research on
poly(aspartic acid)s concerns the use of these polymers
in pharmaceutical applications. One example is the use
of poly(aspartic acid)s as inhibiting agents of amino-
glycoside-induced nephrotoxicity [4, 42-44]. Amino-
glycoside antibiotics are widely used to treat serious in-
fections. These compounds can be damaging to the
kidneys, though. Poly(aspartic acid), given in concert
with aminoglycoside antibiotics, inhibits the potentially
toxic effects of these drugs.
In addition to this pharmaceutical application,
poly(aspartic acid) and its copolymers can be used as
components in drug delivery systems. Polymer micelles
have been formed from copolymers of poly(ethylene ox-
ide) and poly(aspartic acid) [45]. Also, the ability of
poly(aspartic acid) to bind drugs has been described.
Copolymers of poly(ethylene glycol) and poly(aspartic
acid) have been bound to a conjugate of adriamycin, an
anticancer drug, at the poly(aspartic acid) chain to pro-
duce a novel target drug [46]. Another novel drug was
produced by binding daunorubicin, an antitumor drug,
to poly(L-aspartic acid) [47]. The use of poly(aspartic
acid) as a carrier has proven to be effective in reducing
drug toxicity without diminishing drug activity.
Other biomedical applications for poly(amino
acid)s and their copolymers have been suggested [3, 5,
21, 32]. In addition to the applications described above,
these polymers are suitable as temporary artificial skin
substrates in burn therapy and as temporary barriers for
the prevention of tissue adhesion as well as for other
synthetic tissues and devices. The above description is
intended to be a brief overview of this growing area of
research.
Roweton, Huang, and Swift
CONCLUSION
Poly(aspartic acid) is a unique biodegradable and
water-soluble polymer that has a range of valuable cur-
rent and potential applications, both as a homopolymer
and as a component in novel copolymers. This review
has focused on the methods of synthesis of these mate-
rials, biodegradation studies, and applications. Recent
investigative and patent literature highlights the impor-
tance of poly(aspartic acid) and related materials with
tailored physical and chemical characteristics as new
biodegradable materials.
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