Controlled activity polymers. VII

Journal of Controlled Release, 7 (1988) 109-121 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

CONTROLLED ACTIVITY

109

POLYMERS. VII

ACRYLAMIDE COPOLYMERS WITH STRUCTOPENDENT NAPHTHYLACETIC AND INDOLEACETIC ACID ESTERS: RELEASE BEHAVIOR

ACID

Charles L. McCormick, KiSoo Kim and Stephen A. Ezzell Department of Polymer Science, University of Southern Mississippi,

Hattiesburg,

MS 39406

(U.S.A.)

(Received June 20, 1987; accepted in revised form October 2 1, 1987)

The hydrolytic controlled release behavior of copolymers with pendent esters of the plant growth regulators naphthaleneacetic acid and indoleacetic acid have been studied utilizing reversedphase liquid chromatography with ultraviolet spectrometric detection. The release profiles for copolymers of acrylamide (AM) with 2- (I-napthylacetyl) ethyl acrylate (NAEA), 4- (1 -napthylacetyl) butyl acrylate (NABA), 2-(I-napthylacetyl) ethyl acrylate (NAEMA), and 2-(indole3-acetyl) ethyl acrylate (IAEA) were shown to depend upon the nature of the auxin monomer structure and its composition, molecular weight, and copolymer microstructure. Increasing the mean sequence lengths of the hydrophilic sections of the copolymers was shown quantitatively to result in higher rates of hydrolytic release.

molecular tent, microstructure.

INTRODUCTION

In our continuing efforts to develop model copolymers for use as controlled release systems [l-12], we recently reported the synthesis, characterization, and release properties of the copolymers of 2 (l-naphthylacetyl) ethyl acrylate (NAEA) with hydrophilic comonomers [ acrylamide ( AM ) , methacrylic acid (MAA), acrylic acid (AA), N-vinyl-2-pyrrolidone (VP), and 2-hydroxyethyl methacrylate (HEMA)] [ 13,141. In the preceding paper of this series we detailed the synthesis and structural characterization of copolymers of AM with the structopendent auxin esters of naphthylacetic acid and indoleacetic acid (NAEA, NABA, NAEMA, and IAEA). We now report the release properties of these copolymers as related to auxin monomer structure, auxin con-

0168-3659/88/$03.50

weight,

and

copolymer

EXPERIMENTAL Materials

Copolymers of AM with NAEA, NABA, NAEMA, and IAEA were prepared by radical solution polymerization. Details of synthesis and characterization procedures are reported in the accompanying paper [ 151. Analytical

methods

The copolymer structure from polymerization of AM with auxin monomers is shown in Scheme 1. Molecular weights, residual monomer content, and copolymer composition are

0 1988 Elsevier Science Publishers B.V.

110

s

cl-d,=c

COPOLYMERIZATION

t

B

--fC~,-y~*cH,-t+

k=o AH,

-ft

c=o

b

AH,

6, 1

w-yf+

t=o

(fH2)n

Q 2

': F=O

R = H,CH, ll

Scheme

1.

= 2,4

Structural change of monomer via polymerization. (1 and 2 denote the two hydrolyzable sites)

presented in the previous paper [ 151. Viscosity measurements were performed in dimethyl sulfoxide (DMSO ) at 30’ C using an Ubbelohde dilution capillary viscometer. The intrinsic viscosities were obtained by extrapolating the reduced viscosities and the inherent viscosities to zero concentration. Molecular weights (A4,) were obtained by membrane osmometry (with a Knauer Membrane Osmometer) in NJV-dimethylacetamide at 45.5’ C using a 600 W type membrane from Arro Laboratories, Inc. The amount of residual monomer in each polymer sample was determined by the dialysis/ RPLC method in DMSO. Copolymer compositions were obtained by UV spectroscopy and NMR measurement. Copolymer microstructures were calculated using a statistical method described in the previous paper, and are tabulated there ]151. Sample preparation for release experiments was as follows: The polymer samples were ground and sieved to a particle size of 75-100 pm (No. 200-No. 100 mesh U.S.A. Standard testing sieve). About 35 mg of each polymer sample was weighed to the nearest 0.01 mg into 10 cm length cellulose membrane dialysis tubing (cylinder diameter 6 mm, Spectrapor No. 2 ) obtained from Spectrum Medical Industries, Inc. After adding a known amount of the appropriate buffer solution, the tubing was tied and placed into a screw-capped vial (10 cm X 2.5 cm diameter) having a Teflon-backed silicon rubber septum as the cap liner.

The vial was filled with a measured quantity (about 40 ml) of the same buffer solution. The vial was wrapped with black vinyl tape to avoid any photolytic effects and rotated end-over-end at 30-60 rpm at ambient temperature. This rotation, combined with the fact that the dialysis tubing was disintended with solution and was long enough to prevent inversion in the vial, served to agitate the particles within the tubing very efficiently and prevent agglomeration. Periodically, a 20 ~1 sample was withdrawn and analyzed by RPLC to determined the concentration of released products from the polymer. All chromatography was conducted with a Waters Model 2000 A solvent delivery system with a Waters Model U6K injector. The detector was a Perkin-Elmer LC 75 variable wavelength detector operating at 283.5 nm. All solvents were filtered and degassed using 0.45 pm membrane filters. The mobile phase of reversed-phase liquid chromatography (RPLC ) was 50 v/v% acetonitrile and 50 v/v% of pH 7 aqueous buffer solution (0.05 M KH,PO, and 0.0291 M NaOH ) . The column was a Waters ,uBondapak C-18 (3.9 mm i.d. x 30 cm). A precolumn filter (5 pm) and a guard column packed with 30-50 ,um C-18 Corasil (Waters) were used to protect the analytical column. The flow rate was 1.2ml/min. Under these conditions 1-naphthylacetic acid (NAA) eluted at 3.6 ml, 1-naphthylacetic ethylene glucol (NAA-EG) eluted at 5.3 ml, and 1-naphthylacetic butylene glycol (NAA-BG)

111 NAA

NAEA

NAEMA

NAEMA

L NABA

NABA

/uT”2-------“l?*-

t

”

”

4

5

*

t

‘I

Time (min)

11 10

8

Fig. 1. RPLC chromatograms of hydrolysis products from NAEA, NABA, and NAEIvfA.

eluted at 6.2 ml (Fig. 1) . Standard solutions in aqueous buffer solutions were prepared for calibration. Calibration curves (peak height vs. concentration) were generated for each determination using at least four external standard solutions in the appropriate concentration range. The percentage of the available NAA or NAA-EG released from each sample was calculated by multiplying the concentration by the volume of aqueous buffer solution in the vial and dividing by the mole concentration of attached NAA in each sample.

RESULTS

AND DISCUSSION

Rates of hydrolysis of pendent bioactive agents from copolymers depend upon a number of factors, including the nature of the hydrolysis site and accessibility of the nucleophile ( Hz0 or OH- in this case) to the site. In most instances the polymer backbone limits approach of the nucleophile to the active site by exerting steric and hydrophilic influences. It is hypothesized that hydrophilic spacer groups and longer

spacer length would increase the hydrolysis rate by removing the active site from the backbone. In this study we first examine the hydrolysis behavior of three monomers differing in spacer length, steric effects and backbone hydrophobicity. Next, copolymers of these monomers with acrylamide were investigated as a means of introducing hydrophilic moieties into the vicinity of the labile site. Further insight into copolymer release behavior was gained via study of the effects of variation of auxin monomer content and molecular weight. Scheme 1 illustrates structures of the copolymers under study; all auxin monomers possess the two hy~olyzable sites shown. The first site is near the polymer backbone and the second site beyond the spacer moiety. First-site hydrolysis yields NAA or IAA. Second-site hydrolysis gives the corresponding glycols, NAAEG, NAA-BG, or IAA-EG, depending upon the specific monomer employed. Auxin monomer

hydrolysis

Monomer hydrolysis tests were performed at selected pH values; products were subsequently analyzed by reversed-phase liquid chromatography ( Fig. 1) . Concentration of auxin monomer during the hydrolysis test was held near 1.0 x 10e5 mol/l since these auxin monomers are very hydrophobic and only sparingly soluble in water. Chromatographic separation of the two expected hydrolysis products was obtained by optimizing the RPLC conditions. Release data for NAEA, NAEMA, and NABA as a function of time at pH 8 and pH 10 are shown in Tables 1 and 2, and depicted graphically in Figs. 2 and 3. Tables 1 and 2 exhibited the ratios of the hydrolysis products of each monomer type while Figs. 2 and 3 show total release of the NAA hydrolysis product only. The pH 10 environment would be expected to contribute to a greater hydrolysis rate, simply due to the greater availability of OH-. Comparison of Tables 1 and 2 shows enhanced hydrolysis

112 TABLE 1 Release data from auxin monomer hydrolysis, at pH 8 Monomer

NAEA

NAEMA

NABA

Release concentration (mol% ) at day 0.2

1

2

4

9

40

2.5 1.3 3.8

5.5 2.8 8.3

11.7 9.1 20.8

30.7 8.0 38.7

t

9.1 4.4 13.5

26.5 4.4 30.9

3.4 2.7 6.1

9.5

NAA NAA-EG Total

t

t

t t

t t

NAA NAA-EG Total

-

-

-

-

t t

4.6 t 4.6

NAA NAA-BG Total

-

-

-

t t t

6.1 17.4

t = trace - = below detection limits.

TABLE 2 Release data from auxin monomer hydrolysis, at pH 10 Monomer

NAEA

NAEMA

NABA

Release concentration ( mol% ) at day 0.2

1

2

4

9

NAA NAA-EG

19.6 15.7

51.9 19.1

63.6 5.7

73.5 -

86.5 -

Total

35.3

71.0

69.3

73.5

86.5

NAA NAA-EG

11.8 4.2

41.8 9.5

63.9 5.5

77.4 -

96.7 -

Total

16.0

51.3

69.4

77.4

96.7

NAA NAA-BG

3.4 4.2

19.0 14.6

35.8 17.5

59.3 11.3

79.3 -

Total

7.6

33.6

53.3

70.6

79.3

- = below detection limits

rates at pH 10, as anticipated. The release data of Figs. 2 and 3 illustrate the strong influence of monomer structure upon release behavior. Relative rates of release of NAA are shown to be NAEA > NAEMA > NABA, with NAEA and NAEMA reaching a common asymptote after day 4 at pH 10. Structural effects which impact the above

trend are those which influence the steric and hydrophobic characteristics of the active sites. NAEA is apparently the most hydrophilic of the three monomers, facilitating entry of the nucleophilic species to the active sites and consequently displaying the greatest release rate. Placement of a methyl group on the alkene substituent (NAEMA) should have the effect of

113

Time

Fig. 2. The hydrolysis versus time at pH 8.

(day)

concentration

of auxin monomers

making the monomer more hydrophobic. An additional steric effect, particularly upon entry of nucleophiles to site one, may also be important. These effects should lower hydrolysis rate relative to NAEA; Figs. 2 and 3 confirm this prediction. NABA provides an example of increased spacer length (butylene versus ethylene) over NAEA. Interestingly, Figs. 2 and 3 show NABA to have consistently lower release rates than NAEA and NAEMA. Comparison of NABA release data with that of NAEA suggests the butylene spacer of NABA exerts an unexpected hydrophobic effect upon the polymer active

sites, relative to the ethylene spacer of NAEA. In fact, the enhanced hydrophobicity of NABA appears to exert a greater influence upon release than the steric and hydrophobic effects of the alkenylmethyl moiety of NAEMA. Examination of the data of Tables 1 and 2 suggests that NABA may show lower release rates due to an increase in the hydrophobic character of site two. Site-two hydrolysis is seen to predominate for all data of Tables 1 and 2, except that of NABA at 0.2 day. NABA data consistently show a smaller acid/glycol ratio than either NAEA or NAEMA, i.e., a greater proportion of site-one hydrolysis is apparent for NBA. Two factors may account for this enhancement of NAA-BG release: (1)enhanced hydrophobicity of site two imposed by the butylene spacer; and/or ( 2 ) slower sequential-step hydrolysis of NAA-EG, again due to the hydrophobic contributions of butylene relative to ethylene moiety. Further examination of Tables 1 and 2 reveals the lowest proportions of site-one product (greatest acid/glycol ratios) to be present for the NAEMA data; this is particularly evident at pH 8. Here steric and/or hydrophobic effects of the methyl-substituted alkene apparently are limiting approach to site one. Also noteworthy of the data of Tables 1 and 2 is the disappearance of glycol hydrolysis product due to a sequential-step hydrolysis, as previously shown [ 141. Sequential-step hydrolysis is most evident at pH 8, beyond 9 days and pH 10, after 6 hours. Effect of variation of auxin monomer structure upon copolymer release behaviour

.:

NAEA

A:

NAEMA

n:

Time

NABA

(day)

Fig. 3. The hydrolysis concentration versus time at pH 10.

of auxin monomers

A number of studies have shown that hydrolysis near the polymer backbone is more difficult for steric and/or hydrophobic reasons. Typically hydrolysis at site two (Scheme 1) would be favored regardless of pH. Our previous work [ 13,141 demonstrated that copolymerization of hydrophilic monomers containing Lewis-base moieties with NAEA resulted in enhancement of site-one release rates. Enhanced

114

NABA(lB.O)-AM

Time (min)

Fig. 4. RPLC chromatogram of polymer release.

site-one release rates were attributed to: (1) anchimeric assistance of the pendent Lewisbase moieties and (2) greater polymer hydrophilicity, which in turn was shown to be dependent upon copolymer microstructure. The copolymers prepared for this study were described in the previous paper [ 151. These materials contain 20 + 2.5 mol% of pendently attached plant growth regulator. Residual monomer content was below 0.1% as determined by RPLC (Fig. 4). Total release product concentration as a function of time for the four copolymers at pH 8 is presented in Table 3 and Fig. 5. These data reflect differences in structural properties of the copolymers. IAEA (18.4 ) -AM seems to possess the most hydrophilic structure, facilitating approach of nucleophilic species to the active sites. The indole group of IAEA may contribute to this effect by increasing the hydrophilicity relative to the napthyl group of the other monomers. The greater acidity of the indoleacetic group relative to napthylacetic may also contribute. Figure 6 shows the greatest release of auxin by the IAEA copolymer relative to the other copolymers at pH 8. The effect of the butylene spacer group of NABA is to lower the overall (sites one and two combined) release rates relative to the other

copolymers, at pH 8 (Figs. 5 and Table 3). Overall auxin release at pH 8 is also lowest for the NABA copolymer (Fig. 6). We originally anticipated that use of a spacer group would enhance release rates by removing site two from the relatively hydrophilic polymer backbone. The reverse effect is observed instead, apparently due to an overall increase in hydrophobic character. Other copolymer compositions, NAEA( 22.5) -AM and NAEMA (20.5) -AM, evidently are intermediate in hydrophobicity between the previously discussed materials at pH 8 (Figs. 5 and 6). Slightly greater auxin release rates and overall release rates were measured for the NAEA copolymer relative to the NAEMA copolymer. The methyl group of the NAEMA would be expected to make the polymer backbone more hydrophobic relative to the NAEA copolymer. Auxin release data at pH 10 (Figs. 7 and Table 4) differ somewhat from that at pH 8 (Fig. 6 and Table 3). The pH 10 data show a faster release rate for the NABA (18.0 ) -AM copolymer relative to the NAEMA (20.5) -AM copolymer. This behavior is anomalous to monomer hydrolysis and polymer hydrolysis data at pH 8. It is likely that the increase in OH- overwhelms the hydrophobic effect of the NABA butylene spacer but not that of the backbone methyl group. NAEMA ( 20.5) -AM possesses the most hydrophobic microstructure relative to the copolymers of other auxin monomers, of the same composition [ 151. Mean sequence length values of pi = 1.25 and ,u2= 2.62 were obtained for the NAEMA copolymer while values of pi = 1.27 and pz = 5.04, respectively, were calculated for the other copolymer systems. It is evident that the NAEMA copolymer has the most hydrophobic microstructure, due to its comparatively shorter sequences of hydrophilic AM monomer. These microstructural differences have a more pronounced effect upon hydrolysis rates at pH 10, resulting in the trends shown in Fig. 7. All release data for the auxin-AM copoly-

115 TABLE 3 Release data from hydrolysis

of copolymers

of different

auxin monomers,

at pH 8

Release concentration

Copolymers

(moI% ) , at pH 8, and at day

7

2

15

30

NAEAf 22.5) -AM

NAA NAA-EG Total

0.3 1.9 2.2

0.6 6.2 6.8

1.2 12.8 14.0

4.1 23.4 27.5

NABA (18.0) -AM

NAA NAA-BG Total

0.2 0.6 0.8

0.4 2.4 2.8

0.7 4.4 5.1

0.1 7.2 8.2

NAEMA (20.5) -AM

NAA NAA-EC Total

0.4 2.4 2.8

0.9 5.9 6.8

1.6 8.1 9.7

3.1 10.1 13.2

IAEA (18.4) -AM

IAA IAA-EC Total

0.5 2.5 3.0

1.2 10.2 11.4

3.5 13.8 17.3

8.3 20.5 28.8

‘”

A

-I w!

A B

l

0

NABA[lB.Ol-AM

38

N~~A[Z~5]-AM 1 AEAb341-AM

=, .r_

Time

NAEA(22.51-AM

A

NABA[lE.ObAM

B

NAE~[2~5]-AM

.

(NAA+ NAA-EG

etc.)

mers at pH 8 (Table 3) show predominance of first-site hydrolysis. Since monomer hydrolysis yields predominately site-two hydrolysis, we postulate the existence of an anchimeric assistance mechanism involving the pendent amide nitrogen and the neighboring site-one ester carbony1 on the polymer backbone. A basic hydrolysis mechanism was likewise evidenced for NA~MA-AM copolymers previously [ 14 1. At

IAA) at

pti 8 !

I AEA[if3dbAM

Time

(day)

Fig. 5. Total release concentration versus time at pH 8.

NAA(or

0

Fig. 6. Release concentration at pH 8.

(day)

(NAA or IAA) versus time

pH 10 (Table 4)) site-two hydrolysis predominates for all cases except that for NABA (18.0) AM. This parallels the monomer release behavior, in which NABA showed greater site-one release at 0.2 day, but a larger proportion of acid at longer times. The effect of increasing pH is to increase site-two hydrolysis. Structural differences among the copolymers of Tables 3 and 4 appear to be largely respon-

116

thereby two.

limiting

nucleophilic

approach

Compositional and microstructural upon release performance

Fig. 7. Release concentration at pH 10.

to site

effects

Polymerization or copolymerization of the auxin-containing monomer allows incorporation of a large percentage of the bioactive agent in a comparatively small quantity of polymer matrix. In most cases homopolymers showed an extremely slow rate of hydrolysis due to the hydrophobicity of these polymers. Hydrophilichowever, is easily introduced by ity, copolymerization of the auxin-containing monomer with an appropriate amount of comonomer. The auxin content of the polymer was varied from 9.7 mol% to 70.0 mol% by changing the monomer feed ratio in the copolymerization. Analysis of copolymer microstructure revealed a nearly linear relationship between auxin content and microstructural properties [ 151. Increasing blockiness and mean sequence length

(NAA or IAA) versus time

sible for the variations in release data shown. The NABA (18.0) -AM copolymer consistently exhibits a greater proportion of site-one release than the other copolymers, at any given time. Evidently, the butylene spacer group renders site two more hydrophobic relative to the ethylene spacer of NAEA, NAEMA, or IAEA,

TABLE 4 Release data from hydrolysis

of copolymers

of different

Copolymers

auxin monomers,

at pH 10

Release concentration

(mol% ) at day

2

7

15

30

NAA NAA-EG

40.5 19.4

85.2 3.3

90.0 0.5

99.2 -

Total

59.9

88.5

90.5

99.2

NAA NAA-BG Total

4.3 6.7 11.0

38.6 10.0 48.6

73.8 3.5 77.3

77.8 79.0

NAEMA(20.5)-AM

NAA NAA-EG Total

18.8 5.8 24.6

29.8 1.8 31.6

38.1 0.8 38.9

49.5 0.5 50.0

IAEA(18.4)

NAA NAA-EG

50.9 12.3

76.8 -

82.7 -

85.5

Total

63.2

76.8

82.7

85.5

NAEA(22.5)-AM

NABA (18.0) -AM

-AM

- = below detection

limits

1.2

117

of the auxin component correlate with increasing auxin content. This is a consequence of the nearly ideal copolymerization behavior of the NAEA-AM copolymer combination [ 131. Release behavior of copolymers of varied auxin mole percent is shown in Tables 5 and 6. Two general trends are apparent and are explained in terms of the interaction of the copolymer with water so as to provide accessibility into the particle and diffusional paths for auxin migration outward. Clearly the rate of auxin release increases with decreasing auxin content in the polymer and with increasing pH. The former is due to increased hydrophilicity of the acrylamide units (longer mean sequence length of AM) relative to the NAEA units. Increased hydrophilicity facilitates swelling of the polymer by water, resulting in faster migration of water and auxin. This trend extends up to the point where the copolymer becomes water sol-

uble. Water solubility is observed for a 30% NAEA content at pH 10, and a 10% content at pH 8. With high mole percentages of IAA or NAA in the copolymer the rate of release is quite small. At about 50 mol% of NAEA in polymer there is hardly any release detected at either pH. At this polymer composition the same mean sequence lengths are present for both components (pNAEA=2.10 and pAM=1.93 for the NAEA (48.30-AM sample). This suggests a very hydrophobic microstructure. The released quantity (in pg/l ) of auxin (NAA) from each polymer versus time at pH 8 is shown in Table 7. Highest release rates are observed for the NAEA (9.7) -AM copolymer. The importance of polymer hydrophilicity is emphasized by these data; the fastest release rates are observed for the copolymer of highest AM content, which consequently possesses the longest mean sequence lengths of hydrophilic

TABLE 5 Effect of variation of copolymer composition on release data, at pH 8 Release concentration (mol% ) at day

Copolymer

2

7

15

30

NAEA(9.7)-AM

NAA NAA-EG Total

0.9 12.0 12.9

2.8 29.6 32.4

7.5 50.3 57.8

9.8 54.4 64.3

NAEA (22.5) -AM

NAA NAA-EG Total

0.3 1.9 2.2

0.6 6.2 6.8

1.7 12.8 14.5

4.0 20.5 24.5

NAEA (30.9) -AM

NAA NAA-EG Total

0.2 1.8 2.0

0.3 3.4 3.7

0.8 5.2 6.0

1.8 6.5 8.3

NAEA (48.3 ) -AM

NAA NAA-EG Total

NAEA (70.0) -AM

t = trace - = below detection limits

NAA NAA-EG Total

-

-

-

0.1 t

-

50

3.3 8.3 11.6

0.2 t

0.1

0.3 t

0.2

-

-

-

-

0.3 t t t

118 TABLE 6 Effect of variation

of copolymer composition

on release data, at pH 10 Release concentration

Copolymer

(mol% ) at day

2

7

15

NAA NAA-EG Total

69.0

13.3 82.3

86.1 0.4 86.5

99.9 -

NAA NAA-EG Total

40.5 19.4 59.9

85.2 3.3 88.5

0.5 90.5

NAEA (30.9) -AM

NAA NAA-EG Total

13.3 6.5 19.8

30.4 1.4 31.8

NAEA (48.3 ) -AM

NAA NAA-EG Total

-

-

NAA NAA-EG Total

-

NAEA(9.7)

-AM

NAEA(22.5)-AM

NAEA (70.0) -AM

t = trace - = below detection

30

50

47.8 1.8 49.6

66.1 1.2 67.3

80.1 0.5 80.6

0.4

0.6

0.8

0.4

0.6

0.8

99.9 90.0

-

-

-

0.4 -

0.5 t

0.4

0.5

limits

TABLE 7 Dependence

of auxin release behavior on copolymer

Release concentration

Copolymer

NAEA( 9.7) -AM NAEA (22.5) -AM NAEA (30.9) -AM NAEA (48.3 ) -AM NAEA (70.0) -AM - = below detection

composition,

at pH 8 ( X lo6 g/ml) at day

2

7

15

30

1.6 1.0 0.7 -

4.9 2.0 0.9 -

12.8 5.3 2.8 0.9 -

16.8 12.3 6.5 0.9

limits

component. Microstructural alterability via selection of copolymer composition provides an efficacious means of auxin release control for these copolymers.

Effect of molecular

weight

Copolymers of different molecular weights with the same compositional content of auxin

119 TABLE 8 Effect of molecular weight variation on release performance, at pH 8 Release concentration (mol% ) at day

Sample

2

7

15

30

NAEA (30) -AM-A

NAA NAA-EG Total

0.3 2.8 3.1

0.6 4.8 5.4

1.1 8.0 9.1

2.7 11.5 14.2

NAEA (30) -AM-B

NAA NAA-EG Total

0.3 1.1 1.4

0.4 2.1 2.5

0.5 3.4 3.9

1.3 5.6 6.9

NAEA(30)-AM-C

NAA NAA-EG Total

0.2 1.8 2.0

0.3 3.4 3.7

0.8 5.2 6.0

1.8 6.5 8.3

NAEA (30) -AM-D

NAA NAA-EG Total

0.2 0.4 0.6

0.2 0.7 0.9

0.2 1.2 1.4

0.7 3.4 4.1

TABLE 9 Effect of molecular weight variation on release performance, at pH 10 Sample

Release concentration (mol% ) at day 2

7

15

30

NAEA (30) -AM-A

NAA NAA-EG Total

14.0 6.3 20.3

46.4 4.1 50.5

63.3 2.2 65.5

96.7 0.1 96.8

NAEA (30) -AM-B

NAA NAA-EG Total

15.1 6.0 21.1

39.2 2.0 41.2

41.5 1.1 42.6

77.9 0.3 78.2

NAEA (30) -AM-C

NAA NAA-EG Total

13.3 6.5 19.8

30.4 1.4 31.8

47.8 1.8 49.6

66.1 1.2 67.3

NAEA (30) -AM-D

NAA NAA-EG Total

1.4 1.1 2.5

8.0 1.2 9.2

18.5 1.3 19.8

44.2 1.6 45.8

120

Time (day)

Fig. 8. Molecular weight effect on release rate at pH 10.

were prepared by changing the polymerization conditions. NAEA (30) -AM-A possesses the smallest molecular weight of 5.5~ lo* while NAEA ( 30) -AM-D has the largest molecular weight of 1.8~ lo5 [ 151. The degrees of polymerization range from 400-1300. Tables 8 and 9 and Fig. 8 show that as the molecular weight increases the hydrolysis rate decreases. Even with some discrepancy in release data at pH 8, the general trend with molecular weight is clear. Increasing molecular weight apparently limits diffusion of hydroxide ion or water to the active sites, and may also limit migration of the released species outward. CONCLUSIONS

The release behavior of auxin monomer/acrylamide copolymers has been studied with respect to variations in auxin monomer structure, copolymer composition, and molecular weight. Two release products were observed in most cases. The glycol release product predominated at pH 8 due to an anchimeric assistance effect of the acrylamide moiety. Variations in auxin monomer structure allowed comparison of the effects of auxin moiety, spacer group, and steric hindrance upon release rates. The IAEA-AM copolymer system exhibited the greatest release rates at pH 8, apparently due to the greater acidity of IAA compared to NAA. NABA copolymers exhib-

ited lower total release rates at pH 8 relative to the other systems, all of which contained shorter spacer linkages. We believe these data signify a competitive effect of hydrophobicity of the alkyl group versus spacer effect. The increased hydrophobicity of the butyl group dominates in this instance. Steric and hydrophobic effects of the NAEMA component were found to lower release rates of the NAEMA-AM copolymer relative to NAEA-AM, and to influence the ratio of acidglycol release products. Release rates were shown to depend upon microstructural copolymer composition, particularly with regard to sequencing of hydrophilic monomer units. Alterability via choice of copolymer composition clearly provides an effective means of auxin release control for these copolymers. Copolymer molecular weight proved to be another important parameter which influenced auxin release behavior. Increasing the molecular weight of compositionally constant copolymers diminished auxin release rates, apparently by limiting diffusion of hydroxide ion or water to the hydrolysis sites. REFERENCES C.L. McCormick and D.K. Lichatowich, J. Polym. Sci., Polym. Let. Ed., 17 (1979) 479. CL. McCormick, D.K. Lichatowich, J.A. Pelezo and K.W. Anderson, in: C.E. Carraher, Jr. and M. Tsuda (Eds.) , Modification of Polymers, ACS Symposium Series No. 121, American Chemical Society, Washington, DC, 1980, p. 371. C.L. McCormick, K.W. Anderson, J.A. Pelezo and D.K. Lichatowich, in: D.H. Lewis (Ed.), Controlled Belease of Pesticides and Pharmaceutics, Plenum, New York, NY, 1981. C.L. McCormick,U.S. Patent, 4,267,280, May 12,1981. CL. McCormick, U.S. Patent, 4,267,281, May 12,198l. K.W. Anderson and C.L. McCormick, U.S. Patent 4,496,724, January 19,1985. K.W. Anderson, Ph.D. Thesis, University of Southern Mississippi, Hattiesburg, MS, 1984. C.L. McCormick and K.W. Anderson, Chitin, Chitosan, and Belated Enzymes, Academic Press, New York, NY, 1984, p. 41. C.L. McCormick, Macromolecules as Drugs and Carriers for Biologically Active Material, Ann. N.Y. Acad. Sci., 446 (1985) 76.

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M.M. Fooladi, Ph.D. Thesis, University of Southern Mississippi, Hattiesburg, MS, 1979. CL. McCormick and M.M. Fooladi, in: R.W. Baker (Ed.), Controlled Release of Bioactive Materials, Academic Press, New York, NY, 1980. C.L. McCormick, Z.B. Zhang and K.W. Anderson, J. Controlled Release, 4 (1986) 97.

13 CL. McCormick and K. Kim, J. Macromol. Sci., Chem., submitted. 14 C.L. McCormick and K. Kim, J. Macromol. Sci., Chem., submitted. 15 CL. McCormick and K. Kim, J. Controlled Release, 7 (1988) 101.