Reactive & Functional Polymers 39 (1999) 179187

Synthesis, characterization and controlled release behaviour of adducts from chloroacetylated cellulose and a-naphthylacetic acid
A.I. Martin, M. Sanchez-Chaves, F. Arranz*
de Polmeros ( CSIC), Juan de la Cierva 3, Madrid 28006, Spain Instituto de Ciencia y Tecnologa Received 11 April 1997; received in revised form 18 October 1997; accepted 28 November 1997

Abstract Celluloses partially functionalized with chloroacetate groups were obtained by reaction of cellulose with chloroacetyl chloride using pyridine as catalyst and the dimethylacetamide / LiCl system as solvent. 13 C NMR spectra at 75.4 MHz of partially modied cellulose with chloroacetate groups were studied in order to evaluate the selectivity of the reaction of cellulose with chloroacetyl chloride in the homogeneous phase. Analysis of the spectra of ring carbons in the anhydroglucose units shows that the reactivity of the individual hydroxyl groups decreases in the order C-6 . C-3 . C-2. The coupling of a-naphthylacetic acid to cellulose functionalized with chloroacetate groups was carried out by reaction with their potassium salts or directly in the presence of 1.8-diazabicyclo[5.4.0]-7-undecene. High degrees of modication were obtained by both methods. However, the esterication reaction is somewhat more efcient in the case of the potassium salt. The kinetic results were consistent with a second-order reaction. The hydrolysis in the heterogeneous phase of cellulose a-naphthylacetic acid adducts showed that the release of the bioactive compound is dependent on the hydrophilic character of the adduct as well as on the pH value of the medium. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Chloroacetylated cellulose; Relative reactivity; Cellulose a-naphthylacetic adducts; Heterogeneous hydrolytic behaviour

1. Introduction Controlled release polymeric systems are becoming increasingly important in a variety of agricultural applications because low-molecular weight agrochemical substances dissipate quickly and lose their efcacy when applied by standard methods [13]. Properly formulated controlled activity systems can signicantly

*Corresponding author.

enhance the period of effectiveness and selectivity of some existing bioactive agents. For the preparation of the polymer-bioactive compound conjugates, conversion of the polymer into a reactive derivative is usually required. Various methods have been elaborated to transform the original macromolecular carrier into a reactive derivative in order to make possible the attachment of bioactive agents that lack the appropriate functionality [4,5], as well as to introduce a suitable spacer between the carrier and the bioactive compound.

1381-5148 / 99 / $ see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S1381-5148( 97 )00180-6

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This paper reports the functionalization of cellulose (a natural and abundant material) with chloroacetate groups and its applicability to the coupling of a-naphthylacetic acid, which is one of the auxin group of plant-growth stimulators [6]. The present work also describes the hydrolytic degradation of the resulting adducts in the heterogeneous phase in order to evaluate the release of the active compound.

2. Experimental

2.1. Materials
Cellulose (powder, 20 mm, from Aldrich) was used without further purication. The polymer was dried in vacuo for a few days at 808C in the presence of phosphorus pentoxide to constant weight. N,N -Dimethylacetamide (DMA) (from Scharlau) and dimethylsulfoxide (DMSO) (from Ferosa) were distilled in vacuo and then dried molecular for a few days with a Merck 4-A sieve. Pyridine (from Panreac) was puried following a conventional method [7]. Chloroacetyl chloride (from Fluka) was puried prior to use by distillation under normal pressure. LiCl (from Panreac) was dried in vacuo in the presence of phosphorus pentoxide. a-Naphthylacetic acid (from Fluka) and 1.8diazabicyclo[5.4.0]-7-undecene (DBU) (from Merck) were used as received. The potassium salt of a-naphthylacetic acid was obtained by dissolving 0.1 mol of the acid in 200 ml of chloroform, then neutralized with 0.1 mol of KOH dissolved in 80 ml of ethanol. The solution was precipitated by pouring into 1500 ml of dried acetone. After ltration the salt was dried in vacuo in the presence of phosphorus pentoxide.

method similar to that previously described [8]. Cellulose (20 g l 2 1 ) and LiCl / DMA were introduced into a pyrex double-walled reactor through which thermostatted ethylene glycol at the desired temperature was circulated. The mixture was heated while stirring at 1458C under nitrogen atmosphere. After 1 h, the temperature was lowered to 608C and the mixture was stirred until the cellulose was completely dissolved. A clear homogeneous solution was obtained within several hours. Equimolecular concentrations of pyridine and chloroacetyl chloride were added while stirring at 258C. The polymer remained soluble throughout the process. The degree of substitution (DS) was controlled by the amount of chloroacetyl chloride used. After 2 h, the modied cellulose was isolated by precipitation using distilled water as precipitant. All samples were puried by reprecipitation, using tetrahydrofuran (THF) as solvent and distilled water as precipitant, and then dried in vacuo in the presence of phosphorus pentoxide. In the kinetic study (Fig. 2), the modication extent was followed by sampling the reactant solution, taking aliquot parts at denite periods of time. The isolation and purication of the modied polymers was carried out as indicated above.

2.3. Characterization of chloroacetylated cellulose

The IR spectra were obtained on a PerkinElmer 457 spectrometer using lms prepared on NaCl crystals from THF solutions. The 1 H NMR spectra were registered in DMSO-d 6 at 408C using a 200-MHz Bruker AM-200 spec13 trometer. C NMR spectra (Fig. 1) were obtained in DMSO-d 6 at 408C using a 75.4-MHz Varian XL-300 spectrometer in the proton noise-decoupled mode. Chemical shifts were measured with respect to that of the central peak of methyl carbon of DMSO, which was taken to be at 39.7 ppm downeld from tetramethylsilane. The spectra measurements conditions were similar to those of the structural

2.2. Reaction of cellulose with chloroacetyl chloride

The cellulose was dissolved in DMA containing 10 g of LiCl / 100 ml according to a

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analysis of cellulose derivatives [9]. The spectra were accumulated for about 16 000 scans with a repetition time of 3 s. The signal areas of the spectra were determined by spectral integration as well as by tracing over the peaks with a planimeter. The DS was determined following a known method [10], which implies the alkaline hydrolysis at room temperature using an aqueous solution of sodium hydroxide (0.1 M) and titrating the unreacted base with 0.1 M hydrochloric acid in the presence of phenolphthalein. DS is given as sum of the degrees of substitution of the three different hydroxyl groups of the glucopyranosyl unit. So the maximal value, DS can attain, is 3.0.

2.6. Characterization of cellulose a naphthylacetic adducts

The 1 H NMR spectra were registered in DMSO-d 6 at 408C using a 200-MHz Bruker 13 AM-200 spectrometer. C NMR spectra were obtained from a Varian XL-300 spectrometer operating at 75.4 MHz in DMSO-d 6 at 408C. The modication extent was measured by a total hydrolysis / ultraviolet technique [11,12]. The alkaline hydrolysis was carried out at 608C using a standard solution of sodium hydroxide (0.1 M). The resulting homogeneous solution contained the released a-naphthylacetic acid, which was quantitatively determined as sodium a-naphthylacetate by UV spectroscopy at 281 nm (e 5 6.32 3 10 3 l mol 2 1 cm 2 1 ) using a calibration curve we have previously determined.

2.4. Reaction of chloroacetylated cellulose with potassium a -naphthylacetate

The chloroacetylated cellulose was dissolved in DMSO at room temperature. The solution obtained was thermostatted at the reaction temperature and the calculated amounts of potassium a-naphthylacetate were added while stirring. The polymer remained soluble throughout the process. The modied polymers were isolated by precipitation using distilled water as precipitant. All samples were puried by reprecipitation using THF / DMF mixtures as solvent and distilled water as precipitant, and then dried in vacuo in the presence of phosphorus pentoxide.

2.7. Heterogeneous hydrolysis reactions

For this study we used some partially modied cellulose samples, containing a-naphthylacetate groups, which are insoluble in water, but did swell on standing in this medium. Polymer samples of 0.1 g in ne powder form were placed in glass supports and introduced into small wire-basket devices, which were entirely permeable to water. These devices were placed in pyrex stoppered test tubes, each one containing 25 ml of an aqueous buffer solution. The tubes were then immersed in a thermostatted bath at 378C. A periodic assay of samples was obtained by removing the metallic device, stirring the solution and pipetting a 1-ml sample. The volume pipetted for each sample was replaced by an equivalent volume of fresh solvent, with the corrections being applied in the calculation. The concentration of a-naphthylacetic acid released was determined as sodium a-naphthylacetate by UV spectroscopy at 281 nm. Note that cellulose a-naphthylacetic adducts remain insoluble in the reaction medium along the whole hydrolysis process investigated. The obtained results of the

2.5. Reaction of chloroacetylated cellulose with a -naphthylacetic acid in the presence of DBU
The chloroacetylated cellulose was dissolved in DMSO at room temperature, and the solution obtained was thermostatted at the reaction temperature. Equimolecular amounts of a-naphthylacetic acid and DBU were added while stirring. The isolation and purication of the modied polymers was carried out as indicated above for the reactions with the potassium salts.

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heterogeneous hydrolysis of cellulose a-naphthylacetic adducts are shown in Figs. 8 and 9.

3. Results and discussion The polar aprotic nature of the DMA / LiCl solvent system has allowed the preparation of reactive cellulose intermediates in homogeneous conditions [13,14]. Celluloses modied with chloroacetate groups with different degrees of substitution were synthesized in a homogeneous medium by using the method followed in the bromoacetylation of poly(vinyl alcohol) [15], according to the following scheme:

The IR spectra of partially modied cellulose with chloroacetate groups show the expected characteristic bands at 1750 cm 2 1 (C=O) and 782 cm 2 1 (CCl). The 1 H NMR spectra of the same polymers show a peak at d 5 4.3 ppm, which can be attributed to the methylene protons of chloroacetate groups [16]. The 13 C NMR spectra (Fig. 1) show signals at d 5 41.5 ppm and d 5 166.8166.2 ppm, which correspond to chloromethyl and carbonyl carbon atoms of chloroacetate groups, respectively [17]. The peaks between d 5 60.1 ppm and d 5 102.1 ppm were assigned to sugar carbon atoms. Kinetic results for the reaction between cellu-

The structure of the resulting polymers was conrmed by IR and 1 H and 13 C NMR spectroscopies.

lose and chloroacetyl chloride in the presence of pyridine (Fig. 2) showed that a high yield was obtained in this reaction. It may be noted that a nearly total completion was attained after approximately 1 h. On the other hand, considerable attention has

Fig. 1. C NMR spectrum of a partially modied cellulose with chloroacetate groups (42.5 mol% of chloroacetate groups) measured in DMSO-d 6 at 408C.

13

Fig. 2. Plot of the modication extent vs. time in the reaction between cellulose ([OH] 5 0.37 mol / l) and chloroacetyl chloride (0.46 mol / l) using pyridine (0.46 mol / l) as catalyst and DMA containing 10 g of LiCl / 100 ml as solvent at 258C.

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recently been given to the relative reactivity of hydroxyl groups at the glucopyranosyl units of polysaccharides. A special feature of polysaccharide derivatization is that, in many cases, only the partial substitution of its three alcoholic groups is desired or achieved. The DS and also the partial DS in the different positions of the anhydroglucose units are of great importance for determining physical, chemical and biochemical properties. In this work, the relative reactivity of hydroxyl groups in the anhydroglucose units of cellulose (Fig. 3) in the reaction with chloroacetyl chloride was evaluated by 13 C NMR, which has been suggested as an adequate method to determine the relative reactivity of each hydroxyl group in polysaccharides [9] [18]. Accordingly, the relative intensities of the 13 C NMR peaks at d 5 64.5 ppm (ascribed to C-6 carbons bearing a substituted hydroxyl group) and d 5 60.1 ppm (attributed to C-6 carbons bearing an unsubstituted hydroxyl group) can be taken as a measure of the modication degree of hydroxyl groups at C-6 position. The relative intensities of signals at d 5 98.9 ppm (ascribed to C-1 carbons adjacent to C-2 carbons bearing a substituted hydroxyl group) and d 5 102.3 ppm (belonging to C-1 carbons adjacent to C-2 carbons bearing an unsubstituted hydroxyl group) can give the relative DS of hydroxyl groups at C-2 position. The relative DS of hydroxyl groups at the C-3 position may be determined by comparing the intensity of the peak at d 5 79.2 ppm (belonging to C-4 carbons adjacent to C-3 carbons bearing an unsubstituted hydroxyl group) with the sum

of the whole intensities in the range of d 5 71.0 79.2 ppm, ascribed to C-2 and C-3 carbons bearing a substituted or an unsubstituted hydroxyl group as well as to C-4 and C-5 carbons. These assignments allow one to estimate the relative reactivities of the three hydroxyl groups. Fig. 4 shows the variation of the relative DS i of individual hydroxyl groups in the reaction of cellulose with chloroacetyl chloride, as a function of the total DS value. The analysis of data shown in Fig. 4 clearly indicates that the relative reactivities of the three hydroxyl groups of anhydroglucose units decreased in the order: C-6 . C-3 . C-2. The highest reactivity of the hydroxyl groups at the C-6 position is consistent with previous studies of the esterication of cellulose [9,19] and the esterication of lowmolecular weight alcoholic compounds [19]. According to other authors [20,21], the higher reactivity of the hydroxyl groups attached to C-3 carbons with respect to hydroxyl groups at C-2 position, seems to be associated with the intramolecular hydrogen bonding between the hydroxyl group at C-3 position and the heterocyclic oxygen atom in the neighbouring glucopyranose unit.

Fig. 3. Basic structural unit of cellulose.

Fig. 4. Variation of the degree of substitution at individual hydroxyl groups (DS i ) with the total degree of substitution (DS) in modied celluloses prepared by reaction with chloroacetyl chloride.

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The coupling of a-naphthylacetic acid to cellulose functionalized with chloroacetate groups was carried out by using the potassium salt of a-naphthylacetic acid, according to the following scheme:

where r 5 a / b, a 5 initial concentration of chloroacetate groups, b 5 initial concentration of potassium a-naphthylacetate and X 5 fraction of reacted chloroacetate groups at time t. Plots of r / a(r 2 1) ln(1 2 X ) /(1 2 rX ) values

The H and C NMR spectra of cellulose anaphthylacetic acid adducts show the characteristic bands of the pendant bioactive agent, as can be seen in Table 1. Fig. 5 exhibits the kinetic results for the reaction between a partially modied cellulose with chloroacetate groups (42.5 mol% of chloroacetate groups) and potassium a-naphthylacetate at various temperatures. It is evident that the reaction rate depends on the temperature. By analogy with small-molecule reactions, the reaction between a partially modied cellulose with chloroacetate groups and potassium a-naphthylacetate is expected to involve a second-order reaction [16], which can be expressed for an equimolecular process as: r 12X kt 5 ]]] ln]] a(r 2 1) 1 2 rX
Table 1 Characteristic data of the 1 H and a-naphthylacetic adducts Group

13

against time (not shown) for the reactions represented in Fig. 5 consist of two straight lines instead of a simple line. Fig. 6 shows the variation of the apparent rate constant with time for the reaction of chloroacetylated cellulose with potassium a-naphthylacetate at various temperatures (represented in Fig. 5). The values of the apparent rate constant were calculated by using the equation:

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C NMR spectra of cellulose

d (ppm)
1

H NMR

13

C NMR

COCH 2 C 10 H 7 ] C 10 H 7 COCH 2 C 10 H 7 ]

4.2 7.47.8

37.2 123.0133.0 170.2

Fig. 5. Plot of the modication extent vs. time in the reaction of a partially modied cellulose with chloroacetate groups (42.5 mol% of chloroacetate groups) [Chloroacetate groups 5 0.039 mol / l] with potassium a-naphthylacetate (0.043 mol / l) in DMSO at various temperatures: ( n ) 508C; ( s ) 408C; ( h ) 308C.

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Fig. 6. Variation of reaction rate constant, k, vs. time in the reaction between a partially modied cellulose with chloroacetate groups (42.5 mol% of chloroacetate groups) [Chloroacetate groups 5 0.039 mol / l] and potassium a-naphthylacetate (0.043 mol / l) in DMSO at various temperatures: ( n ) 508C; ( s ) 408C; ( h ) 308C.

Fig. 7. Plot of the modication extent vs time in the reaction of a partially modied cellulose with chloroacetate groups (42.5 mol% of chloroacetate groups) [Chloroacetate groups 5 0.039 mol / l] with a-naphthylacetic acid (0.043 mol / l) using DBU (0.043 mol / l) as catalyst and DMSO as solvent at various temperatures: ( n ) 508C; ( s ) 408C; ( h ) 308C.

dx ] 5 k(a 2 x)(b 2 x) dt where x 5 concentration of a-naphthylacetate groups formed at time t. It can be observed from Fig. 6 that the values of the reaction rate constant decreased during the course of the reaction according to an autoretarded kinetic pattern. A similar behaviour was found with other reactive polymer systems [22,23]. This trend, different from a normal kinetic pattern, may be attributed to steric effects [24], since the remaining chloroacetate groups are expected to become less accessible because of the increased size of the neighboring a-naphthylacetate groups previously incorporated. Direct reaction of chloroacetylated cellulose with a-naphthylacetic acid in the presence of DBU gives modied polymers with the same structure as those obtained in the reaction with the potassium salt. Fig. 7 shows kinetic results for the reaction between chloroacetylated cellulose (42.5 mol% of chloroacetate groups) and a-naphthylacetic acid using DMSO as solvent and DBU as catalyst. As may be seen from Fig.

7, the direct esterication reaction is somewhat less efcient when it is compared with the reaction with potassium a-naphthylacetate. These results can be interpreted by taking into consideration that in this case the reactive intermediate may be the complex [25]:

which is more bulky in comparison to the carboxylate ion, and consequently the steric effects may be more accentuated. It may be noteworthy that in the reaction with a-naphthylacetic acid in the presence of DBU, the kinetic pattern (not shown) is very similar to that which we previously obtained in the reaction with potassium a-naphthylacetate (Fig. 6). In order to study the active ingredient release, polymeric derivatives were hydrolyzed heterogeneously. Fig. 8 presents the release behaviour at 378C and pH 8.1 of three adducts of cellulose a-naphthylacetic acid with differ-

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Fig. 8. Heterogeneous hydrolysis of three cellulose a-naphthylacetic acid (NAA) adducts at 378C and pH 8.1. ( s ) 23.0 mol% of NAA; ( h ) 30.0 mol% of NAA; ( n ) 41.0 mol% of NAA.

Fig. 9. Heterogeneous hydrolysis at 378C of a cellulose a-naphthylacetic acid adduct (23.0 mol% of a-naphthylacetic groups) at various pH values. ( h ) 9.0; ( s ) 8.1; ( n ) 7.4.

ent composition. As may be seen, the total release of the active compound was reached more quickly in the case of the adduct with lower degree of substitution, which may be justied in terms of the interaction of the polymer with water. Decreasing the content of a-naphthylacetic acid groups renders the polymers more hydrophilic and, therefore, facilitates the entry of the hydrolytic species into the polymer to the active sites. On the other hand, the shapes of the kinetic curves in Fig. 8 suggest the occurrence of autocatalytic effects. The interpretation of apparent released bioactive agent concentrations as a function of the percentage of bioactive agent attached is difcult probably because of several competing mechanisms involved. Hydrophilicity and distance of the labile bond from the polymer backbone often have large effects. Polymers with pendant bioactive agents appear to hydrolyse by a mechanism in which the degradation occurs uniformly, and it would be expected that the release rate decreases with time as the number of hydrolysable bonds decreases. However, as indicated above, curves in Fig. 8 revealed the existence of autocatalytic effects. According to the literature, only a small amount of data exist concerning this behaviour

and no conclusive explanation has been given [26,27]. Nevertheless, the effect mentioned above has been tentatively assumed to be related to an increase of hydrophilicity, particularly when the product of the hydrolysis reaction is a very hydrophilic group that causes the remaining polymer-bioactive agent to swell, thereby facilitating the approach of nucleophilic species to the active sites, effectively increasing the relative hydrolysis rates. Fig. 9 shows typical proles of the heterogeneous hydrolysis at 378C of a cellulose a-naphthylacetic acid adduct (23.0 mol% of a-naphthylacetic groups) in the alkaline medium. Greatly enhanced release rate is observed at pH 9.0, as would be expected.

4. Conclusions The functionalization of cellulose with chloroacetate groups provides a reactive derivative, which facilitates the immobilization of bioactive agrochemical carboxylic acids, such as a-naphthylacetic acid, to cellulose. The coupling of a-naphthylacetic acid to chloroacetylated cellulose is an approach to products that can gradually release the bioactive compound in aqueous

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medium. The release of a-naphthylacetic linked to cellulose carrier through a spacer arm is dependent on the pH value as well as on the hydrophilic / hydrophobic ratio of the polymer structure.

Acknowledgements The nancial support provided by the Di General de Investigacion Cientca reccion y Tecnica (DGICYT) is gratefully acknowledged. References
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