Advanced Polymeric Systems for Site-Specific Release Control of

Chapter 17

Advanced Polymeric Systems for Site-Specific Release Control of Insecticides in Foliar Applications 1

Downloaded by UNIV OF MASSACHUSETTS AMHERST on September 21, 2015 | http://pubs.acs.org Publication Date: June 24, 1988 | doi: 10.1021/bk-1988-0371.ch017

Dieter Lohmann and Christian D'Hondt

Central Research Laboratories and Agricultural Division Ciba-Geigy Ltd., CH-4002 Basel, Switzerland

Chlordimeform (CDF), an i n s e c t i c i d e / a c a r i c i d e commonly used f o r foliar applications in cotton, as well as it's desmethyl analogue (CMF) have been converted into polymeric controlled release systems with tailored site-specific release c h a r a c t e r i s t i c s . Based on the microenvironmental conditions p r e v a i l i n g on cotton leaves, as the s i t e of the insects action and of the pesticides' application, a l k a l i - c a t a l y z e d hydrolysis, photolysis and cation exchange were employed t o trigger the release by cleavage o f susceptible chemical bonds connecting the active agents with a macromolecular c a r r i e r . Corresponding polymers com p r i s e ethyleneglycol carbamate and benzoin carbamate either as hydrolyzable o r light-sensitive spacer groups, o r they contain CDF bound as a s a l t to sulfonic acid groups i n the r e s i n . In vitro and in vivo investigations provide evidence f o r the benefits of the site-specific release p r i n c i p l e with respect to improved e f f i c i e n c y and safety o f pesticides i n practical use. In conventional applications o f pesticides c e r t a i n inherent loss factors can often r e s u l t i n a p a r t i a l l y useless waste of the chemicals and in t h e i r undesired d i s t r i b u t i o n to the environment and to non-target animals. In recent years controlled release systems based on the use of polymers have shown a considerable potential to overcome those disadvantages and r i s k s (1-17). With respect to agrochemicals the current controlled release technology covers mainly three d i f f e r e n t approaches how t o govern the active agents' b i o a v a i l a b i l i t y in crop protection. The pesticide can be p h y s i c a l l y dissolved, adsorbed or dispersed i n a polymer matrix, i n order to control i t ' s release by d i f f u s i o n or by matrix erosion. Current address: International Research Laboratories, Ciba-Geigy Ltd., 665 Takarazuka, Japan 0097-6156/88/0371-0208$06.00/0 ° 1988 American Chemical Society

P.O.

Box 1,

In Pesticide Formulations; Cross, B., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

17.

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D'HONDT

Release Control of Insecticides

209

- The p e s t i c i d e can be p h y s i c a l l y entrapped in polymeric reservoir systems, such as microcapsules hollow f i b e r s etc., i t ' s release i s regulated by permeation, osmosis or evaporation.


- The p e s t i c i d e can be chemically bound to macromolecular c a r r i e r s , e i t h e r as part of the polymer backbone or as a pendent moiety, and i t ' s release i s governed by the cleavage of susceptible chemical bonds. A large v a r i e t y of d i f f e r e n t polymers and copolymers has been used in numerous devices of various forms and dimensions. The main goal in the development of a l l those c o n t r o l l e d release p e s t i c i d e systems has so f a r been the r e l i a b l e control of the active ingredient's release rate, in order to keep i t ' s temporal b i o a v a i l a b i l i t y at a constant optimum l e v e l . The l o c a l i z e d release control by targeting the pesticide's d e l i v e r y s p e c i f i c a l l y to the p a r t i c u l a r pest or crop has hardly been drawn any attention to, although targeting of drugs i s an established and i n t e n s i v e l y studied subject in the pharmaceutical f i e l d (18). Our own research in t h i s f i e l d has been focussed on the achievement of additional s i t e - s p e c i f i c i t y in the release control of i n s e c t i c i d e s . It i s the aim of t h i s paper to shortly review some of the work accomplished or presently in progress within our laboratory. Concepts and Objectives f o r S i t e - s p e c i f i c Release Control in Cotton The most distinguished c h a r a c t e r i s t i c of s i t e - s p e c i f i c release control i s the f a c t that the release of a bioactive material i s in p a r t i c u l a r triggered and governed by a s p e c i f i c phenomenon occurring in the target biosystem. Regarding the three fundamental approaches to release control by polymers we came to the conclusion that a chemically bound system only implies a dimension of a c t i v a t i o n energy, which meets the requirements f o r the high s e l e c t i v i t y in the p e s t i c i d e release aimed at. Accordingly the general model of a polymeric s i t e - s p e c i f i c p e s t i c i d e relase system i s thought to be composed of a polymeric backbone containing comonomers and/or c r o s s l i n k i n g agents besides a monomer connected with the pendent p e s t i c i d e molecule (Figure 1). Whereas the components of the polymer chain should enable a c e r t a i n fine-tuning of the release c h a r a c t e r i s t i c s , the key p o s i t i o n in the system i s hold by a t a i l o r e d spacer group and a susceptible bond l i n k i n g the p e s t i c i d e to the polymeric c a r r i e r . Both these elements f i n a l l y determine mechanism, rate and s e l e c t i v i t y of the release process. N - ( 4 - c h l o r o - o - t o l y l ) - N N dimethyl-formamidine J_, (Chlordimeform, CDF), has been selected as a model p e s t i c i d e f o r f e a s i b i l i t y studies on the s i t e - s p e c i f i c release concept. CDF i s an i n s e c t i c i d e / a c a r i c i d e commonly used in f o l i a r applications to f i g h t pests in cotton e.g. spodoptera l i t t o r a l i s , h e l i o t h i s and others (19). Unfortunately Chlordimeform lacks a s u i t a b l e functional group which could be u t i l i z e d f o r the chemical binding to a polymeric c a r r i e r . The corresponding monomethyl compound, N -(4-chloroo-tolyl)-Nl methylformamidine 2 (CMF), usually referred to as N-Desmethyl-chlordimeform, shows an i d e n t i c a l spectrum of b i o l o g i c a l 2

1

1

2


210

PESTICIDE FORMULATIONS: INNOVATIONS A N D D E V E L O P M E N T S

a c t i v i t y and i s i n f a c t the a c t i v e form of J_ generated in vivo by demethylation (20, 21).

CMF


CDF

2

Due t o t h e r e a c t i v e secondary amino group CMF 2 was used in t h i s study f o r t h e synthesis o f those systems which imply the covalent binding to a macromolecule. CDF 1 was used f o r systems based on heteropolar linkages to polymers, aricl in bioassaying experiments i t was employed as a standard f o r comparision. With respect t o s i t e - s p e c i f i c i t y i n t h e release a d e t a i l e d knowledge of the biosystem one i s going to deal with, i s by a l l means an i n e v i t a b l e requirement f o r t h e r e a l i z a t i o n o f the targeting p r i n c i p l e . With CDF 2 actual target i s of course the insect which destroys leaves aricJ seed capsules of the cotton plant. Since these i n s e c t i c i d e s are a c t i v e against quite a v a r i e t y of insect pests in cotton, a general alignment of the release t r i g g e r with the metabolism of a l l these insect species was regarded as not f e a s i b l e . Therefore we have directed our search f o r possible t r i g g e r i n g e f f e c t s to t h e cotton leaf as the s i t e where the insects' eggs, larvae and adults appear. Consequently a s p e c i f i c property in the cotton l e a f ' s microenvironment was t o be u t i l i z e d as a s p e c i f i c release t r i g g e r . However, checking t h e microenvironmental conditions p r e v a i l i n g on cotton leaves resulted i n three d i f f e r e n t phenomena (Figure 2) probably employable f o r release t r i g g e r i n g by cleavage of chemical bonds according to the basic idea: a n d C M F

2 t h e

- pH values in the range of 8-10 existent on the leaf surfaces caused by a l k a l i n e excretions (22) - the optimum o r i e n t a t i o n of the leaves to sunlight with i t ' s photochemical potency - cation concentrations leaf dew (23).

o f 18-20 m moles/ltr. found in cotton

As a consequence a l k a l i - c a t a l y z e d hydrolysis, photolysis and cation exchange have been i d e n t i f i e d as the most promising t a r g e t - s p e c i f i c t r i g g e r s t o be u t i l i z e d in the new s i t e - s p e c i f i c release systems. Synthesis of Polymer-Bound Insecticides The f i r s t approach based on hydrolysis as a release mechanism required as a weak link between the polymer backbone and the pendent i n s e c t i c i d e moiety a l a b i l e bond to be hydrolyzed in a desired way under the cotton leaves a l k a l i n e conditions. Previous investigations (24) with model compounds containing CMF 2 linked with a l i p h a t i c moieties v i a urea-, amide-, ester-, carbamate- and p h o s p h o n i t r i l i c amide bonds, had c o n c l u s i v e l y proven only the carbamate linkage to be



17.

LOHMANN AND D'HONDT

Figure 1.


211

General model f o r s i t e - s p e c i f i c c o n t r o l l e d release pesticides

Atmosphere

Soil Spher

Figure 2.

•

pH 8 - 10 / dew

•

1 8 - 2 0 mmoles cations /

•

optimum orientation

Itr. dew

to sunlight

Microenvironmental conditions p r e v a i l i n g on cotton leaves



212

PESTICIDE FORMULATIONS: INNOVATIONS AND DEVELOPMENTS

suitably hydrolyzed a t the pH value concerned. By reaction of 2-hydroxyethyl-methacrylate, phosgen and CMF 2 the CMF d e r i v a t i v e 3 is obtained which can subsequently be polymerized by r a d i c a l techniques to form homo- or copolymers (Scheme 1). The polymers thus obtained containing the ethyleneglycol ester unit as a spacer group and the carbamate moiety as a susceptible bond are in perfect accordance with the model lead structure (Figure 1). The homopolymer 4 and the more h y d r o p h i l i c 1:1 copolymer with N-vinylpyrrolidone TNVP) 5 were s e t to modest molecular weights favouring convential f o l i a r a p p l i c a t i o n by spraying. The second concept based on the idea of a p h o t o l y t i c cleavage of the susceptible bond as a release t r i g g e r required a s u i t a b l e photoresponsive spacer group. Among various model compounds including a number of photoremovable protecting groups (25-27) connected with CMF 2 by carbamate linkages, f i n a l l y the benzoin-carbamate of CMF 2 was Tound to undergoe the desired photofragmentation under formation of CMF (28). A corresponding polymeric system can be synthesized from 4-methacrylamido-benzoin 6 by reaction with the carbamoylchloride of CMF (24) and by r a d i c a l poTymerization of the monomer _7 thus obtained (Scheme 2 ) . The 1:1 methyl-methacrylate copolymer 8 and the corresponding N-vinyl-pyrrolidone copolymer 9 were adapted in the molecular weights t o the h y d r o l y t i c systems 4 and 5. A d e t a i l e d investigation o f the photochemistry of the monomeric and polymeric CMF-benzoin-carbamates using CIDNP-NMR techniques (29, 30) confirmed the -cleavage o f the benzoin moiety as an absolutely predominant process r e s u l t i n g i n the formation o f CMF, C 0 and 2-phenylbenzofuran moieties (Scheme 3). The t h i r d approach we were thinking o f i s based on the u t i l i z a t i o n o f the r e l a t i v e l y large c a t i o n concentration p r e v a i l i n g on cotton leave surfaces as a release t r i g g e r . Since Chlordimeform J[ is a weak base i t i s capable of forming stable s a l t s with strongly a c i d i c polymeric s u l f o n i c acids. Among various l i n e a r and c r o s s l i n k e d a l i p h a t i c and aromatic polymeric s u l f o n i c acids those CDF-resinates formed with sulfonated highly porous s t y r e n e / d i v i n y l benzene copolymers showed by f a r the most superior s t a b i l i t y and release capacity (Scheme 4). The release process of CDF could be simulated in v i t r o with spray deposits on f i l t e r paper obtained from aqueous formulations o f the products. Whereas a deposit obtained from conventional CDF emulsion concentrate (EC) i s completely depleted a f t e r 5 days due to CDF-evaporation, deposits obtained from the CDF resinate JO do not loose any a c t i v e agent f o r weeks. Subsequent spraying with d i s t i l l e d water has no influence. Only when increasing amounts of sodium bicarbonate are sprayed onto the CDF-resinate deposits there are gradually well-defined portions of CDF released and exposed to regular evaporation. The complete release of CDF from the resinate requires under these conditions almost 4 equivalents of cations (Figure 3). 2

Physicochemical and B i o l o g i c a l Properties of the S i t e - S p e c i f i c Controlled Release Systems Evaporation, wash o f f by r a i n , leaching and chemical degradation are among t h e most important loss f a c t o r s which often decimate a pesticide's b i o a v a i l a b i l i t y in open f i e l d a p p l i c a t i o n s within a short



17.

LOHMANNANDD'HONDT


£ HOMOPOLYMER

M ~ 7800

5 NVP-COPOLYMER ( 1:1 )

Scheme 1.

213

M - 7600

Hydrolytic systems: monomer synthesis and polymeri zation (NVP=N-vinyl-2-pyrrolidone)

7_

6.

SL MMA - COPOLYMER

( 1:1 )

9 NVP - COPOLYMER ( 1:1 )

Scheme 2.

M M

8300 8000

Photolytic systems: monomer synthesis and polymerization (MMA=methy1-methaerylate; NVP=Nvinyl-2-pyrrolidone)




214

CDF - LOADINGS : 30 - 36

Scheme 4.

%

Preparation of CDF-resinates



17.

Release Control ofInsecticides

LOHMANNANDD'HONDT

215

remaining deposit

% A

0

5

10

15 ****

Figure 3. CDF evaporation from CDF resinate spray deposits (CDF, dotted line: deposits from conventional CDF emulsion concentrate). (Reproduced with permission from ref. 31. Copyright 1987 Controlled Release Society.)



216


period of time. Table I summarizes some physicochemical properties of the three d i f f e r e n t types o f new c o n t r o l l e d release systems. In comparison t o CDF Jl and CMF 2 the polymers 4, 5, 8, 9 and _10 show a dicrease in vapour pressure aricl water s o l u b i l T t y by several orders of magnitude. In t h e absence of those t r i g g e r i n g influences which the respective design of the system i s based on aqueous formulations of the polymers e x h i b i t highly improved s t a b i l i t i e s and do not contain detectable amounts of f r e e CDF. Two days a f t e r a e r i a l applications in cotton plantations, CDF recoveries on the crop were determined to be 40-60 % increased when the new polymers were used compared to the conventional CDF emulsion concentrate. This r e s u l t exemplifies c l e a r l y the s u b s t a n t i a l l y reduced environmental losses obtained with the new s i t e - s p e c i f i c release systems - a f a c t o r of considerabel importance with regard to economical and e c o l o g i c a l aspects. A f t e r t h e f e a s i b i l i t y of the three d i f f e r e n t s i t e - s p e c i f i c re lease mechanism had been v e r i f i e d by simulating in v i t r o experiments, the new systems were to be tested on the real b i o l o g i c a l target under p r a c t i c a l conditions. In greenhouse experiments laboratory-reared spodoptera l i t t o r a l is larvae o f t h e f i r s t i n s t a r on young cotton plants (30 cm) were used f o r the bioassaying experiments. Larval m o r t a l i t i e s were assessed 4 and 8 days a f t e r treatment of the plants with wettable powder (WP)-, emulsion concentrate (EC)- or flowable (FO)-formulations o f t h e new polymers 4, 5, 8, 9, H). Some of the polymers were also tested i n f i e l d experiments and n a t u r a l l y occurring eggs and larvae were used f o r assessing the a c t i v i t i e s . The r e s u l t s (Table II) give evidence of the two photolytic systems (8, 9) as well as t h e CDF-resinate (10) being at l e a s t equal in TheTr i n s e c t i c i d a l potency to the standard CDF. EC- and FO-formulations are always more e f f i c i e n t than t h e corresponding WP-formulations, presumably due t o t h e i r favourable film-forming properties. The b i o a c t i v i t y o f t h e h y d r o l y t i c systems 4 and 5 i s found to be not completely s a t i s f a c t o r y . The lack of dew in greenhouse experiments - occurring every night in the f i e l d - might r e s u l t in an i n s u f f i c i e n t level of hydrolysis-triggered CMF-release. Further investiga tions require a c a r e f u l simulation of dew formation in greenhouse experiments and additional f i e l d t r i a l s under p r a c t i c a l conditions to give evidence o f t h e actual e f f i c i e n c y of the h y d r o l y t i c systems under p r a c t i c a l conditions. Since t h e aqueous formulations o f the new polymeric release systems do not contain d i s t i n c t amounts of f r e e CMF or CDF, the r e s u l t s from the bioassaying experiments provide c l e a r proof of the s i t e - s p e c i f i c release mechanisms conceived being e f f e c t i v e in the target biosystem. On t h e other hand due to the absence of f r e e i n s e c t i c i d e s t h e p r a c t i c a l formulations showed no t o x i c e f f e c t s during o r a l and dermal studies on r a t s . Thus s i t e - s p e c i f i c i t y of the release mechanism can contribute in a substantial way to handling safety and environmental clearance of p e s t i c i d e s . The forementioned environmental losses i n conventional applications o f p e s t i c i d e s lead t o i n s u f f i c i e n t duration of the p e s t i c i d a l a c t i v i t y . Therefore prolonged duration of a c t i v i t y i s another main goal advanced c o n t r o l l e d release systems aim at. A longterm a c t i v i t y t e s t with t h e polymers 5, 9 and JO has been performed in such a way that cotton plants in a greenhouse a f t e r the treatment with aqueous formulations of the polymers were stored f o r



Standards

CDF J_

CMF 2

CDF-Resinate H)

Ion Exchange

196

100

100

30

crosslinked

182

24

30

40

53

8000

8300

MMA-Copolymer (1:1) 8

NVP-Copolymer (1:1) 9

7600

7800

NVP-Copolymer (1:1) 5

Homopolymer 4

Systems

Photolyt.

Systems

Hydrolyt.

Controlled Release Polymer

CDF (CMF) Content % weight

250

350

«0,5

«0,5

«0,5

«0,5

« 0,5

Water Solubility 20°C ppm

7

«10"

3,6M0'

7,2M0"

7

7

«10"

«10"

7

7

«10"

«10"

4

5

Vapour Pressure 20°C mm Hg

Table I. Physiochemical Properties of Site-Specific Release Systems


2

2

H 0, 0 , l i g h t

sensitive to

stable i n absence o f cations

stable i n lighttight containers

hydrolytically stable a t pH 5 - 7,5

Stability


MMA-Copolymer (1:1) 8 NVP-Copolymer (1:1) 9

Photolyt.

44 66

WP-25 (4)

Standards

CDF 2

CMF 2 100

94

96

98

90

78

92 (F0)

97

100

98 (F0)

90

64 82

98

80 90

EC-50 (4) EC-50 (8)

% Larval M o r t a l i t y

Ion Exchange CDF-Resinate H) 92

Systems

Homopolymer 4 NVP-Copolymer (1:1) 5

Hydrolyt. Systems

Controlled Release Polymers

GREENHOUSE EXPERIMENTS

88 (EC)

-

larvae

72 (EC) 90 (EC)

76 (F0) 96 (F0)

-

43 (WP) 74 (WP)

eggs

% Mortality

FIELD EXPERIMENTS

Table II. Bioactivities of Site-Specific Release Systems (greenhouse experiments: Spodoptera littoralis larvae L I on cotton plants; field experiments: naturally occurring eggs and larvae of Spodoptera littoralis; WP=wettable powder, ED=emulsion concentrate, FO=flowable)



17.

LOHMANNANDD'HONDT


219

increasing periods o f time before i n f e s t a t i o n with spodoptera l i t t o r a l is larvae and assessment of the larval mortality. The r e s u l t s thus obtained from greenhouse experiments are shown in Figure 4. The photolytic NVP-copolymer 9 e x h i b i t s by f a r the highest duration of a c t i v i t y i n comparison t o the h y d r o l y t i c NVP-copolymer j>, t h e CDF-resinate 10 and the CDF standard. Under these conditions t h i s p a r t i c u l a r polymer keeps the i n s e c t i c i d a l potency on a high l e v e l o f 80-100 % f o r a period of four weeks compared to 10 days only found for the CDF standard. We assume that the minor e f f i c i e n c y of the polymer 5 and the CDF-resinate _H) observed in the longterm studies are again due to the f a c t that there i s water involved in the release processes concerned, hydrolysis and cation exchange. Under t h e influence o f dew in open f i e l d s the longterm a c t i v i t y of the l a t t e r systems might turn out more p o s i t i v e l y than the behaviour in the greenhouse. F i n a l l y i t was to be prooved that the photolytic systems, also containing carbamate linkages, not only in v i t r o (s. Scheme 3) but also i n vivo are subject t o the p a r t i c u l a r photoreaction under release o f CMF. For t h i s purpose a number of cotton plants was treated with aqueous formulations of the polymer 8. When the plants were stored under reduced l i g h t i n t e n s i t y in the shade the larval m o r t a l i t i e s found on those plants dropped to 15 % only within 10 days, compared to 98 % larval mortality a f t e r 10 days obtained with plants stored under f u l l daylight. With CDF used as a standard the larval m o r t a l i t i e s undergoe in both cases only the regular longterm decrease t o 76 % within 10 days. Based on these r e s u l t s , l i g h t i s considered t o be the actual release t r i g g e r in the polymer 8 thus confirming the f e a s i b i l i t y of the o r i g i n a l concept.

% larval mortality A100-

80-

60-

x

Hydrolytic NVP-Copolymer £

40-

}

CDF - Resinate 12

20-

4

Figure 4.

8

12

16

20

24 28 32 3 — - time ( d a y s )

Longterm b i o a c t i v i t y of s i t e - s p e c i f i c release systems (spodoptera l i t t o r a l is larvae L1, greenhouse, cotton plants 30 cm high)


220


Conclusions The new polymerbound c o n t r o l l e d release systems e x h i b i t s i t e - s p e c i f i c release c h a r a t e r i s t i c s , which are s p e c i f i c a l l y directed t o cotton leaves as a target biosystem. Hydrolysis, photolysis and cation exchange as release mechanisms can s e l e c t i v e l y be triggered under the biosystem s conditions. Reduced environmental losses and a general d e t o x i f i c a t i o n i s found as a benefit i n a l l the three systems. The preparation o f t h e new polymers includes r e l a t i v e l y simple and unexpensive processes, with the CDF resinate being at the head. Conventional formulation and spraying techniques can be used f o r the p r a c t i c a l a p p l i c a t i o n . Preliminary greenhouse and f i e l d experiments have given evidence o f t h e advantages o f s i t e - s p e c i f i c release systems. Expecially l i g h t - t r i g g e r e d release as a concept showed most promising r e s u l t s with respect t o a remarkably prolonged duration o f a c t i v i t y . Further investigations w i l l be directed t o the t r a n s f e r of the new concepts to various types of bioactive materials.


1

Acknowledgments The authors are g r a t e f u l t o Dr. G. R i s t f o r the NMR-spectrocopic investigation o f the photorelease mechanism and t o Dr. F. Bourgeois, F. Buholzer, Dr. V. Fluck, Dr. E. Neuenschwander and Dr. H. Schwitulla f o r the extensive b i o l o g i c a l t e s t i n g . L i t e r a t u r e Cited 1. G.G. A l l a n , C.S. Chopra, J.F. Friedhoff, R.I. Gara, M.W. Maggi, A. N. Neogi, S.C. Roberts, R.M. Wilkins, CHEMTECH. 1973 (3), 171 2. "Controlled Release Pesticides Formulations", edited by Nate Cardarelli, CRC Press, Inc., Cleveland, Ohio, 1976 3. "Proc. Controlled Release Pesticide Symposium", August 22-24, 1977, Corvallis, Oregon, edited by R.F. Goulding 4. "Controlled Release Technology-Bioengineering Aspects", edited by K.G. Das, John Wiley & Sons, New york, 1983 5. "Controlled Release o f Bioactive Materials", edited by R. Baker, Academic Press, New York, 1980 6. " B i o l o g i c a l Activities o f Polymers", edited by C.E. Carraher, C. G. Gebelein; ACS Symp. Ser. 1986, 13 (1981) 7. "Proc. Controlled Release Pesticide Symposium", Sept. 16-18, 1974, Akron, Ohio, edited by N.F. Cardarelli 8. A.N. Neogi, G.G. A l l a n i n "Advances i n Experimental Medicine and Biology", Vol. 47 edited by A.C. Tanquary, R.e. Lacey, Plenum Press, New York, 1974, p. 195-224 9. "Proc. Controlled Release Pesticide Symposium", Sept. 1975, Dayton, Ohio, edited by F. W. Harris 10. "Controlled Release P e s t i c i d e s " , edited by H.B. Scher; ACS Symp. Ser. 53, (1977) 11. "Proc. Controlled Release P e s t i c i d e Symposium", Aug. 1978, Gaithersburg, Maryland, edited by G.A. Montemarrano 12. "Controlled Release Technologies: Methods, Theory and Applications", Vol. 1 and 2, edited by A.F. Kydonieus, CRC Press Inc. Boca Raton, Florida, 1980



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