Formulation of insect controlling agents with β‐cyclodextrin

Pestic. Sci. 1990. 28, 7 16

Formulation of Insect Controlling Agents with p-C yclodextrin

Lajos Szente, Halina Magisztrak & Jozsef Szejtli

Cyclodextrin Laboratory of Chinoin Pharm.-Chem. Works, Budapest, Endrodi S. 38/40, Hungary

(Revised manuscript received 13 March 1989; accepted 5 May 1989)

ABSTRACT

Two insecticides, mi insect repellent arid un insecticide synergist have been complexed with P-cyclodextrin yielditig tnicrocrjstulline, wettable, non- hygroscopic ji>rmulations. The insecticides j2nitrothion rind maluthion, the repelleiit diethyltoluamide and the synergist MGR-263 were jounci to jbrw stable iticlusiori complexes with P-cycloriestriri.

The molecular encapsiilutioti resulted in improoed heat trrid chemicul stability, storuhilitp, enhanced wettability arid dissolution properties of' these rather rolatile. poorl?' )cuter-soluble ugents.

1 INTRODUCTION

The application of cyclodextrin to poorly water-soluble, volatile, unstable pesticides generally results in similar effects to those found with drugs.' which can be summarised as follows:

-The cyclodextrin complexes have improved wettability, faster rates of dissolution and increased solubility compared to the non-coniplexed hydrophobic parent substances. The consequent improvement in bio- availability can allow a reduction in dosage, and hence a reduction in cost and in possible environmental effects. Other advantages of the use of cyclodextrin- complexed pesticides include:

-Volatile liquids or sublimable crystalline substances can be transformed into stable, solid powders. Losses through volatilisation can be reduced.2 There are many highly effective substances having intolerable odours (e.g. thiophosphates). When these are complexed with cyclodextrins, they appear to have reduced odour but unaltered efficacy.

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Prstic. Sci. 0031-613X/90/$03.50 0 1990 Society of Chemical Industry. Printed in Great Britain

-A further advantage is that the entrapped substances are released on contact with water (e.g. rain) and are thus liberated from the complex at the right time.

--Degradable, labile (to light, heat, oxygen, ions) substances can be stabilised and made more compatible with other constituents of the formulation.

-Cyclodextrin complexation may also result in a retarded release of biologically active substances. For example, the hormone activity of ethylene can be prolonged and more favourable results can be achieved by a treatment that provides a controlled low ethylene level, than from a short term high level treatment . 3

The published examples confirm the assumptions that in the next decade, a rapid development can be expected in the application of cyclodextrin in pesticide formulation . '

2 MATERIALS AND METHODS

P-Cyclodcxtrin V-CD) of over 99 % purity (loss on drying: 12 % m/m) was obtained from Chinoin Pharm. Chem. Works Ltd, H-Budapest. Fenitrothion, diethyltoluamide (deet) and MGK-264 (N(2-ethylhexyl)-8.9,1 O-trinorborn-S-ene- 2,3-dicarboximide) were donated by Johnson Wax Co., USA. Malathion was purchased from Als Cheminova, Denmark in 96",, purity. All other materials used were of analytical reagent grade.

2.1 Preparation of the solid complexes

The complexes of the pesticides with ,!I-CD were prepared by co-crystallisation as described previously . ' 2.2 X-ray powder diffraction

The X-ray powder diagrams were registered on a PW 1060 diffractometer (Philips, Almelo, The Netherlands) using normal Cu-K, ray in the 20 angle range of 2-30.

2.3 Thermo-analytical investigations

Thermo-analytical investigations were carried out on a DuPont 990 Thermal Analyser System (Stevenage, UK).

Thermogravimetric analysis (TGA), differential thermogravirnetric analysis (DTGA) and thermoevolution analysis (TEA) curves of the insecticides as well as of their simple mechanical mixtures and inclusion complexes were taken simultaneously.

2.4 TAS-assay (thermofractometry combined with thin-layer chromatography)

The thermofractometric studies were carried out using a 'Tasomat' (Desaga) oven.' Thin-layer chromatography was performed on silica gel plates (Merck GF,,,) in dichloromethane solvent. The spots on the chromatograms were visualised either by 1OOg litre-' ethanolic molybdophosphoric acid or by l o g litre-' aqueous potassium permanganate solutions.

2.5 Storage stability

The accelerated storage stability studies were carried out in open test tubes at 60°C for two weeks. The changes in the pesticide content of treated samples were determined by UV-spectrophotometry, in SO”.; v/v cthanolic solutions 011 a Specord UV~-VIS photometer (Carl Zeiss, Jena, DGR).

2.6 Wett abili t y studies

The wettability of solid formulations was determined using a modified Enslin a p p a r a t ~ s . ~ The height of wet zones was measured and the upward migration of water into the powder-packed tubes was registered as a function of time. All data represent the mean of three parallel measurements.

2.7 Dissolution studies

The rate of dissolution of free and complexed pesticides from formulations was studied in distilled water at 22°C using the standard ‘Dispersed Amount Method’.’

3 RESULTS AND DISCUSSION

3.1 Characterisation of the insecticide fl-cyclodextrin complex formulations in the solid state

Since the guest molecules are not solid, crystalline substances, a simple comparison of the X-ray powder diffractograms of the starting /?-cyclodextrin-hydrate and the crystalline P-cyclodextrin complexes is sufficient to prove the formation of a new crystalline structure. Significant changes in the X-ray diffraction patterns directly indicated the existence of an inclusion complex between host and every guest molecule studied. This is illustrated for the deet//?-CD complex (Fig. 1).

7--_T-, . I . I 1 7 - 1 1 I-._

33 30 25 i o ’ ’ ’ 15 10 5 2 8

Fig. 1. X-ray powder diagrams of pcyclodextrin and the crystalline deet/pcyclodextrin complex.

3.2 Comparative heat stability tests

3.2.1 Thermo-analytical inoestiyations The detailed results of thermal analyses are presented on the MGR-264//3-CD formulations by way ofexample. As Fig. 2 shows, the evaporation of parent MGR- 264 starts at 70 C and continues up to 220'C. The mechanical mixture of MGK-264 and P-cyclodextrin gives thermo-analytical curves which show additive thermic properties of both the host and guest molecules (Figs 3 and 4). The MGR-264//3-CD

600 mV I i T €A

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100 200 300 "C

Fig. 2. Thermo-analytical (TGA, DTGA and TEA) curves of MGR-264.

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Fig. 3. DTGA (upper) and TGA (lower) curves for: -, MGR-264/bcyclodextrin mixture (200 g kg-' MGR-264); , MGR-264/~-cyclodextrin complcx (102 g kg-' MGR-264); -.-.. MGR-264/8-

cyclodextrin complex with excess MGR-264 (210 g kg-' ).

complex sample with an MGR-264 content of 102-106 g kg- ' can be considered as a proper inclusion complex since thermo-analyses show that no thermal release of any extent takes place from this sample before 200°C. This indicates that the entire amount of the insecticide synergist is entrapped into the host molecule (Figs 3 and 4).

12

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100 200 300 "C

Fig. 4. TEA curves for the MGR-264;/~-cyclodcxtrIii mixture (upper curve). MGR-lh4i/~-cyclodextrin complex (lower curve) and complex containing MGR-264 in excess (middle curve). The dotted curves

represent decomposition products of the /icyclodextrin matrix; note the change i n calibration.

Although all the TGA curves show a weight loss from the complex sample at 90°C. this is due to the loss of water from the complex and therefore it is not apparent in TEA curves. (The flame ionisation detector ofthe TEA instrument does not respond to water.)

The other MGK-264/[j-cyclodextrin formulation was deliberately prepared to contain loo?,, exce~s MGR-264, i.e. an MGR-264 content of 210 g kg- ' .

A11 the TGA, DTGA and TEA curves of this sample show thermo-analytical behaviour representative both of the mechanical mixture and the proper inclusion

Fownu/atio,i oJ. insect contro//ing agetits with /?-cyclokutrin 13

complex (Figs 3 and 4). Similar thermo-analytical patterns were observed with the other insecticide formulations discussed in this paper, indicating their improved heat resistance.

3.2.2 TAS-assay (Thermofiactometry combined with thin-layer chromatography) TAS-assay is a fast and simple procedure used for the qualitative description of the thermal release of absorbed and entrapped (complexed) volatiles from cyclodextrin complex formulation^.^ Figure 5 shows the thermofractograms of absorbed and complexed MGR-264 samples. The results of TAS-assay show that the mechanical mixture of MGR-264 and p-cyclodextrin releases the insecticide synergist above 100-120°C and this thermally induced escape of MGR-264 continues up to 260°C. The two complex samples show obviously retarded thermal release of the guest molecule. The complex of MGR-264 and p-CD containing 102 g kg - ' of the former does not lose the entrapped MGR-264 below 220°C, while the other complex formulation containing excess MGR-264 releases the synergist at 180°C. The above qualitative thermal stability data were found to support the more sophisticated thermal analyses (TGA, DTGA and TEA).

3.3 Storage stability of insecticidelfl-cyclodextrin formulations

Mechanical mixtures and inclusion complexes of identical insecticide content were tested for loss of volatiles during storage for two weeks at 60°C. The results of the storage stability test are listed in Table 1. As the results indicate, the storability of p- cyclodextrin complexed pesticides significantly surpasses that of the mechanical mixtures. Among complexed substances, fenitrothion was found to have the shortest shelf life at 60°C.

3.4 Wettability studies

As expected, the formulations containing only mechanically mixed hydrophobic

TABLE 1 Two-Week Storage Stability of Insecticide/fi-Cyclodextrin Formulations at 60°C

Time Insecticide content ( % of initial formulation) (dnys)

Deet MGR-264 Malathion Fenitrothion

A C A C A C A C _ _ _ _ ~ ~ _ _ _ _ _ _

0 13.5 14.0 10.0 10.2 22.0 22.4 17.0 17.0 I 10.1 15.4 8.2 11.0 15.4 22.9 15.2 16.3 3 10.3 14.5 8.0 9.8 14.5 21.8 14.0 16.0 6 6.9 13.0 6.7 9.9 14.7 21.0 12.2 15.0

10 3.8 13.5 6.9 9.7 10.5 21.7 6.6 12.2 14 3.3 13.1 4.9 9.3 6.8 21.0 4 3 10.9

A: adsorbed (mechanical mixture). C: complexed.

14 L . Szente, H . Magisztrak, J . Szejjtli

insecticides show poor wettability. However, the P-cyclodextrin complexes appear to be fairly wettable, due to the more hydrophilic shell provided by the cyclodextrin ring. This is shown by the examples of malathion and MGR-264 formulations (Fig. 6).

3.5 Dissolution studies

Cyclodextrin complexation results in the guest molecules being entrapped in a molecularly dispersed state, which usually leads to an enhanced dissolution rate for poorly water-soluble substances. '

Figure 7 shows the rate of dissolution of free, adsorbed and molecularly

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Fig. 5. Thermofractograms of: (a) MGK-2h4/~cyclodextrin mixture. (h) MGR-264/fl-cyclodextrin complex.

Formulation qf insect controlling agents with P-cyclode.xtrin 15

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Fig. S -co~td . (c) Complex containing MGR-264 in excess.

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* 0 5 10 15 20 25 Time (min)

Fig. 6. Wettability of solid MGR-264 and malathion formulations. 0 -0, MGR-264//l-cyclodextrin complex; .I -L'. malathion:/~-cyclodextrin complex; ;I-- :.', MGR-264:Bcyclodextrin complex with

excess MGR-264; -.. malathion/kaolin: 0 - 0 . MGR-264/kaolin.

16 1,. S x n t r . H . Mayisirrak, J . Szvjtli

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Fig. 7. Dissolution profile\ of MGR-264 formulations in water at 22 C 0 . MGR-263//lcyLlodextrin complex, A, MGR-264//?cyclodextrin mixture, x , MGR-264 alone

encapsulated (complexed) MGK-264 in distilled water at 22°C. The dynamic dissolution data show that even simple addition ofP-CD to the formulation (MGR- 264/8-CD mixture) can improve t he dissolution properties of the hydrophobic guest molecule, which is in good accordance with previous observations.'

It has been shown that P-cyclodextrin acts both as a stabilising host molecule and a biologically inert solubilising agent, and it is therefore attracting more and more attention in the field of pesticide formulation.

ACKNOWLEDGEMENTS

The authors' thanks are due to Dr K . Simon for X-ray studies and Dr Cs. Novak for thermal analyses.

REFERENCES

1. Szejtli, J., Cyclodexfrins und their inclusion complexes, Akademiai Kiado, Budapest,

2. Szente, L. & Szejtli, J., Acta Chim. Acud. Sci. Hung., 107 (1981) 195-202. 3. Tetenyi, M. & Szejtli, J., Acta Agron. Acad. Sci. Hung., 33 (1984) 345-8. 4. Stahl, E., J . Chromatog., 37 (1968) 99-102. 5. Szente, L. & Szejtli, J., Acta Pharm. Hung., 57 (1987) 73-6. 6. Nogami, H. & Nagai, T., Chem. Pharm. Bull., 17 (1969) 499-502. 7. Kernoczy, Zs., Tetenyi, P., Mincsovics, E. & Szejtli, J., Quart. J . Crude Drug Res., 16

Hungary, 1981, pp. 217~-20.

(1979) 153-6.