J. MICROENCAPSULATION, 1989, VOL. 6, NO. 1, 53-58

Design and in vitro evaluation of polyvinyl chloride microcapsules containing sulphamethoxazole

SUDIP K. DAS and SHRABANI PALCHOWDHURY

Division of Pharmaceutics, Department of Pharmacy, Jadavpur University, Calcutta 700 032, India

(Received 28 January 1988; accepted 25 February 1988)

Polyvinyl chloride microcapsules containing sulphamethoxazole have been prepared by phase separation coacervation in non-aqueous solvents. Phase separation of the polyvinyl chloride in the solution of chloroform was achieved with n-hexane. Scanning electron micrographs revealed uniform encapsulation of the sulphamethoxazole particles. In vitro dissolution studies were conducted under changing pH conditions. The reproducibility of the in vitro drug release was highly significant. The mechanism of drug release was suggested as an integrated process of diffusion controlled dissolution. Controlled drug release was obtained over a prolonged period of 8 h.

Introduction A large amount of work into microencapsulation techniques has taken place in

recent years and various new wall-forming materials with specific advantages have been introduced. The microencapsulation of pharmaceuticals using thermoplastic polymers, adopting the principle of non-aqueous phase separation, involves the dispersion of the core material into a solution of the coating polymer in a suitable solvent followed by the addition of an incompatible solvent, which is immiscible with the polymer, produces coacervation and the subsequent deposition of the polymer on the dispersed core material.

Polyvinyl chloride has been used in the preparation of sustained release aspirin tablets (Vora et al. 1964). Microencapsulation of water insoluble pharmaceuticals by films of polyvinyl chloride, using the solvent tetrahydrofuran and the non-solvent water, has been reported (Kondo 1979).

The present method for the manufacture of the polyvinyl chloride microcapsules employed a non-aqueous medium, chloroform, in which the wall forming material was dissolved and from which it was caused to separate by the addition of an incompatible solvent, n-hexane. The polymer rich liquid coating was later set to a film condition by the ‘rigidization’ step. This method is highly suitable for microcapsulation of water soluble pharmaceuticals as well as water insoluble ones.

Experimental Materials

Sulphamethoxazole-Indian Pharmacopoeia, passed through a no. 100 sieve, (courtesy of Smith Stanistreet Pharmaceuticals Ltd, Calcutta), polyvinyl chloride- mw 37 400, density 1.4 gm/ml (Aldrich, U.S.A.), chloroform and n-hexane were extra pure grades.

0265-2048/89 $340 0 1989 Taylor & Francis Ltd

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54 S. K . Das and S . Palchowdhury

Method Triangular phase diagram

At 25"C, the turbidimeter was used to construct the isothermal triangular diagram of phase boundaries for the coacervating system: polyvinyl chloride- chloroform-n-hexane. Volumes of n-hexane were added to polyvinyl chloride in chloroform solutions of various concentrations. The point of phase change was when the turbidity started to increase rapidly. The phase diagram was constructed based upon these points.

Microencapsulation Polyvinyl chloride was purified by precipitation with methanol, from a solution

of tetrahydrofuran. Five grams of polyvinyl chloride was uniformly dispersed in 15 ml n-hexane. One hundred and fifty millilitres of chloroform was added to the system whilst stirring. Quantities of sulphamethoxazole were dispersed into the solution. The non-solvent, n-hexane, at 20°C was added drop-wise to the system at a rate of 3 ml/min, while stirring at constant speeds of between 400 and 1100 rpm. After the addition of 300 ml of the non-solvent, the system was chilled to 5°C for 1 h. Stirring was continued for a further 1 h at 5°C. The microcapsules were washed several times with chilled n-hexane and recovered by filtration at reduced pressure. The microcapsules were dried in air and afterwards in an air-circulated oven at 50°C.

In vitro dissolution In vitro drug release profiles were studied using a USP XX basket type

dissolution apparatus with a no. 100 mesh nylon screen covering the basket to prevent the escape of the microcapsules. Five hundred ml of dissolution fluid at an initial pH of 1.2 was used. The basket containing the microcapsules was rotated at 100 f 5 rpm. Five ml aliquots were withdrawn at intervals of 30 mins and the mixture replenished with the same volume of buffer of a higher pH in order to achieve an increasing pH profile (see figure 4). The dissolved drug in the aliquots was assayed spectrophotometrically (Bratton and Marshall 1939).

Results and discussion Triangular phase diagram

The triangular phase diagram of the system polyvinyl chloride-chloroform-n- hexane is shown in figure 1. The microencapsulation occurred within the area under the curve. When the liquid coacervated polymer deposited on the hydrophobic surface of the drug the resulting microcapsule wall had a varied wall thickness. The weight of polyvinyl chloride in the coacervate increased with increasing amounts of n-hexane.

Microencapsulation After the addition of n-hexane, part of the total polyvinyl chloride available is

coacervated, separating in the form of viscous liquid drops. These drops tend to deposit on the surface of the drug particles suspended in the solution. The subsequent cooling of the system causes further polyvinyl chloride to coacervate. During cooling below the transition glass temperature, the coacervate phase is gradually deposited on the already formed walls of polyvinyl chloride coacervate.

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Figure 1 .

Polyvinyl chloride microcapsules 5 5

Triangular phase diagram of the coacervate system polyvinyl chloride- chloroform-n-hexane.

r . p . m .

microcapsules. Figure 2. Effect of stirring speed on the mean particle size of the sulphamethoxazole

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56 S. K . Das and S. Palchowdhury

Figure 3. Scanning electron micrograph of the sulphamethoxazole microcapsules.

Table 1 . Composition and pharmaceutical properties of the microcapsules.

Polyvinyl Content Wall Mean particle Sulphamethoxazole chloride uniformity Yield thickness diameter

(per cent) (per cent) (per cent) (per cent) (pm) (Pm)

33.3 66.7 93.5 87.8 16-4 550 50.0 50.0 95.8 88.2 15-2 550 6 6 7 33.3 947 87.6 14.5 550

Each figure is the average of six batches.

Stirring speed had a very special effect on the formation of the individual, non- aggregated microcapsules. Stirring speeds below 800 rpm resulted in a degree of aggregated particles. The effect of stirring rate on the production of mean microcapsule size is presented in figure 2. Stirring speeds of 1100-1000rpm produced the optimum size distribution of the microcapsules. The position of the stirrer had to produce efficient mixing, without non-convected regions.

Protective colloids, polyisobutylene and polybutadiene, in concentrations of up to 7 5 per cent wlw had no effect on the physical properties of the microcapsules, as revealed from the scanning electron micrographs.

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Polyvinyl chloride microcapsules

2 100

0" 80-

Q)

c +

0, 0 N

0

-

60- 5 E 40- 0 'c 3 v)

f 0,

+ 20-

57

-

I I I I I I I I 0 1 2 3 4 5 6 7 8

Time, h r .

release profile of sulphamethoxazole; mean particle size: 550 pm. Figure 4. Effect of sulphamethoxaxole (SMX): polyvinyl chloride (PVC) ratio on the in witro

I 5 M X : P V C : : 2:l 0

1 : 1 A 1:2 0

M E A N PARTICLE S I Z E

5 5 0 ~ r n - 7 6 7 ~ m ----- 912fim -.-.-

2 I I I I I I

L O 1 2 3 4 5 6 7 Q) 01

Dissolution t 50%. hour Figure 5 . Effect of percent sulphamethoxazole content of the microcapsules on the in w h o

dissolution t5,, per cent.

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58 Polyvinyl chloride microcapsules

Scanning electron micrography Scanning electron micrographs of the sulphamethoxazole microcapsules showed

that the surface and the shape of the microcapsules were irregular (see figure 3) , due to the amorphous nature of the drug particles used. There were no appreciable pores visible on the surface.

Sulphamethoxazole : Polyvinyl chloride ratio Table 1 shows the percentage yield and the drug content of the various

formulations studied. The data show good reproducibility of the microencapsulation process with regard to the drug content and the percentage yield. The mean microcapsule size increased with a decrease in the sulphamethoxazole : polyvinyl chloride ratio. The effect of this ratio on the in vitro dissolution t5, per cent is shown in figure 4. The dissolution rate increased with the increase of this ratio.

In vitro dissolution The sulphamethoxazole (SMX) release profile, figure 5, demonstrates a high

degree of correlation between the drug content of the microcapsules and the dissolution tsO per cent. The dissolution t,, per cent varies with the particle size and the drug: polyvinyl chloride ratio because of the variations in the shell thickness. Figure 5 shows the tendency of the dissolution tsO per cent to rise when the particle size of the microcapsules increase, due to the decrease of the effective surface area.

From figure 4, it is evident that the drug exhibits a slow dissolution from the polyvinyl chloride microcapsules and that the drug release is linearly related to time for the first part of the drug release profile. In view of this dissolution profile, the effect of agitation intensity and the microscopic evidence of pore formation, the mechanism proposed for the in vitro drug release from the sulphamethoxazole microcapsules is the transport of the drug through the capillary channels formed in the coat only after immersion of the microcapsules in the dissolution fluid, and not present in the original wall. Therefore, the overall drug release process is controlled by diffusion, coupled with a dissolution process. The sulphamethoxazole release was prolonged up to a period of 8 h.

In conclusion, microencapsulation using polyvinyl chloride coacervated droplets shows that, by means of particle size modification and alteration of the core : coat ratio, the effective coating efficiency can be controlled. In terms of in vitro dissolution this may be varied between high and the low levels with a consequent change of wall thickness although always retaining a true film coating.

Acknowledgements We are particularly indebted to Professor Bijan K. Gupta for invaluable advice.

We would also like to thank Mr Sarat C. Chattaraj and Mr Tarun K. Mandal for their utmost cooperation during this investigation. We gratefully acknowledge the financial assistance from the University Grants Commission of India.

References BRATTON, A. C., and MARSHALL, E. K. , 1939, A new coupling component for sulfanilamide

KONDO, A., 1979, Microcapsule Processing and Technology, edited by J. W. V. Valkenburg

VORA, M. S., ZIMMBR, A. J., and MANEY, P. V., 1964, Sustained-Release Aspirin Tablet

determination. Journal of Biological Chemistry, 128, 537-550.

(New York: Marcel Dekker), pp. 95-105.

Using an Insoluble Matrix. Journal of Pharmaceutical Sciences, 53, 487-492.

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