M U L T I L A Y E R E D SYRUP GRANULES S T A B I L IT Y
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A M E T H O D FOR I M P R O V I N G P R O D U C T
D. B a l l , G. E l g e r , J. Ryder, H. Seager, D. Sharland. Beecham Pharmaceuticals, Biosciences Research Centre, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, mi8 S X Q The separation of incompatible i n g r e d i e n t s of a product by i n c o r p o r a t i n g them i n t o d i f f e r e n t l a y e r s o f a multilayered granule has been attempted. I n i t i a l l y magnesium carbonate and copper sulphate were used as models f o r t h e two compounds t o be separated, and t h e i r p o s i t i o n i n t h e granule s t u d i e d u s i n g a JXA Microprobe Analyser. The technique w a s then applied t o t h e separation of a drug substance and a p r e s e r v a t i v e . Magnesium carbonate (145.5g) and c a s t o r sugar (5.6 kg) were granulated by wet massing with a 0.5% W/V aqueous s o l u t i o n of Amaranth i n a p l a n e t a r y mixer. The dye w a s included t o provide a v i s u a l i n d i c a t i o n of t h e progress of t h e subsequent coating. Examination of t h e granules by o p t i c a l microscopy i n d i c a t e d t h a t t h e magnesium carbonate w a s evenly d i s t r i b u t e d over t h e sugar. Using a f l u i d bed g r a n u l a t o r , 9 k g of syrup B.P. were sprayed onto t h e f l u i d i s e d wet massed granules. Examination using an o p t i c a l microscope and a Stereoscan Electron Microscope showed a complete c o a t i n g o f sugar over t h e granule. The r a t i o of weight o f syrup sprayed t o weight o f sugar used i n the wet massing was s e t as high as reasonably p r a c t i c a l , t o maximise separation of t h e incompatible i n g r e d i e n t s . F i n a l l y a t h i n o u t e r c o a t i n g o f copper sulphate s o l u t i o n was sprayed onto the granules. The granule s t r u c t u r e w a s examined by s e t t i n g a number of granules i n a r e s i n mould, and, a f t e r hardening, g r i n d i n g down using an abrasive c l o t h u n t i l a s a t i s f a c t o r y smooth f l a t s u r f a c e w a s obtained. The samples were s p l a t t e r e d with carbon and examined by e l e c t r o n microscopy u s i n g a JXA Microprobe Analyser. The method employed w a s t o d i r e c t a f i n e l y focussed beam of high energy e l e c t r o n s onto a p a r t i c u l a r p o i n t on t h e surface o f t h e granules whose chemical composition was t o be examined. The s m a l l volume o f m a t e r i a l i r r a d i a t e d by t h e e l e c t r o n beam, about one micron cube, then emits X-rays whose energy and wavelength i s c h a r a c t e r i s t i c of t h e elements present within t h i s region. Photomicrographs have shown t h e magnesium carbonate t o be separated from an o u t e r copper sulphate s h e l l by a l a y e r of sugar. I n t h e second stage of t h e i n v e s t i g a t i o n , t h e process was applied t o a syrup granule formulation which had previously shown poor s t a b i l i t y due t o a r e a c t i o n between t h e drug substance and a preservative. I n t h i s case, t h e drug substance w a s incorporated i n t o t h e core granule, and t h e p r e s e n r a t i v e i n t o t h e o u t e r shell.