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Determination of compaction parameters of pharmaceutical powders with an instrumented hydraulic press Doroudian, Ahmad 1991

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DETERMINATION OF COMPACTION PARAMETERS OF PHARMACEUTICAL POWDERS WITH AN INSTRUMENTED HYDRAULIC PRESS by AHMAD DOROUDIAN B . S c , The U n i v e r s i t y o f B r i t i s h Columbia, 1987 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES D i v i s i o n o f Pharmaceutics o f the F a c u l t y o f Pharmaceutical S c i e n c e s We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA March, 1991 (c) AHMAD DOROUDIAN In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. The University of British Columbia Vancouver, Canada Date flfol U, m i 5-DE-6 (2/88) A B S T R A C T P r e d i c t i o n of the t a b l e t t i n g b ehavior of powdered drugs i s of g r e a t importance i n the p h a r m a c e u t i c a l i n d u s t r y . An instrumented h y d r a u l i c p r e s s and punch and d i e assembly were used t o study compaction b e h a v i o r of 5 w i d e l y used p h a r m a c e u t i c a l m a t e r i a l s , A v i c e l , Emcompress, spray-d r i e d l a c t o s e , c r y s t a l l i n e acetaminophen USP and acetaminophen DC g r a n u l e s . The h y d r a u l i c p r e s s was a b l e t o compress the above m a t e r i a l s a t compaction speeds comparable t o those of r o t a r y t a b l e t p r e s s e s . The compression c y c l e of the Betapress c o u l d not be d u p l i c a t e d by the h y d r a u l i c p r e s s s i n c e , w i t h the h y d r a u l i c p r e s s , the displacement was not c o n s t a n t a t peak p r e s s u r e . The compaction parameters measured by the h y d r a u l i c p r e s s were e l a s t i c r e c o v e r y (ER), punch t r a v e l d i s t a n c e beyond peak p r e s s u r e (D) , punch t r a v e l time beyond peak p r e s s u r e (PTT) decrease i n the f o r c e d u r i n g punch t r a v e l beyond peak p r e s s u r e (F) . The s t r e n g t h of the t a b l e t s was measured w i t h a CT40 t a b l e t hardness t e s t e r . D and PTT appeared t o be measures of flow and bonding and t o be u s e f u l parameters f o r the t a b l e t t i n g b ehavior of the above m a t e r i a l s . In g e n e r a l , m a t e r i a l s t h a t d i s p l a y e d r e l a t i v e l y l o n g D and PTT v a l u e s formed c o h e r e n t t a b l e t s r e g a r d l e s s o f t h e i r e l a s t i c r e c o v e r y . A v i c e l w h i c h d i s p l a y e d t h e l o n g e s t D and PTT v a l u e s (and t h e l a r g e s t r e c o v e r y ) formed t h e s t r o n g e s t t a b l e t s w h i l e c r y s t a l l i n e acetaminophen USP d i s p l a y e d t h e s h o r t e s t D and PTT v a l u e s and d i d n o t form c o h e r e n t compacts. Thus f o r p a r t i c u l a t e m a t e r i a l s t h a t were a b l e t o f l o w and bond, e l a s t i c r e c o v e r y d i d n o t appear t o p l a y an i m p o r t a n t r o l e i n t h e t a b l e t t i n g p r o c e s s . A v i c e l and s p r a y - d r i e d l a c t o s e d i s p l a y e d s i m i l a r D and PTT v a l u e s ( i e . s i m i l a r e x t e n t o f f l o w and d e f o r m a t i o n ) and A v i c e l ' s e l a s t i c r e c o v e r y was about 3 t i m e s as much as o f t h a t o f s p r a y - d r i e d l a c t o s e , b u t A v i c e l formed t a b l e t s t h a t were about 5 t i m e s s t r o n g e r t h a n t h o s e o f s p r a y - d r i e d l a c t o s e . T h e r e f o r e t h e n a t u r e and number o f bonds t h a t a r e formed between t h e p a r t i c l e s (which a r e r e l a t e d t o t h e i n h e r e n t p r o p e r t y o f t h e m a t e r i a l s ) appeared t o be t h e most i m p o r t a n t f a c t o r i n t a b l e t f o r m a t i o n . The e f f e c t s o f peak p r e s s u r e (Pmax) and average c o m p r e s s i o n r a t e (ACR) were examined on t h e above p a r a m e t e r s . G e n e r a l l y peak p r e s s u r e i n f l u e n c e d t h e e l a s t i c r e c o v e r y , D, PTT and hence t h e s t r e n g t h o f t h e t a b l e t s more t h a n t h e average c o m p r e s s i o n r a t e . i v TABLE OF CONTENTS SECTION ABSTRACT LIST OF TABLES LIST OF FIGURES ABBREVIATIONS ACKNOWLEDGEMENT 1 INTRODUCTION 1.1 E l a s t i c Recovery 1.2 S t r e s s R e l a x a t i o n 1.3 Creep 1.4 Punch T r a v e l 1.5 P l a s t i c Flow 1.5.1 C r y s t a l 1.5.2 P l a s t i c 1.5.3 B r i t t l e 1.6 O b j e c t i v e s PAGE i i v i i i i x x i v xv 1 3 7 9 Time 9 and B r i t t l e F r a c t u r e 10 St r e n g t h 11 S o l i d s 12 S o l i d s 14 16 V 2 EXPERIMENTAL 18 2.1 M a t e r i a l s 18 2.2 Equipment 19 2.2.1 H y d r a u l i c P r e s s 19 2.2.2 Punch and D i e Assembly 21 2.2.3 L i n e a r V a r i a b l e D i f f e r e n t i a l T r a n s d u c e r 21 2.2.4 Load C e l l 24 2.2.5 CT40 T a b l e t S t r e n g t h T e s t e r 24 2.2.6 Measurements o f t h e T a b l e t Dimensions 26 2.3 O p e r a t i o n 26 2.4 Data Treatment Programs 28 2.4.1 Data A c q u i s i t i o n 28 2.4.2 Data T r a n s f e r 28 2.4.3 Data A n a l y s i s 28 2.4.3.1 Force-Time P l o t s 29 2.4.3.2 Displacement-Time P l o t s 29 2.5 E x p e r i m e n t a l P r o c e d u r e 36 2.6 D e t e r m i n a t i o n o f t h e Punch and D i e Recovery 37 2.7 V a r i a t i o n i n Peak P r e s s u r e and Average Compression Rate 39 2.8 V a r i a t i o n i n Average Compression R a t e a t F i x e d Peak P r e s s u r e 40 v i 2.9 C a l c u l a t i o n o f P o r o s i t y o f T a b l e t s a t Peak P r e s s u r e 40 2.10 C a l c u l a t i o n of p e r c e n t ER 42 2.11 Determination o f the Force o f F a i l u r e and Deformation of T a b l e t s 42 2.12 S t a t i s t i c a l A n a l y s i s 43 3. RESULTS AND DISCUSSION 44 3.1 High Speed Compaction 44 3.2 Recovery of the Punch and Die Assembly 52 3.3 V a r i a t i o n of Pmax 52 3.3.1 V a r i a t i o n o f P o r o s i t y w i t h Pmax 54 3.3.2 T a b l e t Recovery 58 3.3.2.1 ER of D i r e c t l y Compressible Powders 60 3.3.2.2 ER of Acetaminophen USP and DC 62 3.3.3 Punch T r a v e l D i s t a n c e Beyond Peak Press u r e (D) 65 3.3.3.1 D of D i r e c t l y Compressible Powders 65 3.3.3.2 D of Acetaminophen USP and DC 68 3.3.4 Decrease i n the Force During D (F) 70 v i i 3.3.4.1 F o f D i r e c t l y C o m p r e s s i b l e Powders 71 3.3.4.2 F o f Acetaminophen USP and DC 73 3.3.5 Punch T r a v e l Time Beyond Peak P r e s s u r e (PTT) 75 3.3.5.1 PTT o f D i r e c t l y C o m p r e s s i b l e Powders 75 3.3.5.2 PTT o f Acetaminophen USP and DC 78 3.3.6 F o r c e o f F a i l u r e and T a b l e t D e f o r m a t i o n (DF) 80 3.4 E f f e c t o f Compression R a t e 84 3.4.1 V a r i a t i o n o f ER w i t h ACR 86 3.4.2 V a r i a t i o n o f D w i t h ACR 92 3.4.3 V a r i a t i o n o f F w i t h ACR 98 3.4.4 V a r i a t i o n o f PTT w i t h ACR 98 3.4.5 V a r i a t i o n o f F o r c e o f F a i l u r e w i t h ACR 109 SUMMARY CONCLUSIONS REFERENCES 114 118 121 v i i i LIST OF TABLES Page 1. True D e n s i t y and Weight of 0.452 cm3 of 38 Powder 2. L i s t o f Compaction Speeds of v a r i o u s 46 compaction machines 3. Y i e l d P r e s s u r e o f experimental m a t e r i a l s 57 4. P e r c e n t ER and E of the 5 m a t e r i a l s T e s t e d 63 5. D of t h e 5 m a t e r i a l s t e s t e d 67 6. PTT of t h e 5 m a t e r i a l s t e s t e d . 77 7. Range o f the ACR a t 37 and 148 MPa 85 8. Summary of t h e T y p i c a l R e s u l t s of S e c t i o n 3 115 9. Summary of the T y p i c a l R e s u l t s o f S e c t i o n 3 115 i x LIST OF FIGURES PAGE 1. Schematic diagram of the h y d r a u l i c p r e s s 20 2. Schematic diagram of the punch and d i e assembly 22 3. Schematic diagram of the L i n e a r V a r i a b l e D i f f e r e n t i a l Transducer 23 4. Schematic diagram of the l o a d c e l l 25 5a. Diagram o f Force and displacement p l o t a g a i n s t time 30 5b. A t y p i c a l f o r c e - d i s p l a c e m e n t curve f o r A v i c e l 31 6. A t y p i c a l f o r c e - d i s p l a c e m e n t curve f o r Emcompress 32 7. A t y p i c a l f o r c e - d i s p l a c e m e n t curve f o r s p r a y - d r i e d l a c t o s e 33 8. A t y p i c a l f o r c e - d i s p l a c e m e n t curve f o r acetaminophen USP 34 9. A t y p i c a l f o r c e - d i s p l a c e m e n t curve f o r acetaminophen DC 35 10. V a r i a t i o n of the average compression r a t e w i t h peak p r e s s u r e ( A v i c e l ) 47 11. V a r i a t i o n of the average compression r a t e w i t h peak p r e s s u r e (Emcompress) 48 X 12. V a r i a t i o n of the average compression r a t e w i t h peak p r e s s u r e , ( s p r a y - d r i e d l a c t o s e ) 49 13. V a r i a t i o n of the average compression r a t e w i t h peak p r e s s u r e , (acetaminophen USP) 50 14. V a r i a t i o n of the average compression r a t e w i t h peak p r e s s u r e , (acetaminophen DC) 51 15. Recovery of the punch and d i e assembly 53 16. V a r i a t i o n of p o r o s i t y w i t h peak p r e s s u r e 55 17. Change i n t a b l e t r e c o v e r y w i t h the i n c r e a s e i n peak p r e s s u r e ( A v i c e l , Emcompress and s p r a y -d r i e d l a c t o s e ) 61 18. Change i n t a b l e t r e c o v e r y w i t h the i n c r e a s e i n peak p r e s s u r e (acetaminophen USP and acetaminophen DC) 64 19. Change i n D w i t h peak p r e s s u r e ( A v i c e l , Emcompress and s p r a y d r i e d lactos61) 66 20. Change i n D w i t h peak p r e s s u r e (acetaminophen USP and acetaminophen DC) 69 21. Change i n F w i t h peak p r e s s u r e ( A v i c e l , Emcompress and s p r a y - d r i e d l a c t o s e ) 72 22. Change i n F w i t h peak p r e s s u r e (acetaminophen USP and acetaminophen DC) 74 23. Change i n PTT w i t h peak p r e s s u r e ( A v i c e l , Emcompress andspray d r i e d l a c t o s e ) 76 x i 24. Change i n PTT w i t h peak p r e s s u r e (acetaminophen 79 USP andacetaminophen DC) 25a. Change i n FF w i t h peak p r e s s u r e 81 25b. Change i n t a b l e t deformation w i t h peak p r e s s u r e 82 26a,b. V a r i a t i o n o f t a b l e t r e c o v e r y w i t h average 87 compression r a t e ( A v i c e l ) 27a,b. V a r i a t i o n o f t a b l e t r e c o v e r y w i t h average 88 compression rate(Emcompress) 28a,b. V a r i a t i o n of t a b l e t r e c o v e r y w i t h average 89 compression r a t e ( s p r a y - d r i e d l a c t o s e ) 29a,b. V a r i a t i o n o f t a b l e t r e c o v e r y w i t h average 90 compression r a t e (acetaminophen USP) 30a,b. V a r i a t i o n of t a b l e t r e c o v e r y w i t h average 91 compression rate(acetaminophen DC) 31a,b. V a r i a t i o n o f D w i t h average compression r a t e 93 ( A v i c e l ) 32a,b. V a r i a t i o n o f D w i t h average compression r a t e 94 (Emcompress) 33a,b. V a r i a t i o n o f D w i t h average compression r a t e 95 ( s p r a y - d r i e d l a c t o s e ) 34a,b. V a r i a t i o n o f D w i t h average compression 96 r a t e (acetaminophen USP) 35a,b. V a r i a t i o n o f D w i t h average compression 97 rate(acetaminophen DC) x i i 36a,b. V a r i a t i o n o f F w i t h average compression r a t e 99 ( A v i c e l ) 37a,b. V a r i a t i o n o f F w i t h average compression r a t e 100 (Emcompress) 38a,b. V a r i a t i o n o f F w i t h average compression r a t e 101 ( s p r a y - d r i e d l a c t o s e ) 39a,b. V a r i a t i o n o f F w i t h average compression 102 rate(acetaminophen USP) 40a,b. V a r i a t i o n o f F w i t h average compression 103 rate(acetaminophen DC) 41a,b. V a r i a t i o n o f PTT w i t h average compression r a t e 104 ( A v i c e l ) 42a,b. V a r i a t i o n o f PTT w i t h average compression 105 rate(Emcompress) 43a,b. V a r i a t i o n of PTT w i t h average compression r a t e 106 ( s p r a y - d r i e d l a c t o s e ) 44a,b. V a r i a t i o n o f PTT w i t h average compression 107 rate(acetaminophen USP) 45a,b. V a r i a t i o n o f PTT w i t h average compression 108 r a t e (acetaminophen DC) 46a,b. V a r i a t i o n of FF w i t h average compression r a t e 110 ( A v i c e l ) 47a,b. V a r i a t i o n o f FF w i t h average compression r a t e 111 (Emcompress) x i i i 48a,b. V a r i a t i o n of FF w i t h average compression r a t e 112 ( s p r a y - d r i e d l a c t o s e ) 49a,b. V a r i a t i o n o f FF w i t h average compression 113 rate(acetaminophen DC) x i v LIST OF ABBREVIATIONS ACR Average compression r a t e D Punch t r a v e l d i s t a n c e beyond peak p r e s s u r e DC D i r e c t Compression DF Deformation o f t a b l e t s a t f a i l u r e ER E l a s t i c r e c o v e r y F Decrease i n t h e f o r c e d u r i n g punch t r a v e l beyond peak p r e s s u r e LVDT L i n e a r v a r i a b l e d i f f e r e n t i a l t r a n s d u c e r PC P l a s t i c Compression PTT Punch t r a v e l time beyond peak p r e s s u r e USP U n i t e d s t a t e s pharmacopeia X V ACKNOWLEDGEMENTS I would l i k e t o thank Dr. A l a n M i t c h e l l f o r h i s t e a c h i n g s , guidance and support d u r i n g the course o f t h i s work. My s i n c e r e thanks a l s o t o Dr. Helen B u r t , Dr. S i d Katz, Dr. K e i t h MacErlane and Dr. A l b e r t Chow f o r t h e i r a d v i c e and support a t v a r i o u s stages o f t h i s p r o j e c t . T e c h n i c a l a s s i s t a n c e o f Mr. Randy Oates i s g r e a t l y a p p r e c i a t e d . S i n c e r e thanks t o Mr. Sarvanja Dwivedi and Ms. Marion Wong f o r t h e i r a s s i s t a n c e throughout t h i s work. The support, encouragement and f r i e n d s h i p o f Mr. Matthew Wright, Mr. Swamy Yeleswaram, Mr. George Tonn and Ms. J i n g Wang are g r e a t l y a p p r e c i a t e d . A s p e c i a l s i n c e r e thanks t o John H. M c N e i l l f o r h i s guidance, f r i e n d s h i p and support d u r i n g my undergraduate and graduate y e a r s a t UBC. 1 1. INTRODUCTION Compressed t a b l e t s have been the most w i d e l y used p h a r m a c e u t i c a l dosage forms s i n c e the l a t t e r p a r t of the 19th c e n t u r y . A c c o r d i n g t o the U n i t e d S t a t e s Pharmacopeia compressed t a b l e t s are " s o l i d dosage forms c o n t a i n i n g m e d i c i n a l substances w i t h or without s u i t a b l e d i l u e n t s and they may be prepared by compression or by molding." (U.S.P., 22nd e d i t i o n ) . The way t h a t a t a b l e t i s made may have profound e f f e c t s on i t s p h y s i c a l p r o p e r t i e s such as hardness and s t a b i l i t y ( C e l i k and M a r s h a l l , 1989). Hardness and s t a b i l i t y i n t u r n have s i g n i f i c a n t e f f e c t s on the d i s s o l u t i o n and b i o a v a i l a b i l i t y of s o l i d dosage forms (Abdu, 1989). S i n c e most t a b l e t s are prepared from powders p h y s i c a l c h a r a c t e r i s t i c s of powders upon compression need t o be understood more c l e a r l y . D e veloping a new t a b l e t f o r m u l a t i o n r e q u i r e s a thorough knowledge of the chemical and p h y s i c a l c h a r a c t e r i s t i c s of the drug. A wide range of experiments can be performed i n order t o e s t a b l i s h the p h y s i c o - c h e m i c a l and mechanical c h a r a c t e r i s t i c s of a powder. Compaction i n an i s o l a t e d punch and d i e assembly u s i n g an instrumented h y d r a u l i c p r e s s can be used t o i n v e s t i g a t e some of these p r o p e r t i e s . The h y d r a u l i c p r e s s can be used t o i n v e s t i g a t e the e f f e c t s of compression f o r c e and compression r a t e on s t r e s s r e l a x a t i o n (decrease i n s t r e s s a t c o n s t a n t s t r a i n ) 2 creep ( s t r a i n movement a t constant s t r e s s ) and t h e e l a s t i c r e c o v e r y of pharmaceutical powders. Measurements of the above parameters would a i d i n e s t a b l i s h i n g the i n t r i n s i c c o m p a c t a b i l i t y of a compound which i n t u r n p r o v i d e s i n f o r m a t i o n on i t s predominant compaction mechanism and t a b l e t t i n g b e h a v i o r ( S t a n i f o r t h , e t a l . , 1987 York and B a i l y , 1977). Understanding the mechanism of compaction h e l p s t o s o l v e some of the problems t h a t are a s s o c i a t e d w i t h d e v e l o p i n g a t a b l e t f o r m u l a t i o n . The behavior of s o l i d s i n the powdered s t a t e i s complex. T h i s complexity i s due t o the many simultaneous i n t e r n a l p r o c e s s e s (such as p l a s t i c deformation and b r i t t l e f r a c t u r e ) o c c u r r i n g d u r i n g compression which l e a d t o the f o r m a t i o n of i n t e r p a r t i c u l a t e bonds (bonding) and the i n c r e a s e i n the mechanical s t r e n g t h of the powder mass ( c o n s o l i d a t i o n ) (Carstensen, 1980). S e v e r a l authors have shown t h a t measurements of some of the postcompression parameters of the compacted powder such as e l a s t i c r e c o v e r y , s t r a i n movement a t constant s t r e s s and s t r e s s r e l a x a t i o n can l e a d t o a b e t t e r u n d e r s t a n d i n g of the b e h a v i o r of powders upon compaction (Rubenstein, e t a l . 1987, H i e s t a n d e t a l . 1977, David and Augsburger, 1977). E a r l i e r t h i s century, Stewart (1950) r e c o g n i z e d the importance of p l a s t i c flow i n the p r o d u c t i o n of compacts by powder compression. I t was suggested t h a t the more p l a s t i c a m a t e r i a l , the more l i k e l y i t i s t o form compacts (Rees, 1978 ). 3 Measurement of s t r e s s r e l a x a t i o n was used by s e v e r a l authors ( S h l a n t a e t a l . 1964, David e t a l . 1977) t o examine and q u a n t i f y the r a t e of p l a s t i c d e formation of some d i r e c t compression agents. E l a s t i c r e c o v e r y has been used ( C e l i k e t a l . , 1985, Malamataris e t a l . , 1984) t o p r e d i c t some such p r o p e r t i e s as capping and l a m i n a t i o n . A b r i e f d e s c r i p t i o n of the above mentioned terms and parameters i s g i v e n below. 1.1 E l a s t i c Recovery Before s t u d y i n g e l a s t i c r e c o v e r y i n p h a r m a c e u t i c a l powders, i t i s necessary t o understand the t h e o r y of e l a s t i c i t y i n g e n e r a l . The term e l a s t i c i t y comes from the Greek word elaunein meaning " s e t i n motion" and was f i r s t used i n the 17th century by Robert Boyle, an E n g l i s h p h y s i c i s t , t o d e s c r i b e a p r o p e r t y of the a i r (Encyclopaedia B r i t a n n i c a , 1974 ed. V o l . 3). He noted e l a s t i c i t y t o be a p r o p e r t y of a l l matter ( s o l i d , l i q u i d and gas) whether inanimate or p a r t o f a l i v i n g organism. L a t e r Robert Hooke e s t a b l i s h e d t h a t i n an e l a s t i c body displacement i s p r o p o r t i o n a l t o the l o a d . (Hooke's Law). In the beginning of the 19th c e n t u r y another E n g l i s h p h y s i c i s t , Thomas Young, proposed an e l a s t i c modulus t o measure the r e s i s t a n c e o f m a t e r i a l s t o deformation. (Young's modulus of e l a s t i c i t y ) . By the middle of the 19th century a sound mathematical t h e o r y of 4 e l a s t i c i t y was e s t a b l i s h e d by the French mathematician L o u i s A u g u s t i n Cauchy. The t h e o r y of e l a s t i c i t y accounts f o r m a t e r i a l s which have a c a p a c i t y t o s t o r e mechanical energy w i t h no d i s s i p a t i o n of t h a t energy i n t o any o t h e r form. E l a s t i c b e h a v i o r i s thermodynamically r e v e r s i b l e ( P o i r i e r , 1985). In s o l i d s , f o r c e s are s t r e s s e s m u l t i p l i e d by t h e i r r e s p e c t i v e areas, and d i s t a n c e s are deformations i n a g i v e n d i r e c t i o n . When an e l a s t i c body i s s u b j e c t e d t o some s t r e s s a, i t a c q u i r e s a s t r a i n €. S t r e s s i s d e f i n e d as f o r c e per u n i t a r e a and s t r a i n as change i n t h e l e n g t h per u n i t l e n g t h . The product of the s t r e s s per u n i t area and the d e f o r m a t i o n i s the i n t e r n a l work done i n a body by e x t e r n a l l y a p p l i e d l o a d s . The i n t e r n a l work i s then s t o r e d i n a body as the i n t e r n a l e l a s t i c energy of deformation or the e l a s t i c s t r a i n energy (Popov, 1968) and i s not d i s s i p a t e d i n t o other forms of energy such as heat. T h e r e f o r e f o r a p e r f e c t l y e l a s t i c body, upon the r e l e a s e of the s t r e s s , the s t r a i n i n s t a n t a n e o u s l y d i s a p p e a r s . Most m a t e r i a l s e x h i b i t both v i s c o u s and e l a s t i c b e h a v i o r through simultaneous d i s s i p a t i o n and s t o r a g e of energy d u r i n g mechanical deformation (Pugh, 1970). T h i s i s r e f e r r e d t o as v i s c o e l a s t i c behavior. V i s c o e l a s t i c bodies i n g e n e r a l e x h i b i t a complicated r a t e dependent behavior i n c l u d i n g instantaneous e l a s t i c i t y and v i s c o u s flow ( F e r r y , 1970). In our s t u d i e s of p h a r m a c e u t i c a l m a t e r i a l s we c o n s i d e r simple s t r e s s systems i n which o n l y one component 5 o f t h e s t r e s s and o f s t r a i n i s needed t o c h a r a c t e r i z e t h e p r o c e s s . The i d e a l l i n e a r e l a s t i c element i s t h e s p r i n g . When a f o r c e i s a p p l i e d , t h e i n c r e a s e i n d i s t a n c e between i t s two ends i s p r o p o r t i o n a l t o t h e a p p l i e d f o r c e and t h e r e l a t i o n s h i p between t h e s t r e s s and s t r a i n i s : a = E e (1) where E i s t h e modulus o f e l a s t i c i t y o f t h e s p r i n g w h i c h i s d e f i n e d as t h e measure o f i t s r e s i s t a n c e t o e l o n g a t i o n . The i d e a l l i n e a r v i s c o u s element i s t h e dash p o t . When a f o r c e i s a p p l i e d , t h e s i d e s move a p a r t a t a r a t e t h a t i s p r o p o r t i o n a l t o t h e f o r c e ( F l u g g e , 1967). (example: a l o o s e f i t t i n g p i s t o n i n a l i q u i d f i l l e d c y l i n d e r ) . The s t r e s s -s t r a i n r e l a t i o n i n v i s c o u s m a t e r i a l s i s : o = n dt/dt . ( 2) Where n i s t h e c o e f f i c i e n t o f v i s c o s i t y and df/dt i s t h e s t r a i n r a t e . Thus f o r a v i s c o e l a s t i c m a t e r i a l i n w h i c h t h e s p r i n g and t h e dashpot a r e i n p a r a l l e l ( K e l v i n model) t h e s t r e s s -s t r a i n r e l a t i o n s h i p i s : a - E*c + n dc/dt (3) Upon c o m p r e s s i o n many p h a r m a c e u t i c a l m a t e r i a l s , such as A v i c e l and acetaminophen, undergo a r e d u c t i o n i n b u l k volume due t o p a r t i c l e rearrangement and d i s p l a c e m e n t o f a i r from t h e powder mass ( M a r s h a l l , 1985). Upon c o m p l e t i o n o f r e a r r a n g e m e n t t h e p a r t i c l e s undergo e l a s t i c d e f o r m a t i o n 6 and i f the l o a d i s removed b e f o r e the y i e l d p o i n t has been reached, the deformation i s spontaneously r e v e r s e d . However, f u r t h e r compression causes permanent deformation or b r i t t l e f r a c t u r e i n the p a r t i c l e s . S e v e r a l authors ( M i l o s o v i c h e t a l . , 1963, C a r l e s s e t a l . , 1974, R i t t e r and Sucker 1980 and H i e s t a n d e t a l . , 1977) p o s t u l a t e d t h a t e l a s t i c r e c o v e r y i s the main cause of capping and l a m i n a t i o n i n t a b l e t s . They suggested t h a t the e l a s t i c s t r a i n energy r e l e a s e d d u r i n g decompression, causes e l a s t i c r e c o v e r y i n the t a b l e t . The r e c o v e r y i n t u r n may break some of the i n t e r p a r t i c u l a t e bonds t h a t were formed d u r i n g compression and cause capping o r l a m i n a t i o n i n the t a b l e t . There have been s e v e r a l attempts t o develop methods f o r p r e d i c t i n g capping and l a m i n a t i o n t e n d e n c i e s of ph a r m a c e u t i c a l f o r m u l a t i o n s , but as y e t t h e r e i s no e s t a b l i s h e d standard method. The r a t i o o f e l a s t i c r e c o v e r y (ER) t o the p l a s t i c compression (PC) was i n v e s t i g a t e d by Malamataris e t a l . ( 1 9 8 4 ) , who r e p o r t e d t h a t the t a b l e t s capped as the ER/PC r a t i o exceeded 9. The r e l a t i o n s h i p between the t e n s i l e s t r e n g t h and ER/PC of p a r a c e t a m o l / A v i c e l compacts were s t u d i e d by Bangudu and P i l p e l (1985). They found t h a t the t e n s i l e s t r e n g t h was i n v e r s e l y r e l a t e d t o the ER/PC r a t i o . Yu e t al.(1988) used the ER/PC r a t i o a l o n g w i t h energy a n a l y s i s (from the compression p o r t i o n of the f o r c e - d i s p l a c e m e n t curve) as 7 means of measuring capping t e n d e n c i e s i n acetaminophen and m i c r o c r y s t a l l i n e c e l l u l o s e mixtures. E l a s t i c r e c o v e r y d i s c u s s e d above r e f e r s t o the i n i t i a l r a p i d expansion of the compact w i t h i n the d i e immediately f o l l o w i n g compression and i s g i v e n by: ER = [(Ho - Hmin)/Hmin] x 100 (4) where Ho i s the t h i c k n e s s of the t a b l e t immediately f o l l o w i n g decompression and Hmin i s the minimum t h i c k n e s s of the t a b l e t o b t a i n e d a t peak p r e s s u r e . The v i s c o e l a s t i c r e c o v e r y of the t a b l e t i s determined by simply measuring the t h i c k n e s s of the t a b l e t f o l l o w i n g e j e c t i o n from the d i e and a t d i f f e r e n t time i n t e r v a l s t h e r e a f t e r . T r a v e r s and C e l i k (1985) used the term S t r a i n Movement (SM) t o d e s c r i b e the v i s c o e l a s t i c r e c o v e r y of t a b l e t s . They suggested t h a t the r a t i o of the ER t o SM p r o v i d e s a b e t t e r index (than ER or SM alone) f o r p r e d i c t i n g the c o m p r e s s i b i l i t y of a powder. They l a b e l l e d t h i s r a t i o ERI. They r e p o r t e d t h a t compressible m a t e r i a l s had a lower ERI than the p o o r l y compressible powders. 1.2 Stress Relaxation Another post-compression parameter which can p r o v i d e u s e f u l i n f o r m a t i o n about the behavior of a compact i s s t r e s s r e l a x a t i o n . S t r e s s r e l a x a t i o n can be d e s c r i b e d by c o n s i d e r i n g the f o l l o w i n g case. A m a t e r i a l i s compressed a t a constant 8 speed and the compression i s c o n t i n u e d u n t i l the m a t e r i a l i s deformed beyond i t s e l a s t i c l i m i t and the compression i s stopped. At t h i s p o i n t the s t r e s s on the m a t e r i a l has the v a l u e a, Q (at time t Q ) and the t o t a l s t r a i n on the m a t e r i a l i s € : Q. From t Q , the s t r e s s w i l l decrease w i t h time and w i l l go t o zero a t t = i n f i n i t y . T h i s decrease i n the s t r e s s w i t h time a t c o n s t a n t s t r a i n i s c a l l e d s t r e s s r e l a x a t i o n ( P o i r i e r 1985). S t r e s s r e l a x a t i o n i s r e p r e s e n t a t i v e of the p h y s i c a l p r o c e s s e s t a k i n g p l a c e i n the m a t e r i a l . Some authors (S h l a n t a and M i l o s o v i c h , 1964, C u t t , e t a l . , 1987) have p r o v i d e d evidence t h a t success or f a i l u r e of t a b l e t f o r m a t i o n i s dependent on the nature of the s t r e s s r e l e a s e d u r i n g decompression. H i e s t a n d e t a l . (1977) s t u d i e d the e f f e c t s of s t r e s s r e l a x a t i o n on the capping of t a b l e t s . They showed t h a t t h e r e i s an i n v e r s e r e l a t i o n s h i p between the r a t e of s t r e s s r e l a x a t i o n and the i n c i d e n c e of capping. In another study sodium c h l o r i d e was shown t o e x h i b i t i n s t a n t s t r e s s r e l a x a t i o n upon decompression (Rubenstein and Jackson, 1987). I t was suggested t h a t the q u i c k r a t e of s t r e s s r e l a x a t i o n accounted f o r the h i g h s t r e n g t h of the sodium c h l o r i d e t a b l e t s . S t r e s s r e l e a s e i n a compacted powder mass may be a measure of the degree of bonding among the p a r t i c l e s (Esezobo and P i l p e l , 1986). During t a b l e t p r o d u c t i o n , on a r o t a r y p r e s s , the time i n t e r v a l f o r s t r e s s r e l a x a t i o n i s v e r y s h o r t (a few m i l l i s e c o n d s ) . T h i s time i n t e r v a l was 9 r e f e r r e d t o as the Peak O f f s e t Time ( t Q f f ) (Oates and M i t c h e l l , 1989). Experiments w i t h the r o t a r y p r e s s show t h a t m a t e r i a l s t h a t are known t o form b e t t e r compacts r e l a x more d u r i n g t h a t time i n t e r v a l and t h e r e f o r e have a longer t Q f f (Dwivedi, Oates and M i t c h e l l , 1991, submitted f o r p u b l i c a t i o n ) . 1.3 Creep An i n c r e a s e i n the deformation o f s o l i d s ( s t r a i n movement) a t constant s t r e s s i s r e f e r r e d t o as creep ( W i l s h i r e and Evans, 1985) and has been s t u d i e d e x t e n s i v e l y f o r metals, s i n g l e c r y s t a l and p a r t i c u l a t e systems ( P o i r i e r , 1985). Creep i s a time-dependant phenomenon. T h e r e f o r e an important parameter t h a t i s taken i n t o c o n s i d e r a t i o n i n t a b l e t t i n g i s the time f o r which the p a r t i c u l a t e m a t e r i a l i s h e l d under con s t a n t l o a d ( R i p p i e and D a n i e l s o n , 1981). In the everyday p r o d u c t i o n o f t a b l e t s on a r o t a r y p r e s s the time t h a t the t a b l e t i s under con s t a n t l o a d i s i n the order of m i l l i s e c o n d s . 1.4 Punch T r a v e l Time During t a b l e t compaction on a r o t a r y p r e s s i t has been observed t h a t the p o i n t a t which peak f o r c e i s recor d e d does not c o i n c i d e w i t h the p o s i t i o n o f the minimum d i s t a n c e between upper and lower punch (Dwivedi, Oates and M i t c h e l l , 1991, submitted f o r p u b l i c a t i o n ) . A s i m i l a r phenomenon was 10 a l s o observed by Ho and Jones (1988) who r e p o r t e d t h a t i n a compaction s i m u l a t o r the peak compaction f o r c e was reco r d e d b e f o r e the punch had f u l l y p e n e t r a t e d i n t o the d i e . T h i s was r e f e r r e d t o by Ho and Jones as punch t r a v e l beyond peak f o r c e . P r e l i m i n a r y compaction r e s u l t s u s i n g the h y d r a u l i c p r e s s i n d i c a t e t h a t t h e r e indeed i s punch t r a v e l beyond peak f o r c e d u r i n g t a b l e t compression. During the compression of powders i n an i s o l a t e d punch and d i e assembly w i t h the h y d r a u l i c p r e s s the peak f o r c e i s reached b e f o r e the minimum d i s t a n c e between the punches i s a t t a i n e d . The d i f f e r e n c e between the time t o r e a c h peak f o r c e and the time taken t o r e a c h the minimum d i s t a n c e between the upper and lower punch f a c e s i s c a l l e d the punch t r a v e l time. During the punch t r a v e l time the f o r c e d ecreases and the punch displacement c o n t i n u e s ( F i g 5a). T h e r e f o r e n e i t h e r the s t r e s s nor the s t r a i n i s con s t a n t d u r i n g t h i s time. I t i s s p e c u l a t e d t h a t the compact undergoes a combination of s t r e s s r e l a x a t i o n and creep d u r i n g the punch t r a v e l time. Whether punch t r a v e l time can be used t o c h a r a c t e r i z e p h a r m a c e u t i c a l powders under compaction was i n v e s t i g a t e d i n t h i s study. 1.5 P l a s t i c Flow and B r i t t l e F r a c t u r e A study of the mechanical b e h a v i o r of phar m a c e u t i c a l powders under p r e s s u r e and the mechanism by which these powders form coherent compacts r e q u i r e s an understanding of 11 the p r i n c i p l e modes of deformation i n c r y s t a l s . S p e c i f i c a l l y one needs t o understand why some c r y s t a l s undergo p l a s t i c flow w h i l e o t h e r s f r a c t u r e under l o a d . Most p h a r m a c e u t i c a l m a t e r i a l s e x h i b i t both p l a s t i c d e f o r m a t i o n and b r i t t l e f r a c t u r e p r o p e r t i e s i n a temperature dependant manner ( J e t z e r , e t a l . , 1983). The e f f e c t of temperature i s not examined here. 1.5.1 C r y s t a l Strength To understand the process of p l a s t i c f l o w and b r i t t l e f r a c t u r e , we w i l l b r i e f l y examine the nature of c r y s t a l s t r e n g t h . The e s t i m a t e s and c a l c u l a t i o n s of the s t r e n g t h of a c r y s t a l are based on simple c r y s t a l models. The s i m p l e s t model of a c r y s t a l i s made of two rows of atoms s u b j e c t e d t o a shear s t r e s s . Without going through the process of d e r i v a t i o n , the maximum v a l u e of the shear s t r e s s , ^max/ r e q u i r e d t o d i s r u p t the above l a t t i c e i s (Honycomb, 1984): *max =(G • b)/27r.a (5) Where : G i s the shear modulus of the m a t e r i a l a = I n t e r - p l a n a r s p a c i n g b = I n t e r - a t o m i c d i s t a n c e i n the s l i p d i r e c t i o n . T h e r e f o r e a c c o r d i n g t o the above equ a t i o n , which i s based on a v e r y simple model, the l a r g e r the r a t i o of the i n t e r - a t o m i c d i s t a n c e i n the s l i p d i r e c t i o n (b) t o the 12 i n t e r - p l a n a r s p a c i n g (a) the l a r g e r the c r i t i c a l r e s o l v e d shear s t r e s s . T h e o r e t i c a l l y i f two d i f f e r e n t c r y s t a l l i n e m a t e r i a l s have c r y s t a l s w i t h equal (a) and (b) spaci n g s the d i f f e r e n c e i n the s t r e n g t h of the two c r y s t a l s would be due t o the d i f f e r e n c e i n t h e i r shear modulus G. Si n c e G i s a f u n c t i o n of the i n h e r e n t p r o p e r t y of the c r y s t a l l i n e m a t e r i a l , we can s t a t e t h a t : the s t r e n g t h o f two d i f f e r e n t t y p e s o f c r y s t a l s with equal (a) and (b) spacings depends on the types of i n t e r - a t o m i c bonding t h a t are p r e s e n t i n the c r y s t a l . Thus i n t h i s case the c r y s t a l w i t h the lower G i s l i k e l y t o flow and the one wit h h i g h e r G i s l i k e l y t o f r a c t u r e under l o a d . C o n v e r s e l y i f two d i f f e r e n t types o f c r y s t a l s have s i m i l a r shear modulus G ( s i m i l a r i n h e r e n t i n t r a - a t o m i c bonding) , the c r y s t a l w i t h l a r g e r i n t e r - p l a n a r spacings (a) and s m a l l e r i n t e r - a t o m i c d i s t a n c e s (b) w i l l f low under l o a d and the c r y s t a l w i t h s m a l l e r (a) and l a r g e r (b) are more l i k e l y t o f r a c t u r e . 1.5.2 P l a s t i c S o l i d s When a c r y s t a l i s p l a s t i c a l l y deformed i t ' s s u r f a c e becomes covered w i t h one or more s e t s o f p a r a l l e l f i n e l i n e s which are c a l l e d s l i p l i n e s . These l i n e s a re a c t u a l s t e p s on the s u r f a c e r e s u l t i n g from m i c r o s c o p i c shear movement alo n g w e l l d e f i n e d c r y s t a l l o g r a p h i c p l a n e s which are r e f e r r e d t o as s l i p or g l i d e p l a n e s . The d i r e c t i o n of 13 the shear i n the plane i s c a l l e d the s l i p o r g l i d e d i r e c t i o n ( P o i r i e r 1985). T h e r e f o r e a c r y s t a l s u b j e c t e d t o shear s t r e s s y i e l d s p l a s t i c a l l y by s l i p or g l i d e over a c r y s t a l l o g r a p h i c plane i n a c e r t a i n d i r e c t i o n . The p l a s t i c l i m i t f o r s i n g l e c r y s t a l s i s c a l l e d the C r i t i c a l Resolved Shear S t r e s s . P l a s t i c s o l i d s under l o a d w i l l not permanently deform i f the a p p l i e d s t r e s s i s lower than the t h r e s h o l d s t r e s s c a l l e d the y i e l d s t r e s s . When the s t r e s s reaches and exceeds the y i e l d s t r e s s , permanent s t r a i n appears (the s o l i d i s permanently deformed). The permanent s t r a i n i s the unique c h a r a c t e r i s t i c of the p l a s t i c s o l i d . The p l a s t i c d e formation behavior of s o l i d s i s r e l a t e d i n h e r e n t l y t o the deformation p r o c e s s e s o c c u r r i n g w i t h i n the i n d i v i d u a l s i n g l e c r y s t a l s . In order t o c o n s i d e r the a c t u a l mechanisms of deformation we w i l l have t o examine the u n d e r l y i n g atomic p r o c e s s e s by which a c r y s t a l l i n e s o l i d can deform. The phenomenon t h a t i s c h i e f l y b e l i e v e d t o be r e s p o n s i b l e f o r p l a s t i c flow i n c r y s t a l l i n e m a t e r i a l s i s a c e r t a i n c r y s t a l l o g r a p h i c d e f e c t c a l l e d a d i s l o c a t i o n (Courtney, 1990). The concept of d i s l o c a t i o n , a c r y s t a l l i n e d e f e c t , was necessary t o account f o r the f a c t t h a t the observed s t r e n g t h of metals g e n e r a l l y was about a thousand times l e s s than the t h e o r e t i c a l e s t i m a t e s (Nabbarro, V o l . 2, 1979). Thus much of the o r i g i n a l s t u d i e s and experiments on p l a s t i c i t y were performed on metals (the most 14 c h a r a c t e r i s t i c p r o p e r t y of metals i s the a b i l i t y t o s u f f e r much deformation without b r e a k i n g ) . The p r a c t i c a l knowledge of forming metals such as g o l d i n t o t h i n sheets (without breaking) extends backwards i n time f o r w e l l over two thousand years but the knowledge of t h e p h y s i c a l phenomenon a s s o c i a t e d w i t h deformation has o n l y been developed w i t h i n the l a s t few decades. The d e t a i l e d study of p l a s t i c deformation was i n i t i a t e d w i t h t h e development of techniques f o r growing l a r g e i n d i v i d u a l c r y s t a l s from m e l t s . The c l a s s i c a l experimental r e s u l t s on t h e d e f o r m a t i o n of s i n g l e c r y s t a l s from 1910-1930 l e d t o the i n t r o d u c t i o n o f the concept of d i s l o c a t i o n i n 1934 by Orowan, P o l a n y i and T a y l o r (independently) ( C o t t r e l l , 1956). 1 . 5 . 3 B r i t t l e S o l i d s Many c r y s t a l l i n e s o l i d s f r a c t u r e i n a b r i t t l e f a s h i o n . (Almost a l l s o l i d s undergo b r i t t l e f r a c t u r e i f the temperature i s s u f f i c i e n t l y low). In b r i t t l e f r a c t u r e t h e r e i s a s m a l l amount of p l a s t i c deformation f o l l o w e d by r a p i d c r a c k p r o p a g a t i o n a l o n g w e l l - d e f i n e d c r y s t a l l o g r a p h i c p l a n e s ( R i s h i , 1985). The s t r e s s which w i l l overcome the i n t e r a t o m i c f o r c e s i n a c r y s t a l , c a u s i n g i t t o separate on a plane, depends on t h e type of chemical bonding, c r y s t a l s t r u c t u r e and c h e m i c a l composition. In g e n e r a l i o n i c and c o v a l e n t s o l i d s a re more prone t o e x h i b i t b r i t t l e n e s s than undergo 15 s u b s t a n t i a l p l a s t i c deformation. B r i t t l e f r a c t u r e i s common i n body-centred c u b i c and hexagonal c r y s t a l s w h i l e i s unknown i n f a c e - c e n t e r e d c u b i c c r y s t a l s (Jaeger, 1969). G e n e r a l l y c r y s t a l s t r u c t u r e s t h a t can assume c l o s e s t packed p l a n e s tend t o e x h i b i t b r i t t l e n e s s . There i s experimental evidence t h a t i n c r y s t a l l i n e s o l i d s p l a s t i c deformation i s needed t o n u c l e a t e a crack and i n a d d i t i o n more p l a s t i c deformation o c c u r s d u r i n g c r a c k p r o p a g a t i o n . Although the extent of d i s l o c a t i o n movement p r i o r t o p r o p a g a t i o n of the c r a c k has been shown t o be v e r y s m a l l i t i s apparent t h a t d i s l o c a t i o n i n t e r a c t i o n s are r e s p o n s i b l e f o r the f o r m a t i o n of c r a c k n u c l e i ( R i s h i , 1985). A simple mechanism f o r c r a c k n u c l e a t i o n was proposed by Zener and coworkers (Zener, 1948). T h e i r model i n v o l v e s the p i l e - u p of a s e r i e s of edge d i s l o c a t i o n s a t a g r a i n boundary, or o t h e r s t r o n g o b s t a c l e i n which a c r a c k nucleus i s formed when s e v e r a l of the d i s l o c a t i o n s a t the head of the p i l e - u p c o a l e s c e . T h i s i s made p o s s i b l e by the s t r e s s c o n c e n t r a t i o n which occurs a t the head of the p i l e - u p and which lea d s t o a t e n s i l e s t r e s s on a plane normal t o the s l i p p lane. Nabarro and c o l l e a g u e s c a l c u l a t e d e quation 6 which g i v e s the c o n d i t i o n f o r the f o r m a t i o n of a c r a c k (Honycomb, 1984) n-7 « 0 .7-G (6) Where : n = number of d i s l o c a t i o n s i n the p i l e up 1 ''•= a p p l i e d shear s t r e s s 16 G = the shear modulus Therefore a crack i s i n i t i a t e d when the l o c a l magnified shear stress n-y reaches a value of about three-quarters the shear modulus. 1.6 O b j e c t i v e s The p r a c t i c a l i n t e r e s t i n the mechanical properties of powders i s of major importance to the pharmaceutical industry. The current research plan i s to investigate such properties i n several pharmaceutical powders that are extensively used i n the industry. Investigating these properties would a i d i n understanding the underlying mechanism of compaction. The emphasis of the research was to a t t a i n high speed (fast loading rates comparable to the rotary press) compression i n an i s o l a t e d punch and die assembly with a hydraulic press. S p e c i f i c objectives were to: i) determine whether the hydraulic press can be used to duplicate the t a b l e t t i n g compression cycle of the rotary press. i i ) determine whether the hydraulic press can be used to measure stress relaxation, creep, punch t r a v e l time and e l a s t i c recovery of some pharmaceutical powders at high compression rates. i i i ) investigate the e f f e c t s of loading rate (compression rate) on the above parameters. 17 i v ) determine the e f f e c t s o f the maximum compressional f o r c e on the above parameters. v) measure the hardness of the t a b l e t s and t o i n v e s t i g a t e the r e l a t i o n s h i p between the hardness and the above parameters. v i ) i n v e s t i g a t e p o s s i b l e r e l a t i o n s h i p s between the above parameters and the a b i l i t y of the powders t o form compacts upon compression. 18 2. E X P E R I M E N T A L The powders s e l e c t e d f o r study i n c l u d e d a m a t e r i a l t h a t deforms mainly by p l a s t i c flow ( A v i c e l PH-102); m a t e r i a l s t h a t deform mainly by b r i t t l e f r a c t u r e (Emcompress and acetaminophen) and a m a t e r i a l t h a t i n c l u d e d both types of deformation mechanisms ( s p r a y - d r i e d l a c t o s e ) . The moisture content of A v i c e l , Emcompress, spray-d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC were 4.1, 3.9, 4.0, 3.8 and 3.9% r e s p e c t i v e l y . 2.1 M A T E R I A L S The f o l l o w i n g m a t e r i a l s were used as r e c e i v e d : A v i c e l PH-102 ( m i c r o c r y s t a l l i n e c e l l u l o s e ) , FMC Corp., P h i l . , PA S p r a y - d r i e d l a c t o s e , Foremost Corp., Wisconsin Emcompress ( d i c a l c i u m phosphate d i h y d r a t e ) , Mendel Corp., New York Acetaminophen USP ( f i n e powder), M a l l i n k r o d t corp., R a l e i g h , NC Acetaminophen DC, Rhone Poulenc, France (acetaminophen g r a n u l a t e d w i t h 3% w/w p o l y v i n y l p y r r o l i d o n e t o g i v e a d i r e c t l y c o m pressible form) Magnesium s t e a r a t e , M a l l i n k r o d t Corp. 19 2.2 Equipment 2.2.1 H y d r a u l i c Press H y d r a u l i c Pump was from J.S. Burns Corp., Rockford, I l l i n o i s H y d r a u l i c Ram and oth e r p a r t s o f the p r e s s were custom b u i l t a c c o r d i n g t o our s p e c i f i c a t i o n s by F l e c k Bros. L t d . , F l u i d Power Div., Vancouver, B.C. A s i m p l i f i e d schematic diagram o f the h y d r a u l i c p r e s s i s shown i n F i g . 1. Only the components of t h e p r e s s which p l a y a s i g n i f i c a n t r o l e i n the compression c y c l e a r e shown. As shown i n the diagram, a l l the f l u i d ( o i l ) t h a t i s pumped i n t o t he system must pass through s o l e n o i d 1 and the c o n t r o l v a l v e . A f t e r the o i l passes through t h e c o n t r o l v a l v e i t can flow through 2 r o u t e s . The f i r s t r o u t e i s through the l i m i t i n g v a l v e and i n t o the h y d r a u l i c ram and the second i s through s o l e n o i d 2 and i n t o the pump r e s e r v o i r . The c o n t r o l v a l v e can be s e t a t t h r e e p o s i t i o n s and c o n s i s t s o f two v a l v e s , VI and V2. VI a l l o w s the o i l t o en t e r i n t o the system and V2 al l o w s the o i l t o e x i t from the system. When VI i s open and V2 i s c l o s e d the ram i s r a i s e d and when V2 i s open and VI i s c l o s e d the ram i s lowered. 20 S o l e n o i d 1 Control Valve Limit Valve Reservoir P u m p Fig 1. Schematic Diagram of the Hydraulic Press 21 2.2.2 Punch and D i e Assembly T a b l e t s were compressed i n a RIIC D-01 punch and d i e assembly mounted on the h y d r a u l i c p r e s s . The upper punch and the a d j u s t a b l e arm were b u i l t and m o d i f i e d by T o o l Tech., North Vancouver, B.C. ( F i g . 2) The lower and upper punches were o f f l a t f a c e d hardened s t e e l w i t h a r a d i u s of 12.90 mm. The top of the upper punch was curved with the r a d i u s o f c u r v a t u r e of 114.3 mm which corresponds t o the r a d i u s of c u r v a t u r e of the l o a d c e l l ( d e s c r i b e d i n s e c t i o n 2.2.4). The upper punch was made w i t h a t i g h t f i t i n the d i e t o e l i m i n a t e t i l t i n g . The punch and d i e assembly was c e n t e r e d on the h y d r a u l i c ram and l o c k e d i n t o p o s i t i o n b e f o r e each compression. 2.2.3 L i n e a r V a r i a b l e D i f f e r e n t i a l T r a n s d u c e r (LVDT) Punch displacement was measured w i t h a Sangamo DG5 l i n e a r v a r i a b l e d i f f e r e n t i a l t r a n s d u c e r (LVDT). The LVDT t r a n s l a t e s the r e l a t i v e p o s i t i o n o f the upper punch i n t o an e l e c t r i c a l s i g n a l . I t c o n s i s t s o f t h r e e c o a x i a l c o i l s ( M a r s h a l l , 1985); one (the primary c o i l ) i s sep a r a t e d from the other two by a f e r r o u s magnetic core ( F i g . 3) . An i n p u t AC s i g n a l i s o s c i l l a t e d through the primary c o i l and the output through the secondary c o i l s i s a t t e n u a t e d t o produce a DC v o l t a g e . The generated DC v o l t a g e i s d i r e c t l y p r o p o r t i o n a l t o the displacement of the f e r r o u s c o r e . The f e r r o u s magnetic core i s connected t o the 22 .convex s u r f a c e ferrous magnetic core LVDT 1 z i -adjustable arm upper punch die lower punch Fig. 2. Diagram of the Punch and. Die Assembly 23 Fig. 3. Schematic Diagram of LVDT 24 upper punch v i a an a d j u s t a b l e arm. Any movement of the core unbalances the secondary c i r c u i t and changes the generated DC v o l t a g e from which a change i n the displacement can be determined. The s e n s i t i v i t y and accuracy of the LVDT depend p a r t l y on the e x t e r n a l d e v i c e t h a t i s used t o d e t e c t the output s i g n a l and p a r t l y on the c a l i b r a t i o n and zero s e t t i n g of the d e v i c e ( i d e a l l y , the output i s zero when the f e r r o u s magnetic core i s p o s i t i o n e d i n the c e n t e r ) . The LVDT used i n our experiments was s e n s i t i v e t o 2.5 um. 2 . 2 . 4 Load C e l l Load c e l l s are used f o r the measurement of the a p p l i e d f o r c e s . A Sensotec l o a d c e l l ( F i g . 4.) was p l a c e d d i r e c t l y on top of the h y d r a u l i c ram t o measure the a p p l i e d f o r c e on t h e upper punch. The l o a d c e l l has a s h o r t c e n t r a l column supported from an outer r i n g on s t r a i n gauged elements (Watt, 1988). The s t r a i n gauged column generates a s i g n a l t h a t i s r e l a t e d t o the a p p l i e d f o r c e . The r e s o l u t i o n of a l o a d c e l l i s l i m i t e d by the e l e c t r o n i c s of the data c o l l e c t i o n d e v i c e . To measure the f o r c e over the d e s i r e d range i n t h i s study, the computer s e t t i n g s were such t h a t t h e l o a d c e l l was s e n s i t i v e t o w i t h i n 5 N. 2 . 2 . 5 CT40 T a b l e t S t r e n g t h T e s t e r A commercial CT40 t a b l e t s t r e n g t h t e s t e r (Systems E n g i n e e r i n g , Nottingham, UK) was used t o measure f o r c e of f a i l u r e and deformation of the t a b l e t s . A Sangamo DG5 LVDT 25 flexible support elements plan view rigid housing Fig. 4. Schematic Diagram of Load cell 26 was mounted on the CT40 so t h a t t a b l e t deformation up t o the f r a c t u r e p o i n t c o u l d be measured. 2.2.6 Measurements of the Tablet Dimensions T a b l e t dimensions, (the t h i c k n e s s and r a d i a l diameter) were determined t o w i t h i n 0.01 mm u s i n g a NSK E l e c t r o n i c D i g i t a l C a l i p e r (NSK Corp., JAPAN) 2.3 Operation The d e s i g n and c a p a b i l i t i e s of the h y d r a u l i c p r e s s were s t u d i e d i n order t o d e v i s e an o p e r a t i o n a l procedure t h a t would a l l o w compression a t speeds comparable t o t h a t of a Manesty Betapress (a h i g h speed r o t a r y p r e s s ) . High speed compression was e v e n t u a l l y achieved by b y - p a s s i n g the l i m i t v a l v e of the p r e s s . The l i m i t v a l v e was s e t a t a v e r y h i g h l e v e l (about 10 tons) which allowed the b u i l d - u p of p r e s s u r e i n the system t o be c o n t r o l l e d by the opening and c l o s i n g of the s o l e n o i d v a l v e s . Although the h y d r a u l i c p r e s s c o u l d have been operated a t much h i g h e r speeds (by s e t t i n g the l i m i t v a l v e a t g r e a t e r than 10 tons) t h e 10 t o n maximum was chosen t o p r o t e c t the l o a d c e l l and the punch and d i e assembly from a c c i d e n t a l o v e r l o a d . T h e r e f o r e the compression speeds t h a t were achieved f o r each m a t e r i a l were the f a s t e s t p o s s i b l e without compromising s a f e t y . The s o l e n o i d v a l v e s are c o n t r o l l e d e l e c t r o n i c a l l y , by the computer or by the s w i t c h box t h a t connects t h e p r e s s 27 t o t he computer. The f o l l o w i n g procedure was d e v i s e d f o r the h i g h speed compression o f the powders: a. The s o l e n o i d v a l v e s are s e t t o manual c o n t r o l . S o l e n o i d 1 and 2 are s e t a t open and c l o s e d p o s i t i o n s r e s p e c t i v e l y . The c o n t r o l v a l v e i s s e t a t the c e n t e r p o s i t i o n , (both VI and V2 a r e c l o s e d ) . b. The pump i s tu r n e d on f o r about 10 seconds i n or d e r t o b u i l d - u p some p r e s s u r e i n the system. c. The punch and d i e assembly i s p l a c e d on the ram and secured i n p o s i t i o n (at the c e n t e r of the ram) by t h r e e screws. d. The b a l l v a l v e (not shown i n f i g u r e 1) i s opened and the ram r a i s e d s l o w l y u n t i l t he upper punch i s almost i n c o n t a c t w i t h the l o a d c e l l . e. The s o l e n o i d 1 v a l v e i s c l o s e d by u s i n g the s w i t c h on the c o n n e c t i o n box. f . The c o n t r o l v a l v e i s s e t a t the p u l l e d - o u t p o s i t i o n . g. The d u r a t i o n of the e n t i r e compression c y c l e , t r i g g e r l e v e l , d e l a y c o n s t a n t , i n i t i a l and f i n a l p o s i t i o n o f the s o l e n o i d v a l v e s and the time a t which they should open and c l o s e a re s e t i n the computer. h. The c o n t r o l s a t t h i s p o i n t are switched t o computer c o n t r o l . i . The pump i s tu r n e d on again u n t i l t h e r e i s s u f f i c i e n t back p r e s s u r e (2 000 p s i ) i n the system. j . The pump i s turned o f f and the computer key t h a t s t a r t s the c y c l e i s h i t immediately. 28 2.4 Data Treatment Programs 2.4.1 Data A c q u i s i t i o n The load, c e l l and the LVDT were i n t e r f a c e d v i a a f a s t A t o D c o n v e r t e r t o an Apple 11+ p e r s o n a l computer. A data a c q u i s i t i o n program w r i t t e n f o r an Apple 11+ computer by R. Oates i n t h i s l a b o r a t o r y was used t o c o l l e c t t h e d a t a from the h y d r a u l i c p r e s s . The program a l l o w s the f o r c e s i g n a l from the l o a d c e l l and the displacement s i g n a l s from the e x t e r n a l and i n t e r n a l LVDTs t o be c o l l e c t e d , p l o t t e d and saved f o r a n a l y s i s . 2.4.2 Data T r a n s f e r A n a l y s i s programs w r i t t e n f o r the Apple 11+ computer t o complement the data a c q u i s i t i o n program were found t o be extremely slow. A program was needed t o t r a n s f e r the data saved by the Apple computer i n t o a format t h a t c o u l d be a n a l y z e d by an I.B.M. compatible computer. Such a program was o b t a i n e d by m o d i f y i n g an e x i s t i n g program w r i t t e n by R. Burton f o r the t r a n s f e r of "Working Heart" data i n the D i v i s i o n of Pharmacology. Using " T r a n s f e r " a l l the data was t r a n s f e r r e d and saved i n an I.B.M. compatible computer. 2.4.3 Data A n a l y s i s The data a n a l y s i s program (HPRESS) was w r i t t e n by R. Oates . The program allows the f o r c e and displacement curves t o be p l o t t e d and t o be marked a t v a r i o u s p o i n t s f o r 29 c a l c u l a t i o n s . At each marking p o i n t on the curve ( d e s c r i b e d below) the program d i s p l a y s the f o r c e , displacement and time and arranges t h e i r v a l u e s i n a t a b l e . The f i n a l raw d ata from each compaction run t h a t i s d i s p l a y e d i n a t a b l e i s saved f o r a n a l y s i s . The data i s then compiled u s i n g a program c a l l e d "combhp" and t r a n s f e r r e d t o Lotus spreadsheet f o r a n a l y s i s . T y p i c a l f o r c e and displacement curves t h a t were o b t a i n e d f o r each m a t e r i a l are shown i n F i g . 5b-9. 2 . 4.3.1 Force-Time c u r v e The f o r c e s i g n a l i s r e c e i v e d from th e l o a d c e l l and p l o t t e d by the computer (the f o r c e curve i n F i g . 5a) . The c urve i s a n alyzed a t t h r e e d i f f e r e n t p o i n t s by the HPRESS program. The f i r s t p o i n t i s the one a t which the l o a d c e l l f i r s t d e t e c t s a f o r c e and marks the b e g i n n i n g of compression. The second p o i n t i s the one a t which the l o a d c e l l d e t e c t s maximum force, and marks the end of compression and the b e g i n n i n g of decompression. The t h i r d p o i n t i s the one a t which the f o r c e d e t e c t e d by the l o a d c e l l drops t o zero and marks the end of decompression. 2 . 4.3.2 Displacement-Time c u r v e The displacement s i g n a l i s r e c e i v e d from the LVDT a t t a c h e d t o the punch and d i e assembly (the displacement curve i n F i g . 5a) . The curve i s a nalyzed a t two d i f f e r e n t p o i n t s . The f i r s t p o i n t marks the maximum d i s t a n c e t h a t the 30 Time ER e Elastic Recovery D c Punch Travel Distance Beyond Peak Pressure F = Decrease in the Force During D PTT = Punch Travel Time Beyond Peak Pressure Pmax c Maximum Pressure F i g . 5a. Force and D isp lacement P lot Against Time Force (kN) Displacement (uM) (Thousands) Time (2 msec/Div) Fig. 6. A Typical Force-Displacement Curve of Emcompress 33 Force (kN) Displacement (uM) (Thousands) Time (2 msec/DIv) Fig. 7 . A Typical Force-Displacement Curve of Spray Dried Lactose Force (kN) Displacement (uM) (Thousands) Time (2 msec/DIv) Fig. 9. A Typical Force-Displacement Curve of Acetaminophen DC 36 upper punch has t r a v e l l e d . A t t h i s p o i n t the t a b l e t i s a t i t s minimum t h i c k n e s s . The second p o i n t i s the one a t which the displacement has reached a cons t a n t v a l u e . At t h i s p o i n t the t a b l e t has expanded t o i t s maximum t h i c k n e s s w h i l s t s t i l l i n the d i e . 2.5 Experimental Procedures The e f f e c t s of peak p r e s s u r e (Pmax) and average compression r a t e (ACR) on the f o l l o w i n g compaction parameters were determined: i ) T a b l e t r e c o v e r y i n the d i e i i ) Punch t r a v e l (distance) beyond Pmax (D) i i i ) Change i n the f o r c e d u r i n g punch t r a v e l beyond Pmax (F) i v ) Punch t r a v e l time beyond Pmax (PTT) v) Force of f a i l u r e (FF) and exte n t o f deformation p r i o r t o f a i l u r e (DF) The r e c o v e r y of the t a b l e t s of d i f f e r e n t m a t e r i a l s was compared i n terms of pe r c e n t t a b l e t t h i c k n e s s a t Pmax. To o b t a i n s i m i l a r t a b l e t t h i c k n e s s e s a t a g i v e n Pmax/ the t r u e volume, V^/ (the t o t a l volume of the s o l i d p a r t i c l e s which ex c l u d e s a l l spaces g r e a t e r than the mo l e c u l a r dimensions) o f the m a t e r i a l s was kept co n s t a n t . To determine a s u i t a b l e t r u e volume f o r each m a t e r i a l under study, f i r s t the m a t e r i a l w i t h the l a r g e s t b u l k volume, A v i c e l , was s e l e c t e d . The maximum amount o f A v i c e l t h a t c o u l d be poured i n t o the d i e f r e e l y , without e x t e n s i v e 37 t a p p i n g was found t o be 0.7g. Using the t r u e d e n s i t y of A v i c e l (Table 1) the t r u e volume of 0.7 g was c a l c u l a t e d t o be 0.452 cm 3. Thus knowing the t r u e d e n s i t y of a l l the o t h e r m a t e r i a l s , the amount of each m a t e r i a l c o r r e s p o n d i n g t o 0.452 cm 3 t r u e volume was determined. (Table 1) A l l m a t e r i a l s c o n t a i n e d 0.5% w/w magnesium s t e a r a t e f o r l u b r i c a t i o n . The e f f e c t s of d i e w a l l f r i c t i o n on t a b l e t r e c o v e r y were assumed t o be n e g l i g i b l e . One s e t of experiments ( s e c t i o n 3.2) was designed t o determine the r e c o v e r y of the empty punch and d i e assembly upon th e removal of p r e s s u r e . A second s e t ( s e c t i o n 3.3) was d e s i g n e d t o determine the e f f e c t s of i n c r e a s i n g Pmax and ACR on the above mentioned compaction parameters w h i l e a t h i r d s e t ( s e c t i o n 3.4) was c a r r i e d out t o determine the e f f e c t s of average ACR on the same parameters. 2.6 D e t e r m i n a t i o n o f t h e punch and d i e r e c o v e r y S i n c e one of the main o b j e c t i v e s of t h i s p r o j e c t was t o measure the e l a s t i c r e c o v e r y of compacted powders, i t was f i r s t n ecessary t o determine the r e c o v e r y a s s o c i a t e d w i t h t h e punch and d i e assembly alone. To measure t h i s r e c o v e r y the l i m i t v a l v e of the p r e s s was s e t a t the d e s i r e d Pmax ( i e . 37 MPa). The assembly was h e l d under t h i s p r e s s u r e f o r a few seconds, the p r e s s u r e was then r e l e a s e d and the e l a s t i c r e c o v e r y monitored u s i n g the LVDT a t t a c h e d t o the punch and d i e assembly ( F i g . 2.). The r e c o v e r y was determined by s u b t r a c t i n g the displacement v a l u e when the 38 Ta b l e 1. True D e n s i t y and Weight of 0.452 cm of Powders M a t e r i a l True Den§ Weight (g/cm-t } a (g) A v i c e l 1.548 0.700 Emcompress 2.352 1.063 Spray D r i e d L a c t o s e 1.538 0.695 Acetaminophen USP 1.296 0.586 Acetaminophen DC 1.295 0.585 a) Determined by S. Dwivedi by gas displacement pycnometry (Multipycnometer, Quantochrome Corp.) 39 assembly was under the p r e s s u r e from the one when the p r e s s u r e was r e l e a s e d . The experiment was repeated a t v a r i o u s Pmax's ran g i n g from 37 MPa (0.5 tons) t o 186 MPa (2.5 t o n s ) , and the re c o v e r y was recorded. The v a l u e s o f the r e c o v e r i e s f o r the t a b l e t s were subsequently c o r r e c t e d f o r t he punch and d i e rec o v e r y . 2.7 V a r i a t i o n i n peak p r e s s u r e and average compression r a t e In the second s e t of experiments the t a b l e t s were compressed a t v a r i o u s peak p r e s s u r e s and average compression r a t e s . The Pmax on the t a b l e t s was v a r i e d from 37 MPa (0.5 ton) t o 186 MPa (2.5 ton) . I n the h y d r a u l i c p r e s s an i n c r e a s e i n the Pmax was accompanied by an i n c r e a s e i n the ACR. A s i m i l a r r e l a t i o n s h i p between the Pmax and the ACR i s observed i n a r o t a r y t a b l e t p r e s s ( M i t c h e l l , u n p ublished o b s e r v a t i o n s ) . To compress t a b l e t s a t v a r i o u s peak p r e s s u r e s the h y d r a u l i c p r e s s was setup as f o l l o w s : 1. The l i m i t v a l v e was s e t a t about 10 ton s . 2. The s e t t i n g s f o r the opening and c l o s i n g of the s o l e n o i d v a l v e s , i n order t o a t t a i n a c e r t a i n Pmax, were o b t a i n e d . S i n c e the p r e s s was operated a t h i g h speeds these s e t t i n g s had t o be a d j u s t e d c o n s t a n t l y t o account f o r s l i g h t changes i n the p o s i t i o n of the ram between compressions and other minute changes i n the c o n d i t i o n s o f the p r e s s (e.g. o i l temperature). 40 3. The f a s t v a l v e was opened a l l the way wh i l e the slow v a l v e was c l o s e d . 4. To vary the Pmax the s e t t i n g s o f the s o l e n o i d s were changed. For example, t o i n c r e a s e the Pmax s o l e n o i d 1 was s e t to.remain open f o r a lon g e r p e r i o d of time and s o l e n o i d 2 was s e t t o open a t a l a t e r time. 2.8 V a r i a t i o n i n a v e r a g e c o m p r e s s i o n r a t e a t f i x e d p e a k p r e s s u r e s . In the t h i r d s e t of experiments the t a b l e t s were compressed a t a s e l e c t e d Pmax and the ACR was v a r i e d . The ACR was v a r i e d from the lowest r a t e t o the h i g h e s t r a t e t h a t was p o s s i b l e f o r the gi v e n m a t e r i a l . The ACR was decreased by c l o s i n g the f a s t v a l v e of the h y d r a u l i c p r e s s from % t u r n t o 2% t u r n s a t % t u r n i n t e r v a l s . As the compression r a t e was decreased, the s e t t i n g s of the s o l e n o i d s had t o be a d j u s t e d i n order t o m a i n t a i n a c e r t a i n Pmax ( s o l e n o i d 1 had t o remain open lo n g e r and s o l e n o i d 2 had t o open l a t e r ) . 2.9 C a l c u l a t i o n o f P o r o s i t y o f T a b l e t s a t Peak P r e s s u r e P o r o s i t y i s a di m e n s i o n l e s s q u a n t i t y and i s d e f i n e d as the r a t i o of the t o t a l volume of the v o i d spaces (V v) t o the bulk volume (Vj-,) of the m a t e r i a l ( M a r s h a l l , 1985) . The t o t a l volume of the v o i d spaces i n the m a t e r i a l i s 41 c a l c u l a t e d by s u b t r a c t i n g the t r u e volume, from V b (the t o t a l volume occupied by the e n t i r e powder mass): P o r o s i t y = V v / V b (7) = ( V b ~ V t) / V b = 1 - ( V t / V b) The V t of the t a b l e t was c a l c u l a t e d u s i n g the t r u e d e n s i t y and mass of the powder. V-t = mass / t r u e d e n s i t y = M / D-^  The V b of the t a b l e t a t Pmax was c a l c u l a t e d by s u b t r a c t i n g t h e r e c o v e r y volume of the t a b l e t i n the d i e , V^, from the volume of the t a b l e t a f t e r e j e c t i o n , V e . v b = v e " v d ( 8) V e = A e x H e v d = A d x E R where A e = s u r f a c e area of the t a b l e t a f t e r e j e c t i o n H e = t h i c k n e s s o f the t a b l e t a f t e r e j e c t i o n A(j = area o f the t a b l e t i n the d i e ER = r e c o v e r y of the t a b l e t w i t h i n the d i e The t h i c k n e s s and r a d i a l diameter o f the t a b l e t a f t e r e j e c t i o n were measured immediately, u s i n g d i g i t a l c a l i p e r s . The r e c o v e r y o f the t a b l e t s i n the d i e was determined u s i n g th e LVDT a t t a c h e d t o the punch and d i e assembly. The s u r f a c e area of the t a b l e t s a t Pmax was c a l c u l a t e d from the r a d i a l diameter of the d i e (1.291 cm). T h e r e f o r e a t Pmax, t a b l e t p o r o s i t y i s P o r o s i t y = 1 - { M / D t [ ( A e x H e) - ( A d x ER)] (9) 42 With the c u r r e n t punch and d i e assembly, i t was p o s s i b l e t o meaure t a b l e t r e c o v e r y i n the d i e but not t o make d i r e c t measurements of t a b l e t t h i c k n e s s . In the above c a l c u l a t i o n s i t was assumed t h a t t h e r e was no change i n the t h i c k n e s s of the t a b l e t from end-recovery t i l l measurement immediately a f t e r e j e c t i o n . T a b l e t r e c o v e r y i n the r a d i a l d i r e c t i o n upon e j e c t i o n from the d i e was measured d i r e c t l y , but w i t h our punch and d i e assembly i t was not p o s s i b l e t o determine whether t a b l e t s r e c o v e r i n the a x i a l d i r e c t i o n d u r i n g e j e c t i o n . Equation 9 i s based on t h e bes t approximation o f t a b l e t t h i c k n e s s a t Pmax. 2 . 1 0 C a l c u l a t i o n o f Percent ER To c a l c u l a t e p e r c e n t ER, i t was necessary t o c a l c u l a t e t a b l e t t h i c k n e s s a t Pmax (Hmin) where: Hmin = ( V e - V d ) / A d (10) Percent ER was c a l c u l a t e d from: p e r c e n t ER= (ER x 100)/Hmin 2 . 1 1 D e t e r m i n a t i o n o f the f o r c e o f f a i l u r e and deformation o f t a b l e t s The f o r c e of f a i l u r e measurement or as i t i s commonly r e f e r r e d t o , the d i a m e t r a l compression t e s t , i s a method of a s s e s s i n g the mechanical s t r e n g t h of a t a b l e t . (Rees arid Shotton, 1979). The t h i c k n e s s and r a d i a l diameter of t a b l e t s upon e j e c t i o n from the d i e were measured, and the t a b l e t s were s t o r e d a t room temperature f o r 24 hours (some 43 t a b l e t s d i d not e j e c t from the d i e i n t a c t due t o e i t h e r capping or l a m i n a t i o n ) . A f t e r 24 hours the f o r c e of f a i l u r e a l o n g w i t h deformation of the t a b l e t s were measured u s i n g the CT40 t a b l e t hardness t e s t e r . 2.12 S t a t i s t i c a l A n a l y s i s The r e l a t i o n s h i p between independent v a r i a b l e s (eg. p r essure) and dependent v a r i a b l e s (eg. recovery) was examined by l i n e a r r e g r e s s i o n . When two groups were compared, s t a t i s t i c a l a n a l y s i s was performed u s i n g Student's t - t e s t . P r o b a b i l i t i e s of 0.05 were used t o d e f i n e the l e v e l of s i g n i f i c a n c e . 44 3. RESULTS and DISCUSSION 3.1 High Speed Compaction One of the main o b j e c t i v e s of the c u r r e n t p r o j e c t was t o study compaction a t speeds s i m i l a r t o those of r o t a r y t a b l e t p r e s s e s . Compaction data, o b t a i n e d u s i n g s i n g l e punch e c c e n t r i c p r e s s e s , h y d r a u l i c p r e s s e s and compaction s i m u l a t o r s , are o f t e n c o l l e c t e d a t compaction speeds t h a t a r e much, slower than the speeds of an i n d u s t r i a l r o t a r y t a b l e t p r e s s . In our p r e l i m i n a r y experiments w i t h the h y d r a u l i c p r e s s , compaction speeds h i g h e r than those of the Betapress c o u l d be a t t a i n e d . However, a t such speeds the o p e r a t i o n o f the h y d r a u l i c p r e s s was dangerous and u n r e l i a b l e . A f t e r f u r t h e r p r e l i m i n a r y experiments a s a f e l e v e l o f compaction speed was determined w i t h regards t o the l o a d c e l l and the punch and d i e assembly (and the o p e r a t o r ! ) . Compaction speeds i n the l i t e r a t u r e a re p r e s e n t e d e i t h e r i n terms of the movement of the upper punch i n cm/sec, or i n terms of the development of the f o r c e i n the upper punch i n kN/sec. Compaction speeds f o r the c u r r e n t experiments were c a l c u l a t e d i n terms of the average r a t e o f the development of the f o r c e i n the upper punch and are r e f e r r e d t o as the ACR (ACR) i n kN/sec. The ACR i s c a l c u l a t e d by d i v i d i n g the maximum compression f o r c e by the compression time (the time from 0 t o maximum f o r c e ) . Some 45 p u b l i s h e d compaction speeds along w i t h ones from the h y d r a u l i c p r e s s and the Betapress are shown i n T a b l e 2. I t i s e v i d e n t from T a b l e 2 t h a t the compaction speeds used w i t h most of the t e s t i n g machines are much slower than those of i n d u s t r i a l r o t a r y t a b l e t p r e s s e s such as the B e t a p r e s s . Although compaction parameters, measured a t slower speeds, may be u s e f u l i n the c h a r a c t e r i z a t i o n of powders i n m a t e r i a l s c i e n c e r e s e a r c h , they may not r e f l e c t t h e behavior under h i g h speed compaction. Roberts and Rowe (1987) used a h i g h speed compaction s i m u l a t o r , but d i d not measure the r e c o v e r y and flow parameters measured i n the c u r r e n t p r o j e c t . D i f f e r e n c e s between the ACRs ob t a i n e d u s i n g the h y d r a u l i c p r e s s and the Betapress f o r A v i c e l , Emcompress, s p r a y - d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC g r a n u l e s are shown i n F i g s . 10-14. The ACRs f o r A v i c e l , Emcompress and acetaminophen DC were slower w i t h the h y d r a u l i c p r e s s than the Betapress and f o r s p r a y - d r i e d l a c t o s e and acetaminophen USP were the same or f a s t e r than the Betapress. 46 Table 2. L i s t of Compaction Speeds of Various Compaction Machines M a t e r i a l ' Compaction Speed Machine Ref.No. A v i c e l 0.5-1.5 Compaction S i m u l a t o r 1 cm/sec A v i c e l 0.5-2.2 Compaction S i m u l a t o r 2 cm/sec NaCl 0.003-0.83 I n s t r o n U n i v e r s a l 3 cm/sec A v i c e l 83.3 kN/sec Mayes 4,5 A v i c e l 0.667 kN/sec Dartec M2501 U n i v e r s a l 6 Sucrose 0.00083 I n s t r o n U n i v e r s a l 7 cm/sec A v i c e l 74-580 kN/sec Betapress Acetaminophen 150-880 kN/sec Betapress * A v i c e l 70-400 kN/sec H y d r a u l i c P r e s s T h i s work (3-7 cm/sec) Acetaminophen 250-800 kN/sec H y d r a u l i c P r e s s T h i s work * Unpublished Data (A.G.Mitchell) 1. Ho and Jones, 75P 1988 2. Ho and Jones, 74P 1988 3. Rubenstein and Jackson 1987 4. T r a v e r s e t a l . , 1983 5. C e l i k and T r a v e r s 1983 6. Malamataris e t a l . , 1984 7. P e l e g and Moreyra, 1979 47 AVICEL PH-102 Ave. Compression Rate (kN/sec) 600 i - — - — — Q I I I I I I I I I I 1 0 20 40 60 80 100 120 140 160 180 200 Peak Pressure (MPa) Fig 10. Variation of Ave. Compression Rate with Peak Pressure EMCOMPRESS Ave. Compression Rate (kN/sec) i i i i i i i i i 1 1— 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 Peak Pressure (MPa) Fig 11. Variation of Ave. Compression Rate with Peak Pressure Spray-Dr ied LACTOSE Ave. Compression Rate (kN/sec) 1000r— - — -Q I . I I I I I I I 1 1 1 15 35 55 75 95 115 135 155 175 195 21 Peak Pressure (MPa) Fig. 12. Variation of Ave. Compression Rate with Peak Pressure Fig. 13. Variation of Ave. Compression Rate with Peak Pressure Fig. 14. Variation of Ave. Compression Rate with Peak Pressure 3.2 Recovery o f the Punch and Die Assembly The r e c o v e r y of the punch and d i e assembly was measured a t Pmaxs of 37, 74, 111, 148, 185 and 222 MPa. ( F i g . 15.). The p l o t t e d v a l u e s a re the average o f t e n r e c o v e r y v a l u e s a t each Pmax. The c o e f f i c i e n t of d e t e r m i n a t i o n , r 2 , of the p l o t was 0.995. The p l o t was t r e a t e d as a standard curve f o r p r e d i c t i n g the r e c o v e r y of the punch and d i e assembly w i t h i n the s p e c i f i e d Pmax range (37 t o 222 MPa) . The s l o p e and the i n t e r c e p t o f the sta n d a r d curve were 1.73 and 0.3 r e s p e c t i v e l y . T h e r e f o r e t h e r e c o v e r y of the punch and d i e assembly a t any g i v e n Pmax was c a l c u l a t e d from the equation: Y = 0.30 + 1.73 X (11) The Y - i n t e r c e p t i n the above equation should be zero s i n c e t h e r e s h o u l d be no re c o v e r y a t zero p r e s s u r e . The 0.3 Y-i n t e r c e p t (not s t a t i s t i c a l l y s i g n i f i c a n t ) i s due t o v a r i o u s e r r o r s i n v o l v e d i n the measurement of the punch and d i e r e c o v e r y . However the va l u e of the Y - i n t e r c e p t (0.3 um) can be taken as n e g l i g i b l e s i n c e the r e c o v e r y o f t a b l e t s ranged from 50 t o 250 um. 3.3 V a r i a t i o n o f Pmax In t h i s s e r i e s of experiments i t was found t h a t the i n c r e a s e i n the Pmax was accompanied by an i n c r e a s e i n the ACR. However, i t i s e v i d e n t from F i g . 10 t o 14 t h a t a s i m i l a r r e l a t i o n s h i p between the Pmax and the compression 5 3 Fig. 16 Recovery of the Punch and Assembly 54 r a t e e x i s t s f o r the Betapress. T h e r e f o r e when the e f f e c t s o f i n c r e a s i n g Pmax on the above parameters i s d i s c u s s e d , i t shou l d be kept i n mind t h a t the ACR i s a l s o i n c r e a s i n g . D u c t i l e m a t e r i a l s d i s p l a y e d slower compression r a t e s than the b r i t t l e m a t e r i a l s . With both the Betapress and the h y d r a u l i c p r e s s the maximum compression r a t e s f o r A v i c e l , F i g . 11., (300-500 kN/sec) were c o n s i d e r a b l y slower than those f o r acetaminophen USP, F i g . 14., ( >800 kN/sec). The d i f f e r e n c e between the compression r a t e s o f p l a s t i c and b r i t t l e m a t e r i a l s may be e x p l a i n e d i n terms o f the work and energy of compaction. During compression, i n p l a s t i c m a t e r i a l s , energy i s u t i l i z e d f o r deformation and bonding (Rue and Barkworth, 1980). Energy i s r e l a t e d t o the a p p l i e d f o r c e through work and s i n c e work i s r e q u i r e d t o deform and bond the p a r t i c l e s , the f o r c e t h a t i s t r a n s m i t t e d t o the upper punch per u n i t time i s reduced ( i e . lower compression r a t e ) . For b r i t t l e m a t e r i a l s , d u r i n g compression, the energy i s not u t i l i z e d f o r flow and bond f o r m a t i o n and most of t h a t energy i s remained as the f o r c e i n the upper punch ( i e . h i g h e r compression r a t e ) . 3.3.1 V a r i a t i o n o f P o r o s i t y w i t h Pmax As mentioned e a r l i e r the t r u e volume of each m a t e r i a l b e i n g compressed was kept c o n s t a n t by a d j u s t i n g the mass (Table l ) . Hence a t equal p o r o s i t y the t a b l e t s w i l l have the same volume and t h i c k n e s s . A p l o t o f t a b l e t p o r o s i t y a t Pmax a g a i n s t Pmax i s shown i n F i g . 16. The p o r o s i t i e s o f CM 03 OS 0.1 Porosity Porosity +• Avioel PH-102 4-20 40 00 80 100 120 140 100 180 200 Peak Pressure (MPa) a 20 40 80 80 100 120 140 180 180 200 Peak Pressure (MPa) OA OA OS 0.1 Porosity +• ao. Lao tot* +»-4-_J I I I L_ 20 40 80 80 100 120 140 180 180 200 Peak Pressure (MPa) 0.4 0.3 02 0.1 Porosity +• Ao*tmnlneph*n DC +-•1-_l I l_ 20 40 80 80 100 120 140 180 180 200 Peak Pressure (MPa) Fig. 16. Variation of porosity with peak pressure Ul Ul 56 the acetaminophen USP t a b l e t s c o u l d not be o b t a i n e d due t o f a i l u r e upon e j e c t i o n . There was a s i g n i f i c a n t r e d u c t i o n i n the p o r o s i t y of the compacts wi t h i n c r e a s e i n Pmax. T h i s i s due t o p a r t i c l e rearrangement and fragmentation which reduce and f i l l t he v o i d spaces i n the compact. At h i g h p r e s s u r e s the p o r o s i t i e s appear t o be approaching a l i m i t . The p o r o s i t y of A v i c e l t a b l e t s reached a minimum v a l u e of 0.06 between 180-200 MPa , w h i l e those of Emcompress, spray d r i e d l a c t o s e and acetaminophen DC reached minimum v a l u e s of 0.1, 0.1 and 0.12 r e s p e c t i v e l y . The lowest p o r o s i t y was achieved f o r A v i c e l which i s the most p l a s t i c of the above m a t e r i a l s . I t s p a r t i c l e s deform and hence f i l l i n the v o i d s of the compact more than those of the other m a t e r i a l s . I t i s important t o c o n s i d e r the y i e l d p r e s s u r e , Py of t h e above m a t e r i a l s when comparing' t h e i r compaction parameters. Py i s the p r e s s u r e beyond which the m a t e r i a l deforms permanently ( M a r s h a l l , 1985) . The Py v a l u e s f o r the f i v e m a t e r i a l s used i n t h i s study are g i v e n i n T a b l e 3 (Roberts and Rowe, 1987). These v a l u e s p r o v i d e a d d i t i o n a l i n s i g h t on the v a r i a t i o n of p o r o s i t y w i t h Pmax and on the compaction behavior of the m a t e r i a l . For example, a t a b l e t of a m a t e r i a l w i t h low Py ( A v i c e l ) w i l l have a lower p o r o s i t y , than one w i t h h i g h Py (Emcompress) a t a g i v e n Pmax because i n c r e a s e d p a r t i c l e deformation w i l l decrease the v o i d spaces w i t h i n the compact. 57 T a b l e 3. Y i e l d P r e s s u r e s o f E x p e r i m e n t a l M a t e r i a l s M a t e r i a l P y (MPa) A v i c e l 49 Emcompress 431 La c t o s e 149 Acetaminophen 109 Roberts and Rowe (1987) 58 The Py of the f i v e m a t e r i a l s i n Tab l e 3 can o n l y be taken as es t i m a t e s because the d e t e r m i n a t i o n o f Py f o r p a r t i c u l a t e porous m a t e r i a l s , u n l i k e f o r t h a t of non-porous s o l i d m a t e r i a l s , i s d i f f i c u l t . Roberts and Rowe (1987) o b t a i n e d Py from the s l o p e o f the l i n e a r p o r t i o n o f the p l o t of l o g ( l / p o r o s i t y ) a g a i n s t compression f o r c e (Heckel p l o t ) . The type of p l o t o b t a i n e d v a r i e s w i t h the compaction technique, p a r t i c l e s i z e and compaction r a t e and i s o n l y l i n e a r over a l i m i t e d range of experimental data (Rue and Rees, 1978). Another problem w i t h Py when a p p l i e d t o a p a r t i c u l a t e system under compression, i s t h a t the p r e s s u r e on each p a r t i c l e i s not the same. The p r e s s u r e v a r i e s depending on the p o s i t i o n of the p a r t i c l e i n the powder bed. A l s o d i f f e r e n t r e g i o n s o f each p a r t i c l e ( i e . s u r f a c e s , edges, etc) e x p e r i e n c e d i f f e r e n t p r e s s u r e s . For example i f the m a t e r i a l i s compressed a t a Pmax below i t s Py, some p a r t i c l e s , or r e g i o n s of a p a r t i c l e , may experi e n c e h i g h e r p r e s s u r e s than Py and hence undergo deformation w h i l e o t h e r s do not. The p r e s s u r e d e t e c t e d by the upper punch i s the p r e s s u r e on the compact as a whole does not r e f l e c t the a c t u a l p r e s s u r e on a p a r t i c l e . 3.3.2 T a b l e t Recovery Many authors (David and Augsberger, 1977; T r a v e r s and C e l i k , 1983; K r y c e r , e t a l . , 1982) have a t t r i b u t e d t a b l e t capping and l a m i n a t i o n t o the expansion of the m a t e r i a l 59 upon removal of the l o a d . The nature of t a b l e t r e c o v e r y has been i n v e s t i g a t e d by s e v e r a l authors (Rubenstein and Jackson, 1987; Malamataris, e t a l . , 1984; Bangudu and P i l p e l , 1985) . These authors have used d i f f e r i n g t e r m i n o l o g y such as e l a s t i c , v i s c o e l a s t i c and v i s c o p l a s t i c t o d e s c r i b e t a b l e t r e c o v e r y . In g e n e r a l , i t appears t h a t t a b l e t r e c o v e r y can be d i v i d e d i n t o two d i s t i n c t p a r t s . The f i r s t p a r t i s the i n i t i a l r a p i d expansion of the t a b l e t w i t h i n the d i e d u r i n g decompression. T h i s r a p i d expansion occurs anywhere from 10 t o 100 msec f o l l o w i n g the removal of the l o a d . The r a p i d expansion of the t a b l e t d u r i n g decompression i s r e f e r r e d t o as the e l a s t i c r e c o v e r y (ER) . The second p a r t of the t a b l e t r e c o v e r y e s s e n t i a l l y i s t h e slower expansion t h a t s t a r t s from about 50 msec t o sometimes many days f o l l o w i n g the removal of the l o a d and c o n t i n u e s w e l l a f t e r the t a b l e t has been e j e c t e d from the d i e . The r e l a t i v e l y slower expansion of the t a b l e t i s r e f e r r e d t o as the v i s c o e l a s t i c r e c o v e r y (Danielson, e t a l . , 1983). I t i s e v i d e n t from the t y p i c a l f o r c e and displacement curves of the f i v e m a t e r i a l s ( F i g . 5-9) t h a t the r e c o v e r y measured wi t h our punch and d i e assembly i s e l a s t i c i n n a t u r e and i s complete w i t h i n 10-20 msec from the s t a r t of decompression. T h e r e f o r e w i t h i n the time frame of our experiments (0.5 sec) the t a b l e t r e c o v e r y i s e n t i r e l y e l a s t i c and no o t h e r r e c o v e r y i s measurable. 60 ER was c a l c u l a t e d by s u b t r a c t i n g the displacement v a l u e a t the end of the 0.5 sec c y c l e from t h a t of the maximum displacement. T h e r e f o r e ER corresponds t o the d i f f e r e n c e between the minimum and maximum t h i c k n e s s o f the t a b l e t i n the d i e . 3.3.2.1 ER of D i r e c t l y Compressible Powders The ER of A v i c e l , Emcompress and spray d r i e d l a c t o s e t a b l e t s i n c r e a s e d w i t h Pmax ( F i g . 17). R e g r e s s i o n a n a l y s i s showed t h a t the i n c r e a s e i n ER w i t h Pmax f o r a l l t h r e e m a t e r i a l s i s s i g n i f i c a n t a t the 5% l e v e l . The ER of A v i c e l was s i g n i f i c a n t l y g r e a t e r than t h a t of Emcompress and s p r a y - d r i e d l a c t o s e a t a l l p r e s s u r e s i n c r e a s i n g from about 150 um a t low p r e s s u r e s t o about 2 00 um a t h i g h p r e s s u r e s . Over the same Pmax range the ER of Emcompress and spr a y -d r i e d l a c t o s e i n c r e a s e d from 75 t o 100 um. Ta b l e 3 shows ER i n terms of percent r e c o v e r y r e l a t i v e t o the t h i c k n e s s of the t a b l e t s a t Pmax. The p e r c e n t ER v a l u e s from the h y d r a u l i c p r e s s were g r e a t e r than those from the Betapress (with the e x c e p t i o n o f acetaminophen DC) . T h i s i s expected s i n c e , u s i n g the h y d r a u l i c p r e s s , p e r c e n t r e c o v e r y i s the t o t a l t a b l e t r e c o v e r y ( s e c t i o n 2.10) whereas on the Betapress the c a l c u l a t e d r e c o v e r y i s l i m i t e d t o expansion w i t h i n the d i e be f o r e decompression i s complete (Dwivedi, Oates and M i t c h e l l , u n p u b l i s h e d ) . The d i f f e r e n c e i n the ER of the t a b l e t s may be e x p l a i n e d from the Young's modulus of e l a s t i c i t y , E , o f the 260 200 Tablet Recovery (uM) 160 -100 +• »wiaEL 4- ^ 4 - ' , r 2 = 0.592 N = 54 O 20 40 00 80 100 120 1*0 180 180 200 PEAK PRESSURE (MPs) 200 160 100 Tablet Reaovery (uM] ° EMOOMPBESS r 2 = 0.762 N = 31 0 20 40 80 80 100 120 140 180 180 200 PEAK PRESSURE (MPa) b Tablet Recovery (uM) 100 -60 * 3.0.LAOTOae r 2 = 0.658 N = 86 _1 I I I 1_ 0 20 40 80 80 100 120 140 180 180 200 PEAK PRESSURE (MPs) Fig 17. Change In Total Tablet Recovery with the Increase in Peak Pressure 62 m a t e r i a l s (see equation 1 and Table 4 ) . A c c o r d i n g t o eq u a t i o n 1 the r e c o v e r y ( s t r a i n ) i s i n v e r s e l y p r o p o r t i o n a l t o E. T h e r e f o r e a t a g i v e n p r e s s u r e a m a t e r i a l w i t h lower E e l a s t i c a l l y deforms more than one w i t h a h i g h e r E. 3.3.2.2 T a b l e t ER o f Acetaminophen USP and Acetaminophen DC The ER of Acetaminophen USP decreased w i t h i n c r e a s e i n p r e s s u r e ( F i g . 18). The ER decreased from about 12 0-140 um a t low p r e s s u r e s t o about 50-60 um a t h i g h p r e s s u r e s . The ER of Acetaminophen DC a l s o decreased w i t h i n c r e a s e i n Pmax from about 85 um t o 60 um. The decrease i n the ER of acetaminophen USP w i t h Pmax was s i g n i f i c a n t (at the 5% l e v e l ) whereas t h a t o f acetaminophen DC was not. The decrease i n the ER of acetaminophen USP might be due t o an i n c r e a s e i n p a r t i c u l a t e f r a c t u r e w i t h the i n c r e a s e i n Pmax. Once i n s m a l l e r p i e c e s , they no longer e l a s t i c a l l y deform, th e p o r o s i t y o f the compact i s decreased and t h e r e i s a subsequent decrease i n the ER. I t i s i n t e r e s t i n g t h a t the v a r i a t i o n o f ER of Emcompress and acetaminophen USP w i t h Pmax i s o p p o s i t e . Both m a t e r i a l s are known t o be b r i t t l e and t o deform by f r a c t u r e . However, Emcompress has a much h i g h e r Py than acetaminophen USP (Table 3). T h e r e f o r e w h i l e acetaminophen USP p a r t i c l e s f r a c t u r e as Pmax i n c r e a s e s , Emcompress p a r t i c l e s c o n t i n u e t o deform e l a s t i c a l l y and do not f r a c t u r e t o the same ext e n t and subsequently r e c o v e r more. T a b l e 4. Percent ER and E of the F i v e M a t e r i a l s T e s t e d M a t e r i a l Pmax ER(%) E(GPa)* (MPa) H y d r a u l i c Press Betapress A v i c e l 37 3.0 1.7 6 148 5.1 3.0 Emcom 37 1.4 0.9 30 148 1.9 1.3 L a c t o s e 37 1.8 1.3 17 148 2.9 2.1 Ac. DC 37 1.4 1.0 8 148 1.8 2.3 Ac. USP 11 * M i t c h e l l , u n p ublished o b s e r v a t i o n s 260 Tablot Rsoovsry (uM) 200 160 100 -W-4-+• Aaatamlnophsn USP r N **** rr 0.854 = 51 20 40 60 80 100 120 140 100 180 200 PEAK PRES8URE (MPa) Tablet Rsaovery (uM) I- r 2 = 0.327 N = 63 A Aoatamlnophan 00 A * A A 40 00 60 100 120 140 WO 180 200 PEAK PRE83UHE (MPa) b Fig 18. Change In Total Tablot Recovery with Increase In Peak Pressure 65 3.3.3 P u n c h T r a v e l D i s t a n c e Beyond Pmax (D) E a r l y i n the p r o j e c t i t was e v i d e n t from the compaction f o r c e and displacement curves ( r e g a r d l e s s of the m a t e r i a l ) t h a t the p o i n t a t which peak f o r c e was a t t a i n e d d i d not c o i n c i d e w i t h the p o i n t of maximum displacement ( F i g 5a) . In a l l compaction runs the punch co n t i n u e d t o p e n e t r a t e the d i e even a f t e r the peak f o r c e had been reached. During the punch t r a v e l beyond Pmax, D, the compact i s s t i l l under some l o a d ( i e . the f o r c e i s not zero F i g . 5-9) and t h i s l o a d i s s u f f i c i e n t t o con t i n u e deforming t h e m a t e r i a l . T h e r e f o r e p l a s t i c m a t e r i a l s w i t h low Py would be expected t o have a longer D (the punch p e n t r a t e s f u r t h e r ) than b r i t t l e m a t e r i a l s . 3.3.3.1 P u n c h T r a v e l o f D i r e c t l y C o m p r e s s i b l e Powders Changes i n D w i t h Pmax f o r A v i c e l , spray d r i e d l a c t o s e and Emcompress are shown i n F i g . 19. For a l l t h r e e m a t e r i a l s D decreased s i g n i f i c a n t l y w i t h i n c r e a s e i n Pmax. For A v i c e l , D ranged from 100-150 um a t the lowest p r e s s u r e s t o about 20 um a t the h i g h e s t p r e s s u r e s (Table 5 ) . Emcompress had the s m a l l e s t D (from 50-75 um t o about 10-15 um) , w i t h spray- d r i e d l a c t o s e having D v a l u e s i n between A v i c e l and Emcompress. 0 (uM) 2001 100 60 * X/IOEL r 2 = 0.818 N = 54 20 40 60 60 100 120 140 160 180 200 PEAK PRESSURE (MPa) D (uM) 160 X EMOOMPRESS r 2 = 0.862 N = 31 60 X X X x X 20 40 60 80 100 120 140 160 180 200 PEAK PRE88URE (MPa) 0 (uM) o S.O.LAOTOSE r2 = 0.723! N = 86 „<P a • Q • Bo a i 60 1 • • • _ o » » 0 ° * • D o S « 20 40 00 60 100 120 140 100 180 200 PEAK PRESSURE (MPa) Fig. 19. Change in D with Peak Pressure Table 5. D of the Five Materials Tested M a t e r i a l Pmax D (MPa) (um) A v i c e l 37 120 148 30 Emcom 37 55 148 30 L a c t o s e 37 100 148 45 Ac. DC 37 90 148 50 Ac. USP 37 60 148 30 68 The D v a l u e s f o r A v i c e l and. spray d r i e d L a c t o s e were not s i g n i f i c a n t l y d i f f e r e n t from each o t h e r but, a t low p r e s s u r e s , were s i g n i f i c a n t l y h i g h e r than f o r Emcompress. Punch t r a v e l beyond peak f o r c e was r e p o r t e d by Ho and Jones (1988) u s i n g a compaction s i m u l a t o r a t slower compaction speeds than t h i s work. T h e i r r e s u l t s show t h a t p l a s t i c m a t e r i a l s l i k e A v i c e l have longer D v a l u e s than m a t e r i a l s such as s p r a y - d r i e d l a c t o s e which undergo both p l a s t i c and b r i t t l e deformation. T h e i r data however should be t r e a t e d c a u t i o u s l y s i n c e i t c o n s i s t s o f a s i n g l e measurements of D a t t h r e e d i f f e r e n t compaction speeds and one Pmax. S i m i l a r D v a l u e s a t h i g h e r Pmax i n d i c a t e t h a t the p a r t i c l e s of each m a t e r i a l are r e a c h i n g maximum deformation and a re approaching the l i m i t i n g p o r o s i t y ( F i g . 16) . At t h i s p o i n t the punch cannot p e n e t r a t e the d i e any f u r t h e r and D becomes s i m i l a r f o r each m a t e r i a l . T h e r e f o r e a t h i g h Pmax, D does not d i f f e r e n t i a t e between the deformation b e h a v i o r o f p l a s t i c and b r i t t l e m a t e r i a l s . 3.3.3.2 Punch T r a v e l o f Acetaminophen USP and Acetaminophen DC The D f o r acetaminophen USP i n c r e a s e d from 40 um a t 25 MPa t o about 80 um a t 80 MPa and then decreased t o about 5-10 um a t 200 MPa (Table 4 and F i g . 20a). For acetaminophen DC D ranged from 95 um a t low pr e s s u r e t o about 20-25 um a t h i g h e r p r e s s u r e s ( F i g . 2 0b). At low Pmax, below 80 MPa, the 0 (uM] 2001 160 100 60 4-,+- £ ± t *- 4-+• Aa«t«mlnophen USP r 2 = 0.754 N = 51 4-4. +• 4 - + . L . 20 40 60 60 100 120 140 160 180 200 PEAK PRE83UHE (MPa] 0 (uM) 160 100 60 ° Aastamlnaphan DO r2 = 0.898 N = 63 • • " a • at 20 40 60 80 100 120 140 160 180 200 PEAK PP.E88URE (MPa) Fig 20. Change In D with Peak Pressure 70 D v a l u e s f o r acetaminophen DC were s i g n i f i c a n t l y h i g h e r t h a n t h o s e o f acetaminophen USP, b u t beyond 80 MPa t h e r e was no s i g n i f i c a n t d i f f e r e n c e between t h e two. A g a i n a t low Pmax acetaminophen USP and DC can be d i s t i n g u i s h e d by t h e i r D. T h i s i s c o n s i s t e n t w i t h above o b s e r v a t i o n s on t h e D o f d i r e c t l y c o m p r e s s i b l e powders. The a d d i t i o n o f PVP appears t o have s i g n i f i c a n t l y i n c r e a s e d t h e D o f acetaminophen a t l o w e r Pmax. T h e r e f o r e i t a ppeares t h a t acetaminophen DC g r a n u l e s a r e a b l e t o deform p l a s t i c a l l y t o a g r e a t e r e x t e n t t h a n t h e acetaminophen USP c r y s t a l s . 3 .3 .4 Decrease i n the Force During Punch T r a v e l Beyond Pmax (F) We examined whether F i s s i m i l a r t o s t r e s s r e l a x a t i o n and c o u l d be used as a measure o f t h e p l a s t i c f l o w o f a m a t e r i a l under s t r e s s . S t r e s s r e l a x a t i o n d e f i n e d as t h e d e c r e a s e i n t h e s t r e s s a t c o n s t a n t s t r a i n , has been shown by s e v e r a l a u t h o r s (Cook and Summers, 1988; C u t t , e t a l . , 1987; P e l e g and Moreyra, 1979) t o p l a y an i m p o r t a n t r o l e i n t h e f o r m a t i o n o f compacts. G e n e r a l l y i t i s b e l i e v e d t h a t t h e more a m a t e r i a l can p l a s t i c a l l y f l o w and r e l i e v e i t s s t r e s s d u r i n g c o m p a c t i o n , t h e b e t t e r t h e compacts formed. The F i n our e x p e r i m e n t s , however, was n o t s t r e s s r e l a x a t i o n s i n c e t h e d e c r e a s e i n f o r c e was accompanied by an i n c r e a s e i n d i s p l a c e m e n t ( F i g s . 5-9). 71 3.3.4.1 Decrease i n t h e F o r c e D u r i n g Punch T r a v e l Beyond Pmax o f D i r e c t l y C o m p r e s s i b l e Powders For the d i r e c t l y c ompressible powders, t h e r e was a g e n e r a l i n c r e a s e i n F w i t h Pmax ( F i g . 21) . A v i c e l , Emcompress and spray d r i e d l a c t o s e had s i m i l a r F v a l u e s from 20 t o 80 MPa. At h i g h e r Pmax spray d r i e d l a c t o s e had the h i g h e s t and A v i c e l t he lowest F v a l u e s w h i l e Emcompress had F v a l u e s i n between. F v a l u e s f o r A v i c e l appeared t o drop a f t e r about 180 MPa p r e s s u r e . The F v a l u e s of Emcompress and spray d r i e d l a c t o s e were not s i g n i f i c a n t l y d i f f e r e n t from each other but were both s i g n i f i c a n t l y h i g h e r than those of A v i c e l . R e g r e s s i o n a n a l y s i s showed t h a t the i n c r e a s e i n F v a l u e w i t h Pmax was s i g n i f i c a n t a t the 5% l e v e l . Examination of the change i n F w i t h Pmax from F i g . 21 showed t h a t F i s not r e p r e s e n t a t i v e of s t r e s s r e l a x a t i o n of the t a b l e t s . I f F was a measure of s t r e s s r e l a x a t i o n , the F v a l u e s f o r A v i c e l would be much h i g h e r than those of Emcompress and spray d r i e d l a c t o s e s i n c e A v i c e l has a much g r e a t e r degree o f bonding than the other m a t e r i a l s (Mashadi and Newton, 1987). The F v a l u e s c o u l d be a f f e c t e d by the tendency of the m a t e r i a l t o r e c o v e r d u r i n g D. As d i s c u s s e d i n s e c t i o n 3.3.2.1 A v i c e l r e c o v e r s more upon decompression than Emcompress and spray d r i e d l a c t o s e . Thus d u r i n g D, A v i c e l t a b l e t s have a h i g h e r tendency t o r e c o v e r and e x e r t F (EN) 16 10 o /VICEL r 2 = 0.761 N = 54 cPfF C P , • 1 • • • o CD • 'ft a a" 20 40 60 80 100 120 140 160 180 200 PEAE PRESSURE (MPa) F (EN) 16 10 z EMCOMPKESS r2 = 0.946 N = 31 20 40 60 80 100 120 140 160 180 200 PEAE PRESSURE (MPa) F (EN) 16 10 +• &DJ.ACT06E r z = 0.851 N = 86 ++• **-4-4-4-+ 4* 4-* * t 4- t 4 ^ 4 . A t 4 . + + 4t + + 4- < 4- 4. r 4. 4- + 4. 4 - 4 - 4 -* 4* 20 40 60 80 100 120 140 160 180 200 PEAE PRESSURE (MPa) Flo 21. Change In F with Peak Pressure 73 p r e s s u r e on the upper punch. T h e r e f o r e the f o r c e e x e r t e d on the upper punch d u r i n g D does not drop as much as f o r Emcompress and spray d r i e d l a c t o s e . Thus a t h i g h e r Pmax F d i s p l a y s an i n v e r s e r e l a t i o n s h i p w i t h the r e c o v e r y of the m a t e r i a l . 3.3 .4.2 Decrease i n t h e F o r c e D u r i n g Punch T r a v e l Beyond Pmax o f Acetaminophen USP and Acetaminophen DC The F f o r both the acetaminophen USP and acetaminophen DC t a b l e t s i n c r e a s e d from 2 t o about 5.5 kN a t 20-80 MPa ( F i g . 22). Acetaminophen DC had s l i g h t l y h i g h e r v a l u e s o f F i n t h a t range, but beyond about 80 MPa the F v a l u e s f o r acetaminophen USP dropped and l e v e l l e d o f f a t about 4 kN, w h i l e those f o r acetaminophen DC con t i n u e d t o i n c r e a s e t o 10-12 kN. The i n c r e a s e i n F wit h Pmax was s i g n i f i c a n t f o r both m a t e r i a l s . The F v a l u e s f o r acetaminophen DC were s i g n i f i c a n t l y h i g h e r than those of acetaminophen USP above 80 MPa. The d i f f e r e n c e i n the F v a l u e s of the two m a t e r i a l s c o u l d a g a i n be r e l a t e d t o d i f f e r e n c e s i n r e c o v e r y ( F i g . 18) . The acetaminophen DC gran u l e s appear t o flow and do not r e c o v e r as much as the acetaminophen USP c r y s t a l s . I t i s apparent t h a t F i s a complex f u n c t i o n o f deforma t i o n and r e c o v e r y and i s t h e r e f o r e not l i k e l y t o be a u s e f u l parameter f o r s t u d y i n g powder compaction behavior. F(KN) 16 £ Aaatamlnophan USP r 2 = 0.084 N = 51 * **** fe* 20 40 00 60 100 120 140 160 160 200 PEAK PRESSURE (MPa) F (KN) 16 10 6 Aootamlnophon DO r 2 = 0.894 N = 63 • . ft. » • ft * 20 40 00 80 100 120 140 100 180 200 PEAK PRE83URE (MPa) Fig 22. Change In F with Peak Pressure 75 3.3.5 Punch T r a v e l Time Beyond Pmax Punch t r a v e l time beyond Pmax (PTT) i s the d i f f e r e n c e between the time o f maximum f o r c e and the time t o reach maximum displacement ( F i g 5a) . During the PTT t h e r e i s an i n c r e a s e i n the displacement and a decrease i n the f o r c e . Hence the experimental c o n d i t i o n s do not comply w i t h the requirements e i t h e r f o r s t r e s s r e l a x a t i o n ( s e c t i o n 1.2) or creep ( s e c t i o n 1.3). 3.3.5.1 Punch T r a v e l Time f o r D i r e c t l y Compressible Powders The PTT of the d i r e c t l y compressible powders decreased w i t h the i n c r e a s e i n Pmax ( F i g . 23) . A v i c e l showed the l o n g e s t PTT, a t a l l Pmax, ran g i n g from 12 msec a t low t o 4 msec a t h i g h Pmax Tabl e 6. Emcompress and spray d r i e d l a c t o s e d i s p l a y e d s i m i l a r PTTs a t h i g h e r Pmax (about 4 msec), but a t lower Pmax Emcompress had s l i g h t l y lower PTTs. The t r e n d i n change of PTT wit h Pmax f o r these m a t e r i a l s i s s i m i l a r t o the changes i n peak o f f s e t time r e p o r t e d by Dwivedi, Oates and M i t c h e l l (1991) on the Bet a p r e s s . Peak o f f s e t time ( t Q f f ) i s a measure of s t r e s s r e l a x a t i o n where t 0 f f i s d e f i n e d as the time d i f f e r e n c e between the time of peak f o r c e and the time t o re a c h the p o s i t i o n a t which the punches are a l i g n e d w i t h the c e n t e r s of the upper and lower compression r o l l s . Decreases i n PTT were s i g n i f i c a n t a t the 5% l e v e l f o r a l l t h r e e m a t e r i a l s . The PTTs of A v i c e l were s i g n i f i c a n t l y h i g h e r than those of Emcompress but not of those of spray 14 Punch Travel Tlma (maeo) 2 _ 0.842 54 O 20 40 00 80 100 120 140 WO 160 200 PEAK PRESSURE (MPa) Punch Travel Tlma (masc) & EMOOMPRESS r 2 = 0.859 N = 31 O 20 40 00 80 100 120 140 WO 180 200 PEAK PRESSURE (MPa) Punch Travel Time (msec) 4- anxAcrrosE .7 N = 86 r2 = 0 47 '** o O 20 40 00 80 100 120 140 WO 180 200 PEAK PRE8SURE (MPa) G Fig. 23. Change In Punch Travel Time with Peak Pressure T a b l e 6. PTT o f the F i v e M a t e r i a l s T e s t e d M a t e r i a l Pmax PTT (MPa) (msec) A v i c e l 37 12 148 6 Emcom 37 9 148 5 L a c t o s e 37 9 148 6 Ac. DC 37 10 148 6 Ac. USP 37 6 148 3 78 d r i e d l a c t o s e . A v i c e l was expected t o have h i g h e r PTT v a l u e s than s p r a y - d r i e d l a c t o s e s i n c e i t i s a much more d u c t i l e m a t e r i a l . However i t appears t h a t the exte n t of deforma t i o n of the p a r t i c l e s of these two m a t e r i a l s under l o a d i s the same. I t i s e v i d e n t l y the nature o f the bonding between the p a r t i c l e s t h a t causes the d i f f e r e n c e s i n t a b l e t s t r e n g t h d i s c u s s e d below. 3.3.5.2 Punch T r a v e l Time f o r Acetaminophen USP and Acetaminophen DC The PTT f o r the acetaminophen USP and acetaminophen DC a l s o decreased s i g n i f i c a n t l y w i t h the i n c r e a s e i n Pmax ( F i g . 24). Acetaminophen USP e x h i b i t e d a s i g n i f i c a n t l y lower PTT than t h a t o f Acetaminophen DC a t a l l Pmax. The PTTs ranged from 7 t o 0 msec f o r Acetaminophen USP and 11 t o 5 msec f o r acetaminophen DC r e s p e c t i v e l y (Table 6 ) . Examination o f the PTT v a l u e s suggests t h a t PTT may indeed be a measure of the flow of a m a t e r i a l under l o a d . Acetaminophen USP i s a very b r i t t l e c r y s t a l l i n e m a t e r i a l t h a t does not form coherent compacts, e s p e c i a l l y a t h i g h e r Pmax. Acetaminophen DC gran u l e s on the oth e r hand do form compacts. The c r y s t a l s a l s o g r e a t l y r e c o v e r upon decompression whereas the gran u l e s do not (see s e c t i o n 3.3.5). T h e r e f o r e i t appears t h a t the c r y s t a l s f r a c t u r e under p r e s s u r e and f o l l o w i n g Pmax they r e c o v e r without bonding. T h e r e f o r e PTT i s s h o r t s i n c e the c r y s t a l s a re not deforming and the punch can not t r a v e l f u r t h e r . Punoh Travel Time (mseo) 14 12 X Aaotamlnophen USP r 2 = 0.889 10 - N = 51 e -e XX X X 4 X x x x x X 2 0 1 1 1 « * x x x * x •x 40 00 80 100 120 140 100 180 200 PEAK PRESSURE (MPa) a Punoh Travel Time (rraeo) A Aaatamlnaphan D O r 2 = 0.740 N = 63 4 . 20 40 00 80 100 120 140 100 180 200 PEAK PRESSURE (MPa) b Fig. 24. Change In Punch Travel Time with Peak Pressure 80 3.3.6 Force of F a i l u r e and T a b l e t Deformation T a b l e t s w i l l f r a c t u r e i f they are s t r e s s e d above a c r i t i c a l l e v e l . The r e q u i r e d s t r e s s f o r d i a m e t r a l f r a c t u r e and c r a c k p r o p a g a t i o n i n the t a b l e t i s dependent on the m a t e r i a l . The magnitude of t h i s s t r e s s p r o v i d e s a measure of the s t r e n g t h of the bonds t h a t are formed between the p a r t i c l e s . The mechanical s t r e n g t h of t a b l e t s i s o f t e n determined by the d i a m e t r a l compression t e s t . The change i n the f o r c e of f a i l u r e of a l l the t a b l e t s w i t h the i n c r e a s e i n Pmax i s shown i n F i g . 25a. (acetaminophen USP r a r e l y formed t a b l e t s t h a t s u r v i v e d e j e c t i o n ) . I t was e v i d e n t t h a t A v i c e l forms much harder t a b l e t s than the o t h e r m a t e r i a l s . Thus w h i l e f o r c e of f a i l u r e ranged from 200 t o 800 N f o r A v i c e l , the range f o r t h e o t h e r m a t e r i a l s was 50 t o 100 N, 20 t o 120 N and 50 t o 200 N Emcompress, spray d r i e d l a c t o s e and acetaminophen DC r e s p e c t i v e l y . The i n c r e a s e i n f o r c e of f a i l u r e w i t h Pmax was found t o be s i g n i f i c a n t f o r a l l f o u r m a t e r i a l s a t the 5% l e v e l . A l s o the f o r c e of f a i l u r e v a l u e s f o r a l l f o u r were s i g n i f i c a n t l y d i f f e r e n t from each ot h e r , w i t h A v i c e l forming the s t r o n g e s t t a b l e t s , f o l l o w e d by acetaminophen DC, Emcompress and spray d r i e d l a c t o s e . The change i n the deformation of the t a b l e t s a t f a i l u r e (DF) i s shown i n F i g . 25b. The DF of the A v i c e l , Emcompress, spray d r i e d l a c t o s e and acetaminophen DC d i d Force of Failure (N) 8001 ' men 6 0 0 ' r 2 = 0.958 N = 54 400 -200 -| I 1 I I I 1 I I I I L _ 0 20 40 60 80 100 120 140 160 180 200 Peak Pressure (MPa) a 250 200 ISO 100 SO Force of Failure (N) • S.aiACTOSE r 2 = 0.951 N = 86 20 40 60 80 100 120 140 160 180 200 Peak Pressure (MPa) C Force of Failure (N) 2501 200 -150 EMCOMPRESS r ' = 0.900 N = 31 100 50 20 40 60 80 100 120 140 Peat Pressure (MPa) 160 180 200 250 200 150 100 50 0 Force of Failure (N) ACETAMINOPHEN DC r * = 0.922 N = 63 20 40 60 80 100 120 140 160 180 200 Peak Pressure (MPa) Fig. 25. Change In Force of Failure with Peak Pressure 03 Tablet Deformation (om) 100 160 Peak Pressure (MPa) 280 Tablet Deformation (om) 60 100 160 Peak Pressure (MPa) 200 260 o 0.01 0.008 -0.006 -0.004 0X102 -Tablet Deformation (om) WO 160 Peak Pressure (MPa) 260 Tablet Deformation (om) 0.02 0.016 -0.01 -0.006 -100 WO Peak Pressure (MPa) 260 Fig. 25b Variation of tablet deformation with peak pressure 00 to 83 not change wi t h Pmax (the s l i g h t i n c r e a s e i n the DF of A v i c e l i s not s t a t i s t i c a l l y s i g n i f i c a n t ) . T h i s suggests t h a t the exte n t of d i a m e t r a l deformation o f these compacts i s independent of t h e i r d i a m e t r a l s t r e n g t h . These r e s u l t s agree w i t h the r e s u l t s o b t a i n e d by Oates, M i t c h e l l and Wong (1990) u s i n g t a b l e t s compressed on a Betapress. The above o b s e r v a t i o n s can not be e x p l a i n e d c l e a r l y s i n c e s t r o n g e r compacts must possess a g r e a t e r number of bonds and thus might be expected t o deform t o a l a r g e r e x t e n t b e f o r e f a i l u r e than weaker compacts. F u r t h e r i n v e s t i g a t i o n i n t o the nature of t a b l e t deformation and cr a c k p r o p a g a t i o n i s r e q u i r e d . 84 3.4 E f f e c t o f Compression Rate The e f f e c t of changes i n ACR on the compaction parameters was examined. For each m a t e r i a l the compression r a t e s were v a r i e d a t f i x e d Pmax of 37 and 148 MPa. For each m a t e r i a l t h e r e were l i m i t s t o the v a r i a t i o n of ACR p o s s i b l e on t h e h y d r a u l i c p r e s s . Thus the v a r i a t i o n of D, F, PTT, ER and f o r c e of f a i l u r e were o b t a i n e d a t the lowest and h i g h e s t compression r a t e s p o s s i b l e . The h i g h e s t ACRs were o b t a i n e d f o r acetaminophen (the most b r i t t l e m a t e r i a l ) w h i l e the lowest were obtained f o r A v i c e l (the most d u c t i l e m a t e r i a l ) . B r i t t l e m a t e r i a l s , such as acetaminophen, show f a s t e r r a t e s of f o r c e development i n the upper punch s i n c e d u r i n g compression the f o r c e i s not u t i l i z e d f o r p l a s t i c f low or bond for m a t i o n . However, d u r i n g the compression of d u c t i l e m a t e r i a l s , such as A v i c e l , the f o r c e i s p a r t l y used f o r p l a s t i c deformation and bond f o r m a t i o n r e s u l t i n g i n slower compression r a t e s . The range o f the average compression r a t e s , a t 148 MPa, f o r each of t h e f i v e d i f f e r e n t m a t e r i a l s i s shown i n T a b l e 7. These s e r i e s of experiments were c a r r i e d out t o i s o l a t e the e f f e c t of ACR from t h a t o f the Pmax on D, F, PTT, ER and f o r c e of f a i l u r e . By measuring the above parameters a t d i f f e r e n t ACR and a f i x e d Pmax we were a b l e t o determine whether the v a r i a t i o n of compaction parameters observed i n the l a s t s e r i e s of experiments were due t o Pmax or ACR or both. I s o l a t i n g the f a c t o r s t h a t a f f e c t the above 85 T a b l e 7 . Range of the ACR a t 37 and 148 MPa M a t e r i a l Pmax 148 MPa 37 MPa Low High Low High (kN/sec) (kN/sec) (kN/sec) (kN/sec) A v i c e l 110 200 35 60 Emcom. 150 410 75 135 L a c t o s e 240 540 60 210 Ac. USP 450 710 110 340 Ac. DC 200 420 40 150 86 parameters c o u l d be u s e f u l i n s o l v i n g some of the t a b l e t m anufacturing problems (eg. by m a n i p u l a t i n g the p r e s s u r e or the speed of compaction). 3.4.1 V a r i a t i o n o f ER w i t h ACR The e f f e c t of ACR on the ER of the A v i c e l , Emcompress, spray d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC t a b l e t s a t 37 and 148 MPa i s shown i n F i g s . 26, 27, 28, 29 and 30 r e s p e c t i v e l y . The ER of A v i c e l t a b l e t s s i g n i f i c a n t l y i n c r e a s e d w i t h i n c r e a s e i n ACR a t 37 MPa but not a t 148 MPa ( F i g . 26). To understand the v a r i a t i o n of ER wit h ACR a t 148 MPa, we must r e f e r t o the d e f e n i t i o n and d e s c r i p t i o n o f Py ( s e c t i o n 3.3.1). For A v i c e l a t Pmax below the Py (49 MPa, Tabl e 3) the e x t e n t o f p a r t i c l e deformation i s minimal and an i n c r e a s e i n ACR does hot g i v e the p a r t i c l e s s u f f i c i e n t time t o flow. S i n c e the p a r t i c l e s have had l e s s time t o flow the t a b l e t s w i l l r e c o v e r more d u r i n g and a f t e r s t r e s s r e l i e f . A t Pmax above Py (148 MPa i s about 3 times the Py of A v i c e l ) the p a r t i c l e s undergo e x t e n s i v e p l a s t i c deformation a t a l l compression r a t e s and ER of t h e compact i s independent o f ACR. The ER of the Emcompress, s p r a y - d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC t a b l e t s d i d not s i g n i f i c a n t l y change wi t h the i n c r e a s e i n ACR a t 37 MPa but i t decreased s i g n i f i c a n t l y f o r a l l f o u r m a t e r i a l s a t 148 MPa. At p r e s s u r e s below the P y ( 431, 149 and 109 MPa, Avlcel-PH102 37 MPa Peak Pressure Tablet Recovery (uM) 300 35 37 39 41 43 45 47 49 51 53 55 57 59 Average Compression Rate (KN/sec) Avicel PH-102 148 MPa Peak Pressure Tablet Recovery (uM) 300 260 200 160 100 4- 4-4-* 4-4-+• 4-+ 4- + 4-4- 4- 4- ^ 4 - 4 - 4 -+ 4- 4-4- 4 " 4-4-4" i i i i i i i i 110 120 130 140 150 160 170 180 190 200 Average Compression Rate (KN/sec) b Fig. 26. Variation of Tablet Recovery with Average Compression Rate EMCOMPRESS 37 MPa Peak Pressure Tablet Recovery (uM) 75 80 85 90 95 100 105 110 115 120 125 130 135 Average Compression Rate (KN/sec) EMCOMPRESS 148 MPa Peak Pressure 140 120 100 80 80 40 20 0 Tablet Recovery (uM) _ - 4- 4- 4-4- 4-4-4-4-4- 4--i i i i i i i 150 170 190 210 230 250 270 290 310 330 350 370 390 410 Average Compression Rate (KN/sec) Fig. 27. Variation of Tablet Recovery with Average Compression Rate SPRAY DRIED LACTOSE 37 MPa Peak Pressure Tablet Recovery (uM) 230 -180 130 -60 80 100 120 140 160 180 200 Average Compression Rate (KN/sec) SPRAY DRIED LACTOSE 148 MPa Peak Pressure 250 200 150 100 H 50 Tablet Recovery (uM) + 4-_ i i i i i i [ i i i i i i i i _ 240 260 280 300 320 340 360 380 400 420 440 480 480 500 520 540 Average Compression Rate (KN/sec) Fig. 28. Variation of Tablet Recovery with Average Compression Rate Acetaminophen USP 37 MPa Peak Pressure Tablet Recovery (uM) 200 i 150 100 50 -+ 4- +• 4-4-4-_i i i i i i i i i i i_ 0 110 130 150 170 190 210 230 250 270 290 310 330 Average Compression Rate (KN/sec) a Acetaminophen USP 148 MPa Peak Pressure Tablet Recovery (uM) 200 150 100 -450 470 490 510 530 550 570 590 610 630 650 670 690 710 Average Compression Rate (KN/sec) b Fig. 29. Variation of Tablet Recovery with Average Compression Rate Acetaminophen DC 37 MPa Peak: Pressure Tablet Recovery (uM) 140 -40 50 60 70 80 90 100 110 120 130 140 150 Average Compression Rate (KN/sec) Acelamlnophen/3%PVP 148 MPa Peak Pressure Tablet Recovery (uM) 200 220 240 260 280 300 320 340 360 380 400 420 Average Compression Rate (KN/sec) b Fig. 30. Variation of Tablet Recovery with. Peak Pressure 92 r e s p e c t i v e l y , T a b l e 2) most of the p a r t i c l e s e l a s t i c a l l y deform without f r a c t u r e , and t h e i r ER i s e s s e n t i a l l y independent of the ACR. At Pmax c l o s e r t o Py, the i n c r e a s e i n ACR might cause more p a r t i c l e s t o f r a c t u r e and hence ER dec r e a s e s . 3 .4.2 v a r i a t i o n o f D w i t h ACR The e f f e c t of ACR on D of the f i v e m a t e r i a l s examined a t 37 and 148 MPa Pmax i s shown i n F i g . 31-35. ACR had no s i g n i f i c a n t e f f e c t on the D of A v i c e l a t e i t h e r Pmax ( F i g . 31). For Emcompress and spray d r i e d l a c t o s e , D s i g n i f i c a n t l y i n c r e a s e d w i t h the i n c r e a s e i n ACR a t both Pmax ( F i g . 32, 33). ACR d i d not s i g n i f i c a n t l y change the D of acetaminophen USP wh i l e i t s i g n i f i c a n t l y i n c r e a s e d the D of acetaminophen DC a t 37 MPa ( F i g . 34, 35). At 148 MPa ACR had no s i g n i f i c a n t e f f e c t on the D of e i t h e r m a t e r i a l . These r e s u l t s suggest t h a t i n d u c t i l e m a t e r i a l s , D depends on Pmax but not on the r a t e a t which t h a t Pmax was achiev e d , w h i l e f o r b r i t t l e m a t e r i a l s D depends on the r a t e as w e l l as Pmax. These o b s e r v a t i o n s are i n c o n t r a s t t o those o f Ho and Jones (1988) who r e p o r t e d an i n c r e a s e i n the D of A v i c e l w i t h the i n c r e a s e i n ACR. However t h e i r o b s e r v a t i o n s are s i m i l a r t o t h i s work i n the case of Emcompress and spray d r i e d l a c t o s e . 93 D (uM) 200 150 -100 -AVICEL PH-102 148 MPa Peak Pressure 120 130 140 150 160 170 180 190 200 Average Compression Rate (KN/sec) b Fig. 31. Variation of D with Average Compression Rate WICEL PH-102 37 MPa Peak Pressure D (uM) 200 -150 - * * * * % 100 ** * * *** * *• 50 A 1 1 1 1 1 1 l 1 1 1 ! 1 35 37 39 41 43 45 47 49 61 63 65 67 59 Average Compression Rate (KN/sec) a EMCOMPRESS 37 MPa Peak Pressure D (uM) 120 i 76 80 85 90 95 100 105 110 115 120 125 130 135 Average Compression Rate (KN/sec) EMCOMPRESS 148 MPa Peak Pressure D (uM) 120 | 150 170 190 210 230 250 270 290 310 330 350 370 390 410 Average Compression Rate (KN/sec) Fig. 32. Variation of D with Average Compression Rate SPRAY DRIED LACTOSE 37 MPa Peak Pressure D (uM) 140 120 100 80 60 40 20 --* * *• . * *• * t 1 1 1 1 1 1 1 1 I 0 145 150 155 160 165 170 175 180 185 190 195 200 Average Compression Rate (KN/sec) SPRAY DRIED LACTOSE 148 MPa Peak Pressure D (uM) 140 -120 100 80 * * 60 -* *** * * 40 -20 0 * i i * I 1 I I I I i I I i i I I 240 280 280 300 320 340 360 380 400 420 440 460 480 500 520 540 Average Compression Rate (KN/sec) b Fig. 33. Variation of D with Average Compression Rate Acetaminophen USP 37 MPa Peak Pressure D (uM) 100 110 130 150 170 190 210 230 250 270 290 310 330 Average Compression Rate (KN/sec) a , Acetaminophen USP 148 MPa Peak Pressure D (uM) 100 i 80 -_ i i i i i i 450 470 490 510 530 550 570 590 610 630 650 670 690 710 Average Compression Rate (KN/sec) b Fig. 34. Variation of D with Average Compression Rate Acetaminophen DC 37 MPa Peak Pressure 40 50 60 70 80 90 100 110 120 130 140 150 Average Compression Rate (KN/sec) Acetaminophen DC 148 MPa Peak Pressure D (UM) 140 120 100 80 60 40 * * * 20 n 1 l i i i i i 200 220 240 260 280 300 320 340 360 380 400 420 Average Compression Rate (KN/sec) b Fig. 35. Variation of D wtlh Average Compression Rate 98 3 . 4.3 V a r i a t i o n o f F w i t h ACR The v a r i a t i o n o f F wit h ACR d u r i n g the compaction of A v i c e l , Emcompress, spray d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC a t 37 and 148 MPa i s shown i n F i g . 3 6-40. ACR d i d not s i g n i f i c a n t l y a f f e c t t he F of A v i c e l , acetaminophen USP and acetaminophen DC ( F i g . 36, 39 and 40 r e s p e c t i v e l y ) a t e i t h e r Pmax wh i l e i t s i g n i f i c a n t l y i n c r e a s e d the F of Emcompress and spray d r i e d l a c t o s e a t 148 MPa ( F i g . 37 and 38 r e s p e c t i v e l y ) . T h e r e f o r e under normal t a b l e t t i n g c o n d i t i o n s (Pmax from 100 t o 200 MPa) the F of A v i c e l , acetaminophen USP and acetaminophen DC, appears t o depend on Pmax w h i l e f o r Emcompress and s p r a y - d r i e d l a c t o s e F appear t o depend on both Pmax and ACR. 3 . 4 . 4 V a r i a t i o n o f PTT w i t h ACR The v a r i a t i o n of PTT wit h ACR i s shown i n F i g . 41 t o 45. R e g r e s s i o n a n a l y s i s showed t h a t ACR had no s i g n i f i c a n t e f f e c t on the PTT of A v i c e l ( F i g . 41a, 41b), acetaminophen USP ( F i g . 44a, 44b) and acetaminophen DC ( F i g . 45a, 45b) wh i l e i t s i g n i f i c a n t l y i n c r e a s e d the PTT of Emcompress a t both 37 and 148 MPa ( F i g . 42a, 42b) . For s p r a y - d r i e d l a c t o s e , ACR had no s i g n i f i c a n t e f f e c t on PTT a t 37 MPa but caused a s i g n i f i c a n t i n c r e a s e a t 148 MPa. I t appears t h a t f o r A v i c e l , acetaminophen USP and acetaminophen DC, PTT i s a f f e c t e d by the p r e s s u r e e x e r t e d on the p a r t i c l e s and not the r a t e a t which the p a r t i c l e s AVICEL PH-102 37 MPa Peak Pressure F (KN) 14 35 37 39 41 43 45 47 49 51 53 55 57 59 Average Compression Rate (KN/sec) AVICEL PH-102 148 MPa Peak Pressure F (KN) 14 130 140 150 160 170 180 190 200 Average Compression Rate (KN/sec) b Fig. 36. Variation of F with Average Compression Rate EMCOMPRESS 37 MPa Peak Pressure F (KN) 75 80 85 90 95 100 105 110 115 120 125 130 135 Average Compression Rate (KN/sec) EMCOMPRESS 148 MPa Peak Pressure F (KN) 150 170 190 210 230 250 270 290 310 330 350 370 390 410 Average Compression Rate (KN/sec) Fig. 37. Variation of F with Average Compression Rate SPRAY DRIED LACTOSE 37 MPa Peak Pressure F (KN) 145 150 155 160 165 170 175 180 185 190 195 200 Average Compression Rate (KN/sec) SPRAY DRIED LACTOSE 148 MPa Peak Pressure (KN/sec) F (KN) 12 10 8 6 4 2 0 240 260 280 300 320 340 360 380 400 420 440 460 480 600 520 640 Average Compression Rate (KN/sec) -• • • ° % OJ • • • • n -• — • D < I i i • Fig. 38. Variation of F with Average Compression Rate Acetaminophen USP 37 MPa Peak Pressure 110 130 150 170 190 210 230 250 270 290 310 330 Average Compression Rate (KN/sec) Acetaminophen USP 148 Peak Pressure F (KN) 460 470 490 510 530 550 570 690 610 630 650 670 690 710 Average Compression Rate (KN/sec) Fig. 39. Variation of F with Average Compression Rate Acetaminophen DC 37 MPa Peak Pressure F (KN) 14 40 50 60 70 80 00 100 110 120 130 140 150 Average Compression Rate (KN/sec) F (KN) 14 Acetaminophen DC 148 MPa Peak Pressare 200 220 240 260 280 300 320 340 360 380 400 420 Average Compression Rate (KN/sec) b Fig. 40. Variation of F with Average Compression Rale Avicel PH-102 37 MPa Peak Pressure Punch Travel Time (msec) 15 10 * * * * * * * * * * * 5 i t i i i i i • i i i i 30 32 34 36 38 40 42 44 46 43 50 52 54 56 58 60 Average Compression Rate (KN/sec) a Avicel PH-102 148 MPa Peak Pressure Punch Travel Time (msec) 15 10 0 -1 t * 1 1 1 ** * 1 1 1 1 1 1 70 80 90 100 110 120 130 140 150 160 170 180 190 200 Average Compression Rate (KN/sec) b Fig. 41. Variation of PTT with Average Compression Rate EMCOMPRESS 37 MPa Peak Pressure 12 10 8 6 * * *• * * 1 1 1 l 1 1 1 1 1 76 80 85 90 95 100 105 110 115 120 125 130 135 140 Average Compression Rate (KN/sec) EMCOMPRESS 148 MPa Peak Pressure Punch Travel Time (msec) 12 150 170 190 210 230 250 270 290 310 330 350 370 390 410 Average Compression Rate (KN/sec) b Fig. 42. Variation of PTT with Average Compression Rate SPRAY DRIED LACTOSE 37 MPa Peak Pressure Punch Travel Time (msec) 12 145 150 155 160 165 170 175 180 185 190 195 200 Average Compression Rate (KN/sec) SPRAY DRIED LACTOSE 148 MPa Peak Pressure Punch Travel Time (msec) 180 230 280 330 380 430 480 530 580 630 Average Compression Rate (KN/sec) Fig. 43. Variation of PTT with Average Compression Rate Acetaminophen USP 37 MPa Peak Pressure Punch Travel Time (msec) 10 100 120 140 160 180 200 220 240 260 280 300 320 340 Average Compression Rale (KN/sec) a Acetaminophen USP 148 MPa Peak Pressure Punch Travel Time (msec) 450 470 490 510 630 550 570 590 610 630 650 670 690 710 Average Compression Rate (KN/sec) Fig. 44. Variation of PTT with Average Compression Rate Acetaminophen DC 37 MPa Peak Pressure Punch. Travel Time (msec) 14 45 55 65 ' 75 85 95 105 115 125 135 145 Average Compression Rale (KN/sec) Acetaminophen DC 148 MPa Peak Pressure Punch Travel Time (msec) 14 2C0 220 240 260 280 300 320 340 360 380 400 420 Average Compression Rale (KN/sec) b Fig. 45. Variation of PTT with Average Compression Rate 109 deform. T h i s might be due t o the r e l a t i v e l y low y i e l d p r e s s u r e s o f these m a t e r i a l s (Table 2) . The p a r t i c l e s i n each case a re e i t h e r deformed or f r a c t u r e d e x t e n s i v e l y ( e s p e c i a l l y a t 148 MPa) by the time Pmax i s ach i e v e d and the r a t e a t which the deformation or f r a c t u r e occurs a f f e c t s n e i t h e r the PTT nor the D f o r e i t h e r m a t e r i a l . However f o r Emcompress and s p r a y - d r i e d l a c t o s e , ( b r i t t l e m a t e r i a l s w i t h r e l a t i v e l y h i g h y i e l d p r e s s u r e s , T a b l e 2) a t normal t a b l e t t i n g Pmax, the powder undergoes p a r t i c l e rearrangement but l e s s e x t e n s i v e deformation than p l a s t i c m a t e r i a l s . As the ACR i s i n c r e a s e d the p a r t i c l e s have had l e s s time t o rea r r a n g e and a t Pmax the p a r t i c l e s can s t i l l r e a r r a n g e b e f o r e r e c o v e r y . T h i s causes an i n c r e a s e i n the PTT. 3.4.5 V a r i a t i o n o f Force o f F a i l u r e and DF w i t h ACR The f o r c e o f f a i l u r e of the t a b l e t s o f A v i c e l , Emcompress, s p r a y - d r i e d l a c t o s e and acetaminophen DC ( F i g s . 46, 47, 48 and 49 r e s p e c t i v e l y ) was not s i g n i f i c a n t l y a f f e c t e d by ACR a t e i t h e r p r e s s u r e . These o b s e r v a t i o n s suggest, i n g e n e r a l , t h a t the s t r e n g t h of the bonds formed between the p a r t i c l e s depend o n l y on the p r e s s u r e , and not on the r a t e a t which the p a r t i c l e s u r f a c e s a re brought i n t o c o n t a c t . Avicel PH-102 37 MPa Peak Pressure Force of Failure (N) I I I I I I I I ' 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 Average Compression Rate (KN/sec) a Avicel PH-102 148 MPa Peak Pressure Force of Failure (N) 800 600 400 % x 0 o 0 0 0 0 0 0 0 200 0 • i i 1 1 1 1 1 100 110 120 130 140 150 160 170 180 190 200 Average Compression Rate (KN/sec) b Fig. 46. Variation of FF with Average Compression Rale ouu 600 400 200 _i i i i_ EMCOMPRESS 37 MPa Peak Pressure 120 100 Force of Failure (N) 75 80 85 90 95 100 105 U0 115 120 125 Average Compression Rate (KN/sec) EMCOMPRESS 148 MPa Peak Pressure 120 Force of Failure (N) 100 -160 180 200 220 240 260 280 300 320 340 360 380 400 Average Compression Rate (KN/sec) Fig. 47. Variation of FF with Average Compression Rale SPRAY DRIED LACTOSE 37 MPs Peak Pressure Force of Failure (N) 100 i 80 80 40 20 0 00 0 0 I t_ 0 <> 0 145 150 155 160 165 170 175 180 185 190 195 200 Average Compression Rate (KN/sec) SPRAY DRIED LACTOSE 148 MPa Peak Pressure Force of Failure (N) 100 40 -20 -180 230 280 330 380 430 480 630 680 630 Average Compression Rate (KN/sec) b Fig. 48. Variation of FF with Average Compression Rate Acetaminophen DC 37 MPa Peak Pressure Force of Failure (N) I.4-_1 I I 1 I I I I I-45 55 65 75 85 95 105 115 125 135 145 Average Compression Rate (KN/sec) a Acetamlnophen/3%PVP 148 MPa Peak Pressure Force of Failure (N) 150 -100 -250 270 290 310 330 350 370 390 410 Average Compression Rate (KN/sec) b Fig. 49. Variation of FF with Average Compression Rate 1 3.4.7 Summary The r e s u l t s of s e c t i o n 3.3 are summarised i n Ta b l e s 8 and 9. The m a t e r i a l s s t u d i e d c o u l d be d i v i d e d i n t o 3 groups: 1. A v i c e l which deforms predominantly by p l a s t i c flow 2. Emcompress and acetaminophen which deform predominantly by b r i t t l e f r a c t u r e 3. Spray d r i e d l a c t o s e which appears t o deform by both mechanisms For each' m a t e r i a l t y p i c a l v a l u e s of ER, D, F, PTT, f o r c e o f f a i l u r e and DF are shown a t t h r e e Pmax v a l u e s . I t has been suggested (Jones, 1977; E j i o f o r e t a l . , 1986; Rees and Rue, 1978) t h a t the g r e a t e r the p l a s t i c i t y of a m a t e r i a l the g r e a t e r the number of bonds formed between i t s p a r t i c l e s d u r i n g compaction. The f o r c e of f a i l u r e v a l u e s suggest t h a t A v i c e l has the s t r o n g e s t bonds f o l l o w e d by acetaminophen DC, spray d r i e d l a c t o s e and Emcompress. A r e l a t i o n s h i p between t a b l e t ER (a measure of bond d i s r u p t i o n ) D and PTT (measures o f p l a s t i c flow) might p r o v i d e a c o r r e l a t i o n between these parameters and the t a b l e t t i n g b ehavior of m a t e r i a l s . A v i c e l , Emcompress, s p r a y - d r i e d l a c t o s e and acetaminophen DC produced coherent t a b l e t s w h i l e acetaminophen USP d i d not. A v i c e l d i s p l a y e d t h e l a r g e s t ER f o l l o w e d by acetaminophen USP, Emcompress, s p r a y - d r i e d l a c t o s e and acetaminophen DC. The parameters t h a t most c l e a r l y d i f f e r e n t i a t e between acetaminophen USP 115 T a b l e 8. Summary of the T y p i c a l R e s u l t s o f S e c t i o n 3 M a t e r i a l Pmax ER D F PTT MPa •um um kN msec 40 140 150 2.5 12 A v i c e l 120 175 60 4.5 7 200 200 20 5 5 40 75 75 2.5 8 Emcom. 120 85 50 5 6 200 100 20 9 4 40 60 120 2 11 L a c t o s e 120 85 75 9.5 7.5 200 95 40 12 4 40 130 60 2.5 6 Ac.USP 120 80 55 4 4 200 60 5 3 0.5 40 60 90 3 10 Ac. DC 120 50 55 8 8 200 50 10 11.5 5 T a b l e 9. Summary o f the T y p i c a l R e s u l t s o f S e c t i o n 3 M a t e r i a l Pmax Force of F a i l u r e DF MPa (N) (cm) 40 200 0. 026 A v i c e l 120 550 0.033 200 800 0.036 40 20 0.004 Emcom. 120 50 0.005 200 100 0.005 40 20 0. 006 Lac t o s e 120 60 0.007 200 120 0.007 40 Ac.USP 120 200 Ac. DC 40 120 200 50 120 200 0.012 0.013 0.011 116 and the oth e r m a t e r i a l s are D and PTT. The D and PTT of acetaminophen USP are s i g n i f i c a n t l y lower a t a g i v e n Pmax (the d i f f e r e n c e i n PTT i s e s p e c i a l l y e v i d e n t a t h i g h e r p r e s s u r e s ) . Based on the above o b s e r v a t i o n s , the f o l l o w i n g d e d u c t i o n s are made: 1. For p l a s t i c m a t e r i a l s such as A v i c e l , t h e r e i s a r e l a t i v e l y l o n g D and PTT d u r i n g which the p a r t i c l e s undergo a d d i t i o n a l deformation and bonding. The nature and number of bonds i n these m a t e r i a l s are such t h a t they are not r e a d i l y d i s r u p t e d by ER d u r i n g s t r e s s r e l i e f . The v a l u e s of DF and f o r c e o f f a i l u r e support the n o t i o n t h a t A v i c e l undergoes e x t e n s i v e p l a s t i c deformation and bonding. 2. B r i t t l e m a t e r i a l s such as Emcompress, t h a t form coherent t a b l e t s , have a s h o r t e r D and PTT than p l a s t i c m a t e r i a l s but the degree of ER i s i n s u f f i c i e n t t o break the i n t e r p a r t i c u l a t e bonds. 3. For s p r a y - d r i e d l a c t o s e , D and PTT are s i m i l a r t o A v i c e l but s i g n i f i c a n t l y l o n g e r than f o r b r i t t l e m a t e r i a l s . S p r a y - d r i e d l a c t o s e t a b l e t s r e c o v e r l e s s than A v i c e l , thus one might expect the t a b l e t s t o be s t r o n g e r . The g r e a t e r s t r e n g t h of A v i c e l t a b l e t s must be due t o d i f f e r e n c e s i n the nature and number of the i n t e r p a r t i c u l a t e bonds as i n d i c a t e d by the magnitude of f o r c e of f a i l u r e . 4. The t a b l e t t i n g b e h a v i o r of acetaminophen USP i s ve r y d i f f e r e n t from t h a t of acetaminophen DC. Acetaminophen USP powder has l a r g e r ER and s h o r t e r D and PTT than the DC 117 g r a n u l e s . Acetaminophen USP does not form coherent t a b l e t s because i t s b r i t t l e p a r t i c l e s do not form s t r o n g bonds and t h e i r ER i s s u f f i c i e n t t o break the t a b l e t a p a r t . Acetaminophen DC g r a n u l e s on the o t h e r hand undergo some degree of flow and bonding as shown by t h e i r f o r c e of f a i l u r e . 1 4. C o n c l u s i o n s 1. The h y d r a u l i c p r e s s w i t h the punch and d i e assembly can be used t o measure c e r t a i n compaction parameters of ph a r m a c e u t i c a l powders. These parameters are measured from the f o r c e and displacement-time p l o t s which are ob t a i n e d from the l o a d c e l l and LVDT r e s p e c t i v e l y . Punch t r a v e l d i s t a n c e beyond peak p r e s s u r e , D, punch t r a v e l time beyond peak p r e s s u r e , PTT, and e l a s t i c r e c o v e r y w i t h i n the d i e , ER, appear t o be u s e f u l parameters i n p r e d i c t i n g t a b l e t t i n g b e h a v i o r . The decrease i n the f o r c e d u r i n g punch t r a v e l beyond peak p r e s s u r e , F, i s l e s s u s e f u l due t o the complexity of the pro c e s s o c c u r i n g d u r i n g t h i s phase. a. ER alone does not appear t o be r e s p o n s i b l e f o r capping o r l a m i n a t i o n . A v i c e l had the l a r g e s t ER but i t a l s o had the l a r g e s t f o r c e of f a i l u r e and never showed any s i g n o f capping. Except a t the lowest Pmax, the ER of acetaminophen USP was comparable w i t h or l e s s than spray-d r i e d l a c t o s e o r Emcompress. Hence capping and l a m i n a t i o n cannot be due t o ER. b. D and PTT beyond Pmax c o u l d be used as measures of p l a s t i c flow of the m a t e r i a l under compression. M a t e r i a l s t h a t form coherent compacts have longer PTT (at a g i v e n pressure) than the ones t h a t do not. At normal t a b l e t t i n g p r e s s u r e s , acetaminophen USP which had s h o r t D and PTT produced the weakest t a b l e t s which always capped. 119 c. The presence of PVP i n acetaminophen DC decreased ER and i n c r e a s e d D and PTT compared w i t h acetaminophen USP. PVP improves p l a s t i c flow and i n c r e a s e s i n t e r p a r t i c u l a t e bonding and t a b l e t s t r e n g t h . 2. The v a r i o u s compaction parameters are a f f e c t e d more by changes i n Pmax than changes i n compaction r a t e . At normal t a b l e t t i n g p r e s s u r e s (100-200 MPa): i ) T a b l e t ER of A v i c e l depends on Pmax and i s independent o f ACR. T a b l e t ER of Emcompress, s p r a y - d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC depends on both the Pmax and ACR. i i ) The D of A v i c e l depends on the Pmax and not the ACR w h i l e D f o r Emcompress, s p r a y - d r i e d l a c t o s e , acetaminophen USP and acetaminophen DC depend on both. i i i ) The F of A v i c e l , acetaminophen USP and acetaminophen DC i s dependent on Pmax o n l y w h i l e F of Emcompress and s p r a y - d r i e d l a c t o s e i s dependent on both. i v ) The PTT of A v i c e l , acetaminophen USP and acetaminophen DC depends on Pmax and not ACR, w h i l e PTT of Emcompress and s p r a y - d r i e d l a c t o s e depends on both. v) The changes i n PTT and D of the m a t e r i a l s w i t h Pmax and ACR are s i m i l a r (except f o r s p r a y - d r i e d l a c t o s e a t 37 MPa). T h i s i s expected s i n c e PTT i s the time d u r i n g which the punch t r a v e l s the d i s t a n c e D. However PTT v a l u e s a re more r e l i a b l e s i n c e they are measured by an a c c u r a t e i n t e r n a l 120 c l o c k i n the computer as D i s measured from the LVDT which i s not as s e n s i t i v e . v i ) The f o r c e of f a i l u r e of A v i c e l , Emcompress, s p r a y - d r i e d l a c t o s e and acetaminophen DC i s dependent on the Pmax o n l y . 3. The compaction speed of the h y d r a u l i c p r e s s i s comparable t o t h a t of the Betapress. However due t o d i f f e r e n c e s i n the mechanism by which p r e s s u r e i s a p p l i e d t o the punches, the compression c y c l e s are d i f f e r e n t . T h i s i s p a r t i c u l a r l y t r u e f o r the decompression phase of the compression c y c l e . Hence the h y d r a u l i c p r e s s , as c u r r e n t l y designed, cannot s i m u l a t e the compression c y c l e on the B e t a p r e s s . 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