Physical Processes of Tableting

Transcription

1 Physicl Processes of Tbleting E. N. HIESTANDX, J. E. WELLS, C. B. PEOT, nd J. F. OCHS Abstrct Sher deformtion ws shown to occur during the decompression of lrge compcts mde by nonisosttic compression. Some mterils undergo frcture when these sher stresses re developed. Other mterils withstnd these stresses but frcture upon ejection when the stress concentrtions t the edge of the die re lrge. Filure to frcture seems to be relted to the bility to relieve stresses by plstic deformtion. A test ws devised to mesure this property, clled the brittle frcture propensity. Keyphrses Tblet formtion-frcture cused by sher stresses during decompression, effect of plstic deformtion Dosge formstblets, frcture cused by sher stresses during decompression, effect of plstic deformtion Plstic deformtion-effect on tblet frcture cused by sher stresses during decompression It is generlly ccepted tht compct formtion by pressure occurs becuse of forces cting t the res of true interprticle contct. However, the filure to obtin n intct compct from the compression-decompression cycle is bit more mysterious. A series of rguments nd some supporting evidence indicte tht the stresses induced by elstic rebound nd the ssocited deformtion processes during decompression re principlly responsible for the success or filure of compct formtion. This report presents experimentl results obtined by using severl, sometimes complementry procedures. These dt support the shift of emphsis to the decompression process. To present coherent, conceptul thesis, the discussion of ech individul experimentl procedure is not comprehensive. Insted, the emphsis is on the contribution of the results to the totl concept. Bits re tken from vrious on-going reserch investigtions. Cumultively, these studies, even though incomplete, contribute much to the evidence. Under high compression pressures, the powder prticles in compct re forced into intimte contct, nd extensive res of true contct between prticles re formed. Becuse the mgnitude of vn der Wls forces cross these interfces is dequte to provide strong bonds, one might expect ll mterils to form strong, intct compcts fter being subjected to compression. However, if too much energy is stored elsticlly when under compression, the elstic recovery during decompression my brek most of these bonds nd soft, crumbly compct will be formed. Excipients re dded to most phrmceuticl formultions to compenste for inherent, undesirble properties of the medicment. For exmple, it is possible to eliminte the storge of excess elstic energy during compression by mixing plstic excipient with the hrder elstic mteril. The plstic mteril will permnently deform nd estblish lrge, true contct res with the hrder mteril nd will do so t reltively low pressures. Thus, during recovery, the stored elstic energy will be indequte to seprte extensive res of contct, nd strong bonding will result. Even though these sttements re resonble explntions of mny observtions, every tblet formultor knows tht they re indequte. Often lminted compct is produced. The individul pieces re dense, strongly bonded frgments. Therefore, sufficient res of true contct must form during compression; in generl, these res re not destroyed during the elstic recovery, even though those in the frcture plne re destroyed. Thus, the mechnism of frcture is different from tht of the formtion of crumbly tblet. Both re believed to result from indequte plstic flow. A much more detiled look t compression nd decompression is necessry to explin the compction properties of mterils nd the frcture phenomenon. EXPERIMENTAL Tblet Compression-Mny of the tblets used were mde in hnd press. A squre die ws used. The cross section of the fces of the punches ws 38.1 mm on side. The tblet compression force ws pplied by plcing the ssembly, with punches in plce, into n 18-metric ton hydrulic press. The hnd press could be pumped mnully or by motor-driven externl cylinder to obtin the desired compression force. Both the punch nd die hd inserts contining diphrm-type strin guges on the end of screw2. One guge ws flush with the fce of the die, nd the other guge ws flush with the fce of the punch nd centered in it. In one mode of opertion, the output from the guges ws coupled t the y-input of n x-y recorder through switching circuit tht converts the recorder into two-chnnel input on the y-xis. Clibrtion ws mde by plcing squre rubber plug into the die nd compressing it with known force. At low pressures, rubber bg filled with wter ws used in similr mnner. The known totl force on the punches ws obtined from lod cell:$ mounted on the press. The lod cell ws clibrted by pplying ded weight to check the supplier s clibrtion. Its output could be coupled to the x-input of the x-y recorder. Thus, it ws possible to record simultneously the totl pplied force, locl punch fce pressure, nd locl die wll pressure throughout the entire compression-decompression cycle. An lterntive mode of opertion ws to monitor the output of the lod cell on voltmeter4 nd to couple the die wll guge to the y-xis nd the punch guge to the x-xis of the recorder. In ddition to the plin punch nd n instrumented one, specil punch ws mde which contined t its center spring-loded, retrctble pin 1.09 mm in dimeter. This punch ws used to form the tblet with center hole to be used in the brittle frcture propensity determintion. The rotry tbleting mchine used in the lmintion study ws n instrumented (1) 16-sttion press5. A direct compction formultion6, selected to produce desired levels of lmintion, ws used. Dies nd punches (extr deep cup 12.7 mm dimeter) were used in the mjor study. Flt punches were used only to demonstrte the effect of punch shpe. To obtin the dt on frcture conditions, the precompression force nd speeds were selected rbitrrily, with the finl compression incresed stepwise until lmintion or cpping occurred. Tensile Strength-The tensile strength mesurements were mde by the trnsverse compression of squre compcts. The procedure nd pprtus were described previously (2). Since the hydrulic pressure Model , Loomis Engineering nd Mnufcturing Co., Cldwell, N.J. - Model EPS-1228s (die wll) nd model EPS (punch), Entrn Devices Inc., Little Flls, N.J. Model 1221-Ak lod cell, Interfce Inc., Scottsdle, Ariz. Model 160B digitl multimeter. Keithley Instruments, Clevelnd, Ohio. Mnesty Betpress, Mnesty Mchines, Ltd., Liverpool L24 9LQ, Englnd. li With the cupped punches, ech tblet contined 150 mg of phencetin (bolted), 325 mg of microcrystlline cellulose (Avicel 102), 2 rng of colloidl silicon dioxide (Ch-0-Sil), 167 mg of lctose (bolted), nd 6 mg of mgnesium sterte. With the flt punches, ech thlet contined 150 mg of phencetin (bolted), 221 mg of spry-dried lctose. nd 39 mg of mgnesium sterte Journl of Phrmceuticl Sciences

2 10 r lor L 5 [ x MEAN PUNCH PRESSURE, N/mZ X Figure 1-Sitosterols: chnge of pressures t die wll nd center of punch with verge punch pressure during compression-decompression cycle with time dely t mximum pressure. Key (dshed lines): C-dw, die wll during compression; nd D-dw, die wll during decompression. Key (solid lines): C-cp, center of punch during compression; nd D-cp, center of punch during decompression. Insert grph shows chnges with time while t mximum compression force. in the jck ws developed by compression from n externl motor-driven cylinder whose speed could be selected, the rte of stress ppliction ws controlled. This rte ws not criticl in experiments exploring this fctor. Nevertheless, it is desirble to use stndrd rte so tht ny timedependent effects re reproduced, should they become importnt. Even though the externl cylinder ws driven t constnt rte, the rte of increse of force pproximtes n exponentil curve. In the work reported herein, the rte ws selected so tht the time between l/e of mximum force to the mximum force ws 15 sec. This pprtus lso ws used to determine the unixil compressive force required to cuse compct to sher. A 38.1-mm squre compct ws cut into two pieces. One-hlf ws plced in the press with the long xis verticl. The pltens covered the entire end of the compct. Blotter mteril ws used on the plten s pd. A ring strin-guge system ws used to supply input to chrt recorder to observe the force t frcture. The re of the compct under the plten ws clculted from mesured dimensions obtined with micrometer. Stress Relxtion-The pprtus used by Milosovich ws used in the form described by Shlnt nd Milosovich (3). One ddition ws mde-viz., n oscilloscope7 to the output. This oscilloscope permitted one to record photogrphiclly the trnsducer output for the first few seconds of the experiment. The output for the remining time ws recorded on strip-chrt recorder. A 12.7-mm dimeter die ws used in the studies done in ir. The vcuum die ws 13 mm in dimeter. Powder weights were djusted to give the sme tblet thickness in the two dies. Another procedure for observing stress relxtion ws performed with the hnd press, using the instrumented die nd punch described previously. This pprtus is flexible, nd vrious procedures my be used. In the work reported in Fig. 1, while the totl force on the punch ws held constnt, the x-y recorder monitored the output of the strin guges in the punch nd die wll. Locl pressure chnges were observed t the center of the punch fce while the men pressure remined constnt. With sucrose (Fig. 2), the punch guge ws not used (due to guge filure), but the relxtion of the die wll pressure ws followed. The lod cell on the press indicted the totl force on the punch. Indenttion Hrdness-The indenttion hrdness vlues were mesured using the dynmic impct method described previously (4). The chordl rdius of the dent ws mesured with low powered microscope. The initil nd rebound heights were clculted from the rc of the pendulum movement. The indenter ws 25.4-mm dimeter steel bll suspended on 1-m long steel wire (to form the pendulum). Model B, type 202-1, Tektronix Inc., Portlnd, Ore. MEAN PUNCH PRESSURE, N/m2 X Figure 2-Die wll versus verge punch pressure for some compression-recompression cycles of the sme sucrose compct. Constnt mximum pressure ws held on the punch for 5 min before the first decompression. Note tht ech successiue recompression led to lower mximum die wll pressure. Bulk sher lines were estimted from the unixil compression test, which gve = 67"; us is filure stress under unixil compression. RESULTS AND DISCUSSION Compression-The nonisosttic compression of powdered or grnulr mteril to produce compct is not simple process. The complexity rises from the numerous simultneous internl processes tht led to consolidtion nd bonding. These events include prticle rerrngement (consolidtion), frcture, nd plstic deformtion. At the strt of the compression, the first domintes; t the end of the compression, the third domintes. In some cses, fourth phenomenon occurs (5,6)-viz., loclized melting t the interprticle contct points. This phenomenon is believed to be importnt only with reltively low melting mterils. Even very hrd sperities re pushed into more plstic substrte. Thus, the stresses tht could produce melting of n sperity re limited by prticle hrdness. Prticle frcture occurs when the stresses within the prticles become lrge enough for crck to propgte. With some mterils, the prticles need not frcture becuse the stresses re relieved by plstic deformtion of the prticle before their mgnitude is sufficient to initite frcture. Except in the cse of loclized sperity melting, the effective re of true contct in cross-sectionl re norml to the direction of pressure ppliction is determined by the product of the force cross the plne divided by the permnent deformtion pressure of the solid. For simplicity, ssume tht only one mteril is present. If the deformtion pressure is constnt, then: F=PA (Eq. 1) where F is the pplied force, P is the permnent deformtion pressure of the solid, nd A is the effective true contct re in the norml plne. Therefore, under pressure, desired mximum true contct re cn be estblished simply by pplying dequte pressure. Eqution 1 gives no informtion bout the true contct re fter elstic recovery; therefore, it is not dequte to predict finl compct strength. By mking some generl ssumptions bout the mximum intertomic seprtion distnces tht permit significnt contributions to bond strength nd then pplying the Hertz elstic contct reltionships (7), it cn be deduced tht smller prticles should yield lrger true contct res nd, thereby, stronger bond strengths. However, the results re not independent of the prticle permnent deformtion pressures, i.e., their hrdness, nd hrdness my vry with prticle size. Furthermore, plstic deformtion tends to increse the number of disloctions in crystl; hrd crystl my first become softer nd, if sufficiently "worked," my then become hrd gin. Thus, the mgnitude of P in Eq. 1 usully is unknown. Also, prticle size nd shpe chnges my influence the pcking density. Thus, specultions on the effect of prticle size on tblet bond strength re t best precrious. Theoreticl pproches tht use models for the summtion of contct res nd forces over cross-sectionl re to obtin true contct res Vol. 66, No. 4, April 1977 I511

3 re interesting (8,9) but hve not found significnt ppliction for solving rel problems. Usully, the results devite only slightly from liner reltionship between true re nd force. Unfortuntely, the proportionlity constnt is not known: it is known tht the extent of the plstic deformtion influences the mgnitude of the proportionlity constnt. Thus, P is n importnt prmeter influencing bond strength. A more complete description of compction must include the effects of interprticle friction nd friction with the die wll nd punches. These contribute to vritions of the degree of pcking in the die nd, therefore, cuse nonuniform density compct to be formed. The vritions of density within compct were reported by Trin (10). Furthermore, the effect of die wll friction on pressure t vrious levels in compct ws studied nd described by (11): Pb = P, exp (- %) 0%. 2) where P, is the pplied pressure (punch), Pb is the trnsmitted pressure t L distnce from the punch, D is the dimeter, p is the coefficient of friction, nd q is the rtio of rdil to xil stress in the compct. Compression involving movement of both upper nd lower punches significntly reduces the density vrition within compct; however, this fct does not eliminte the problem completely. Also, the use of lubricnt nd glidnt to reduce both interprticle friction nd friction with the surfces of the punch nd die contribute significntly to the formtion of more homogeneous compct. Usully, these gents cuse n increse in the die wll pressure for given punch pressure (12), probbly becuse the prticles compct more tightly before plstic deformtion becomes the dominnt consolidtion process. Possibly, interprticle wedging occurs more esily when friction is reduced nd, thereby, increses the die wll pressure. Thus, severl fctors my influence the structure of compct nd the mgnitude of the die wll pressure t the mximum compression force. It is not esy to estblish the reltive importnce of ech. However, vlid qulittive generliztion is tht when either powders or grnules re compressed into compct, regions of different reltive density re produced nd the die wll pressure is of higher mgnitude thn would result from the elstic deformtion of single piece of n isotropic solid. During decompression, this extr die wll pressure my led to excessively lrge sher stresses in the compct. It is instructive to think of plstic deformtion both s chnge in prticle shpe nd s the sliding of groups of prticles within the compct. This pproch provides more mcroscopic perspective nd is used to explin the redistribution of stresses when under compression. For exmple, when sitosterols were held under constnt compressionl force (the totl punch force held constnt), loclized die wll pressure decresed s function of time nd the pressure t the center of the punch incresed simultneously (Fig. 1, insert grph, which ws obtined with the instrumented 38.1-mm squre punch nd die set). Apprently, t mximum compression, some points in the compct were stressed to the limit of their.strength. Since their instntneous or dynmic sher strength exceeded their sttic sher strength, internl plstic flow occurred over time to relieve some stresss. The center of the punch lwys is lower pressure region (lo), so the flow ws towrd the center. Thus, regionl density chnges occurred nd the compct density becme slightly less heterogeneous s result of this mcroscopic plstic flow. The rte of the process decresed shrply; thus, totlly uniform density compct did not result. In Fig. 1, the pressures reported were locl pressures known t only two smll regions becuse the strin guges were less thn 6.35 mm in dimeter; the compct ws 38.1-mm squre. In the bsence of better dt, it is expedient to use these pressures s very rough estimtes of the principl stresses for n ssumed isotropic homogeneous compct. In this cse, the sher stress is given by: where 7 is the sher stress t ngle from the direction of the minor principl stress, u is the xil or punch pressure, nd ur is the rdil or die wll pressure. Whenever T just exceeds the sher strength of the mteril, sher filure occurs. If the filure does not cuse frcture plne to develop, the filure is by plstic flow. Obviously, 7 hs its lrgest vlue when = 45O. The sher strength lso is function of the ngle ; therefore, the sher strength my be exceeded t some ngle greter thn 45 before This viscoelstic flow is believed to result from rndom therml fluctutions breking prestressed bonds. Sher Yield Locus 0 Oi (Jrz Jrl NORMAL STRESS,, Figure 3-Sher yield conditions bsed on the use of geometric representtion of stress nlysis equtions, Mohr digrm. Semicircle on right (subscript I) represents the higher pressure cse when the rdil pressure is less thn the xil pressure. Semicircle on left (subscript 2) represents cse when the xil pressure is zero nd the residul die wll pressure is,~ (re in Eq. 6); it lso could describe the unixil compression cse. In Eq. 5, the yielii locus is ssumed to be stright line nd p is constnt. it is exceeded t = 4 5O. For Mohr body, the sher strength is ssumed to be nerly liner function of the compressive stress norml to the sher plne. The norml stress, n, is given by: (Eq. 4) For the Mohr body, the internl friction coefficient, p, becomes the proportionlity constnt for clculting the sher strength, 7/, nd for the liner cse: 7f = N Jnf + 70 (Eq. 5) where n/ is the mgnitude of the norml stress, n, t filure; TO is the sher strength when,, = 0; nd p is the internl friction coefficient nd is relted to by p= -cot 2. Equtions 3-5 re useful in providing some insight into sher filure conditions. A stndrd geometric representtion of Eqs. 3-5 is clled Mohr digrm. Becuse of symmetry, only hlf of Mohr digrm is shown in Fig. 3. It should be useful to use Eqs. 3-5 nd the Mohr digrm to discuss sher filure in both the compression nd decompression of compcts. The grphicl representtion of sher filure is correct only when the Mohr circle of stress is tngent to the sher filure yield locus. Decompression-In this discussion, it is ssumed tht dequte compressionl force ws pplied to produce densifiction nd bonding; i.e., crumbling from lck of dequte compression with plstic deformtion will not be considered further. Even though dequte pressure is pplied, the compression-decompression cycle my or my not produce n intct compct without frcture lines in it. Success is determined primrily by the internl processes tht occur s the compression stresses re removed. These processes include both removl of punch pressure nd ejection from the die. Powder under compression in cylindricl die is confined in rdil direction until ejected from the die. Therefore, the mjor dimensionl chnge during decompression is in the xil direction. Of course, the sme is true for recompression of the compct if it is recompressed without removl from the die. Eqution 6 describes the stresses ssocited with elstic deformtion of n isotropic solid when the strin in the rdil direction is zero: U r - LTro = 1 - u (Eq. 6) where v is the Poisson rtiog, nd r0 is the die wll pressure intercept vlue. The residul die wll pressure, uro, would be zero if the compression of n isotropic solid is strted with confined, but unstressed, solid body. If only elstic deformtion occurred during compression nd decompression, or0 would remin zero. When one strts with powder, finite residul die wll pressure is lwys observed fter completion of the compression-decompression cycle. Obviously, if the compct undergoes sher deformtion in both recompression nd decompression, gross devitions from the elstic cse would be expected nd Eq. 6 would not be pplicble. (Lter, it will become obvious tht Eq. 6 is not pplicble The Poisson rtio is defined s the trnsverse expnsion per unit dimension of solid of uniform cross sectim to its contrction per unit length whrn subjected to unixil compressive stress (dming elstic deformtion). 512 I Journl of Phrmceuticl Sciences

4 Figure I-Sucrose compct frctured in sher under unixil compressivestress of 1.1 X lo1 Nlm2. Compct ws compressed t 9.2 X lo7 Nlm2. Frcture plne ws irregulr so ulue of ws not precise. With vrious compcts, vlues rnged from 64 to 67O. during the decompression process.) Others (13, 14) considered the possibility of plstic deformtion during decompression but pproched the subject differently thn will be done in the following discussion. To describe the mgnitudes of the die wll nd punch pressures tht would cuse the compct to fil in sher, the following equtions re developed. Tking derivtives of Eqs. 3 nd 4 with respect to ur nd combining to obtin dt//do,f yield - dt/ dun{ The subscript f ws dded to indicte condition of filure. By definition: -- f7f - p = -cot 2 on/ Combining Eqs. 7 nd 8 gives: -- duo/ cos dur/ I + C O S ~ ~ w- 1 (Eq. 7) (Eq. 8) Eqution 9 permits the estimtion of the limiting stresses beyond which sher occurs once p or n equivlent vlue hs been determined. While p my not be constnt, lrge vritions re not expected s long s only compressive stresses re used. At lest in theory, the unixil compression of compct should provide the necessry dt for use of Eq. 9. For this experiment, lrge squre compct ws cut into two equl pieces nd compressive stress ws pplied long its long xis until it frctured. If both the frcture ngle,, nd the compressive stress t frcture cn be mesured, Eqs. 8 nd 9 cn be evluted. Figure 4 shows sucrose compct frctured under unixil stress; the mgnitude of the observed frcture stress is plotted on Fig. 2 (point us). The irregulr frcture line shown in Fig. 4 mkes n ccurte evlution difficult. Compcts of most mterils re even less stisfctory becuse of lmintions nd other berrnt frcture plnes. The two bulk sher lines in Fig. 2 hve slopes clculted by Eq. 9 using the unixil compression dt. Both nd p were tken s constnts; hence, stright lines re shown. These lines cross the xis t the unixil compression stress for frcture. The slopes of the two lines re reciprocls of ech other; the distinction between,/ nd urf in Eq. 9 is rtificil; i.e., it does not mtter which is lrger, only the difference is importnt. As is obvious in Fig. 2, these lines do not correspond to the experimentl rnge of urf versus uf. While this finding suggests tht the experimentl compression-decompression stresses re within the elstic limits of the ~ 9 MEAN PUNCH PRESSURE, N/m X lo- Figure 5-Sucrose compct compressed s in Fig. 2 but recompression-decompression cycles were prtils. Key: solid lines on left, recompression-decompression ouer very limited rnge of pressure; dshed lines on left, recompression-decompression cycle extended into decresing slope region; solid lines on right, decompression-recompression cycle ouer limited rnge of pressures but strting from mximum ulues; nd dshed lines on right, decompression-recompression cycle extended into decresing slope region. Loops re believed to indicte tht plstic deformtion occurred t locl points. Very smll loops with solid lines my be due to friction resisting punch mouement. mteril, further exmintion, such s of the dt in Fig. 5, indictes tht sher is occurring in the regions between these lines. The unixil frcture stress is n estimte of the mgnitude of the die wll pressure t filure when the punch pressure is zero nd vice vers. Figure 2 shows dt for die wll uersus punch pressures obtined for compression-decompression cycles using sucrose. The die wll pressure is tht mesured t the center of one side of squre compct. The punch pressure is the men vlue bsed on the totl force pplied to the punch. When the punch pressure went to zero, the die wll pressure becme identicl to the unixil compressive strength, 6,. Obviously, the sher strength limited the residul die wll pressure. This vlue remined essentilly constnt even fter repeted recompression cycles. The shpes of the decompression plot reported here re very different from those reported by Leigh et l. (13) nd Crless nd Leigh (14). Possibly, the differences rise from differences in the procedure nd instrumenttion. Those investigtors mesured totl die wll force nd not locl pressures. Furthermore, the present pprtus is very rigid; i.e., the entire die expnds very little under pressure. Other differences re size nd shpe of compcts nd the rte of compression nd decompression. When Poisson rtios re clculted from the dt reported here, unrelisticlly lrge vlues re obtined. Thus, the dt mesured t seprted regions of the compct surfce do not seem to be representtive of single, smll volume element. However, the theoreticl rguments developed from these dt do not depend on the exct shpe of the die wll uersus punch pressure plot. Upon recompression followed by decompression, s ws done to obtin the dt in Fig. 2, hysteresis type of loop is formed. If the compression-decompression involves only elstic deformtion, the compression-decompression pthwy should be identicl. Therefore, plstic deformtion must be occurring during ech recompression-decompression cycle. Prtil recompression-decompression cycles re even more reveling (Fig. 5). If the recompression pressure is limited to vlue below the first bend, the decompression line from tht point superimposes onto the compression line (solid lines on the left of Fig. 5). However, when the recompression pressure is incresed to point beyond the first bend, loop is formed upon decompression. Apprently, the first portion of the recompression curve represents elstic deformtion while lrger compression forces introduce plstic deformtion. Results of similr experiment t the strt of the decompression is shown on the right side of Fig. 5. If the decompression from mximum pplied force is stopped short of the first bend, recompression from tht point retrces essentilly the sme line. (A slight devition occurs, possibly due to friction.) Therefore, the first prt of the decompression is n elstic deformtion. However, if the decompression is stopped t pressure beyond the first bend, the recompression from tht point forms loop. Therefore, sher or plstic deformtion is occurring during much of the decompression. Vol. 66, No. 4, April 1977 I513

5 ~~ 11 I Mlnuti lntiwil PUNCH PRESSURE, N/mZ X lo-' Figure 8-Spry-dried lctose USP (hydrous): locl die wll pressure versus men punch pressure for compression-decompression cycles. 10 F 9- E! x 8- n. I b I I I I l l 1 1 PUNCH PRESSURE, N/m2 X Figure 6-Sitosterols: locl die wll pressure versus men punch pressure for compression-decompression cycles. The uthors hope to equip the pprtus with distnce-mesuring sensor so tht the work of recompression nd decompression my be determined. Certinly, the loop in Fig. 2 suggests tht the work of recompression is much greter thn the work done on the punch during decompression. Without distnce or volume mesurement, the clcultions cnnot be mde. Figures 6-13 show similr result for sitosterols, spry-dried lctose, erythromycin, nd sodium chloride. While differences in the detiled shpes of the curves re pprent, the generl chrcteristics remin the sme. Apprently, the previous discussion for sucrose pplies eqully to these mterils. Loclized plstic deformtion my occur t lower stresses thn would be required to produce gross sher cross the compct. The locl sher stresses exceed the sher strength becuse of stress concentrtions tht occur round imperfections such s pores nd density grdients. These internl locl regions of sher my ccount for the pprently nelstic behvior in the recompression-decompression cycle. If loclized sher occurs, the recompression-decompression cycle might not be completely reproducible, since there is no reson to expect the shpes of the stress concentrtor regions tht flow plsticlly during compression to be reconstructed in the decompression stge. Thus, it is not surprising tht the observed mximum die wll pressure is less fter ech recompression (Fig. 2). This direction of chnge would be expected, since the die wll - E 7-2 pressure decresed during stress relxtion under constnt punch pressure. The combined evidence of these observtions nd the time-dependent stress redistribution reported in Figs. 1, 2, nd 141 strongly indictes the conclusion tht locl plstic deformtion occurs in compcts. Tble I shows tensile strength vlues for compcts subjected to recompression-decompression cycling. The increse in strength tht occurred with these mterils is interpreted s n increse in true contct re between prticles. Sher under compressive lod could produce n incresed contct re. However, sher lso my induce frcture, especilly during decompression. Since the two processes produce opposite effects on the strength, not ll mterils will show the sme trend. Most plstic mterils, such s those used for the dt in Tble I, show incresed strength. Figure 15 illustrtes the cse where the stresses during decompression led to frcture on the first decompression. Obviously, tensile strengths could not be determined. Phencetin, methenmine, nd cetminophen, mterils known to induce cpping, show this kind of frcture. Apprently, these mterils do not dequtely relieve locl stresses by plstic deformtion; hence, frcture in sher occurs cross the entire compct. For these mterils, recompression curves re meningless. Brittle Frcture-The Griffith crck theory teches tht, for crck growth to occur, the energy stored t the tip of crck must just exceed the energy required to form the two new surfces resulting from the propgtion of the crck. Also, the mount of energy stored t the tip of crck is function of the dimensions of the crck. An elementry description of the criticl condition for crck growth is given by: uc = K d% (Eq. 10) where uc is the criticl tensile stress for crck growth, y is the surfce energy, E is Young's modulus of elsticity, L is one-hlf the crck length, nd K is constnt. In deriving this eqution, the rdius of curvture t the tip of the crck ws ssumed to be of moleculr dimensions. The rdius does not pper in Eq. 10 becuse it cncels ginst the sme rdius term, which occurs in the expression for the pplicble stress concentrtion fctor. Figure 7-Sitosterols: of compct. PUNCH PRESSURE, N/m' X lo-' prtil recompression-decompression cycles PUNCH PRESSURE, N/mz X Figure 9-Spry-dried lctose USP (hydrous): prtil recompression-decompression cycles of compct. lo Figure 14 is bsiclly stress relxtion determintion using the Milosovich pprtus (3) to obtin the dt Journl of Phrmceuticl Sciences

6 8 - P I z 7- X n $ 6 - z u- U 5-3 PI lor Q 0 7 x 8 N $ 7 2 W 6 U w E 4 -I 3 3 i2 n 1 PUNCH PRESSURE, N/mz X Figure 10-Erythromycin USP: locl die wll pressure versus men punch pressure for compression-recompression cycles. The extent of the stress concentrtion, the stress concentrtion fctor f, is multiplier pplied to the mgnitude of the uniform stress clculted s if no flw were present. A simple cse my be used to illustrte stress concentrtion. If slb is subjected to only uniform tensile stress nd the slb contins n ellipticl hole with the long xis norml to the direction of the tensile stress, the tensile stress t the edge of the hole, s long s the hole is much smller thn the width of the slb, is given by: 7 f=l+2d; (Eq. 11) where L is one-hlf the length of the hole, nd R is the rdius of curvture of the tip of the hole. Note tht Eq. 11 reduces to stress concentrtion fctor of 3 for round hole, regrdless of its rdius (its size still must be very much less thn the slb size). When second uniform stress is pplied to the slb norml to the direction of the tensile stress, the stress concentrtion fctor round hole is not exctly 3. Figure 16 shows the stress concentrtion fctor t hole for vrious stress conditions (15). The stress concentrtion concept is useful in understnding why ejection from die cn cuse compct to lminte. Theoreticlly, the rdius of curvture t the edge of the die could be of moleculr dimensions. Therefore, the stress concentrtion fctor to be pplied to the die wll pressure when compct is prtilly ejected could be very lrge number. Figure 17 is photogrph of n erythromycin compct tht split off mny lyers s it ws slowly ejected. The ssumed mechnism is tht crck initited t the edge nd propgted cross the compct. Mterils tht exhibit high sher strength nd, therefore, high residul die wll pressure nd lso hve high propensity for brittle frcture my undergo r I I I I I 1 PUNCH PRESSURE, N/mZ X Figure 1 I-Erythromycin cycles of compct. USP: prtil recompression-decompression lot 5 Minute Intervl t Mximum Eompmsrinn A t/ V C I ~ I,,, I, PUNCH PRESSURE, N/mZ X Figure 12-Sodium chloride: locl die wll pressure versus men punch pressure for compression-decompression cycles different from other mterils. The die wll pressure incresed during the 5-min intervl the mximum punch pressure ws held constnt. brittle frcture from points of very high stress concentrtion such s the die edge. It should be possible to use the knowledge of stress relief t sites of stress concentrtion to chrcterize the tendency of compcts to propgte crcks. Suppose tht round hole is plced in the center of compct nd tht it is subjected to tensile stress. Tensile frcture might be expected to occur t exctly one-third of the tentile stress required to produce tensile frcture when no hole is present. However, this would be true only if the compct did not relieve the loclly concentrted stresses t the edge of the hole by plstic deformtion. If ll excess stresses t the hole s edge were relieved, no observble differences in the tensile frcture force would be observed. Rel mterils should frcture t some intermedite vlue, the mgnitude depending on their bility to relieve loclized stresses. Since frcture by crck propgtion from flw tht concentrtes stress is clled brittle frcture, comprison of the strength with nd without hole hs been used to define prmeter clled the brittle frcture propensity (BFP). The BFP is clculted by: Lo 1 BFP = 1/2 2-1 (Eq. 12) where UT is the tensile strength without hole, nd UTO is the pprent tensile strength with hole present. The subtrction of one nd division by two normlize the vlues of BFP so tht the theoreticl vlue rnge is 0-1 when the stress concentrtion fctor is 3. Since the BFP vlue is n inverse mesure of loclized stress relief, it should indicte the tendency of compct to lminte or cp. A technique for mesuring the BFP of compcts is bsed on the trnsverse compression of squres (2). Erlier work showed tht if P I z 8 X n E 7. z $6 2 z 5 U L1 5 4 Lu n PUNCH PRESSURE, N/m2 X lo- chloride: prtil recompression-decompression Figure 13-Sodium cycles of compct. Vol. 66, NO. 4, April 1977 I515

7 - 1.0 r\\ Tble I-Tensile Strength of Compcts Subject to Vrious Compression Procedures t SECONDS Figure 14-Microcrystlline cellulose: reltiue punch pressure versus log time; Pt is pressure t time t, P, is the mximum pressure pplied, zero time corresponds lo the strt of the stress ppliction, circles re dt for n in ir mesurement, nd tringles re dt for n in vcuo mesurement. Escpe of ir following compression did not lter the generl shpe of the curue. Mximum pressures pplied were 7.24 X lo7 Nlm2 in ir nd 6.89 X 107 N/m2 in vcuo; slope vlues vried slightly with the mximum pplied compression pressure nd were usully steeper with n increse in the mximum pressure. squre compct is centered on edge between two pltens whose width is four-tenths of the width of the compct, the centrl region of the compct is under nerly uniform sher stress (16). Figure 18 shows the fringe ptterns obtined with polrized light through trnsprent model substnce, poly(methy1 methcrylte). (Photoelstic methods of determining stress distributions use more sophisticted techniques to obtin nd evlute fringe ptterns.) Comprison of the two fringe ptterns clerly shows tht when the hole is present, the mgnitude of the stresses is chnged mrkedly. Although isochromtic fringe lines re isosher stress lines, one cnnot determine the principl stresses without dditionl informtion. The techniques of photoelsticity re outside the scope of this discussion but do indeed permit the determintion of stress concentrtion fctors such s those shown in Fig. 16. The stress condition t the center of squre compct in trnsverse compression is not simple tension. A compression stress is present in the direction norml to the tensile stress. Therefore, from the dt displyed in Fig. 16 nd from the nlysis of Berenbum nd Brodie (16), which show tht the rtio of tension to compression is pproximtely 0.28, it is evident tht the stress concentrtion fctor is pproximtely The use of Eq. 12 with this method of tensile strength mesurement will not limit the BFP vlues to less thn unity, t lest in theory, since the eqution ws normlized for stress concentrtion fctor of 3. In prctice, one probbly cnnot mke n intct compct of mteril with BFP of 1. Therefore, the observed rnge of vlues my not exceed the 0-1 rnge. While it might be preferble to bse the BFP on n exct theoreticl nlysis, one must recognize tht the heterogeneous reltive densities of compct mke high level of precision most difficult to ttin. Furthermore, difficulties not yet understood rise with this test. Therefore, the uthors elected to!se Eq. 12 to estimte the BFP, even when the evlution of tensile strengths ws mde by the trnsverse compression of squres". Added specifictions should include the reltive density of the compct becuse very soft compcts do not yield useful dt. Nevertheless, sufficient ccurcy exists for useful reltive vlues to be ob- Number Tensile0 Significntb of Com- Strength, Difference, Mteril pressions N/m: x P Aspirin Sucrose Lctose (spry dried) ] <0.001 ] 0.18 ] 0.08 Averge of five compcts. Mximum compression of 9.50 X lo' N/ m2. b Strengths re significntly different t listed p vlues. Brckets indicte the pir of vlues compred to obtinp vlue. tined simply by dopting stndrd procedure. Of course, compcts contining other flws such s lmintions will yield flse vlues. When one observes stepped frcture plne, one should suspect lmintion nd reject the dt. If vrious lbortories were to ttempt to obtin identicl vlues for the BFP, very detiled specifictions would be needed for high levels of precision, Experimentl vlues for few mterils re listed in Tble 11. Mterils known to induce cpping hve reltively lrge BFP vlues, s expected. The punch used to form compcts with hole in the center is shown in Fig. 19. Stress Relxtion-So fr, the discussion hs ignored n importnt vrible-viz., time. Plstic deformtion is time-dependent phenomenon. Shlnt nd Milosovich (3) showed tht compression stresses re relieved with time. Their experiments were similr to relxtion study, since the size of the compct ws fixed nd the chnge in punch pressure with time ws recorded. The uthors used the Milosovich pprtus nd confirmed the bsic observtion. Furthermore, every mteril exmined by the uthors with this pprtus underwent relxtion of the punch pressure (Figs. 14,20, nd 21). Becuse the compct is not under unixil compression during the stress relxtion, the quntittive interprettion of the experimentl results is complicted. Furthermore, the slope is function of the porosity of the compct. However, for the exmples shown, the rnk order is obvious. Mterils tht re known to cp exhibit slower stress relxtion. The chnge of slope t the short time intervls observed in these stress uersus log time plots suggests tht some initilly prominent mechnism soon becomes negligible. Becuse ir entrpment hs been propounded s the cuse of lmintion nd cpping, it ws of interest to estblish whether the diffusion of ir from the compct ws n initilly prominent mechnism. Therefore, the stress relxtion experiments were repeted but with the powders in n evcuted die12. In no cse were the generl chrcteristics of the stress relxtion curves ltered. Apprently, the ir must escpe in less thn sec from these mterils (Figs. 14,20, nd 21). An pprtus tht reduces the compression time to very smll vlues is needed to explore this point further. The relxtion of die wll pressye ws discussed previously. Obviously, pressures t ll points in compct my not be undergoing stress relxtion identiclly. As indicted previously, the pressure t the center of the punch ws incresing while the die wll pressure decresed (Fig. 1). z 0 l- 4.0 U Figure 15-Phencetin compct tht frctured in the die without ejection. Similr frcture occurs with cetminophen nd with some mixtures of these mterils with excipients. In the uthors' studies, the plten width ws 0.4 the tblet width, pds were used on the pltens, nd the hole dimeter ws 1.09 mm in 38.1-mm squre compct. v) v) UI : t4 t5 OPfF c in Figure 16-Tensile stress concentrtion fctor t the edge of hole for bixil stress conditions; up nd UF re stresses cting t right ngles to ech other. A negtive vlue rises for p/f when one stress is compression nd the other is tension. Hole dimeter is much much smller thn dimensions in direction of stress. (Dt from Ref. 12.) Evcuble die , Perkin-Elmer Corp., Norwlk, Conn Journl of Phrmceuticl Sciences

8 Tble 11-Deformtion Pure Mterils nd Frcture Properties of Mteril BFP P/o tb E,/EDC Methenmine Erythromycin bse Ihunrofen suc;ose Strch, modifiedd Lctose (spry dried) Microcrystlline cellulose Bnttle frcture propensity. All compcts were compressed t 9.5 X 10 N/mZ. bmen deformtion pressure divided by the tensile strength. All compcts hd reltive density of Reltive deformtion energies (elstic/plstic) for deformtion beneth steel sphere; E, + Ep wds the sme for ll mterils. The reltive density of ll compcts ws dstrx. However, men pressures my be decresing if the compct increses its reltive density s result of stress relxtion, i.e., s function of time. Therefore, there is no reson to conclude tht the two pprtuses yield conflicting results. The evidence clerly indictes the existence in compcts of timedependent properties of plstic deformtion nd stress relief. Therefore, the incidence of frcture lso should be time dependent. Intct compcts of some pure medicments, e.g., cetminophen, methenmine, nd erythromycin, were mde when the decompression ws extended over severl hours, even though rpid decompression produced frctured compcts. Differences in the slopes of the initil segments of these plots should reflect the bility of the mteril to relieve stresses in tbleting mchine. As expected, the stresses in methenmine decyed very slowly while those in sitosterols decyedmuch more rpidly. Stresses in erythromycin decyed much more rpidly thn might be expected since they produced lminted compcts. This finding my ccount for the bility of erythromycin to withstnd (not frcture) decompression but to frcture upon ejection where the time intervl for decy of stress is very short. Indenttion Hrdness-If sphere is pressed ginst compct surfce hrd enough to produce plstic flow beneth it, the men pressure over the sphere-compct interfce is essentilly constnt when the chordl rdius of the dent is much less thn the rdius of the sphere. This men deformtion pre~sure ~, P, is mesure of the hrdness of the compct. The yield vlue for plstic flow is pproximtely 0.36 P. The role of plstic flow in determining residul die wll pressure nd in relieving concentrted stresses ws emphsized in the preceding discussion. Therefore, the determintion of P should be of direct interest. A method bsed on the rebound of steel sphere from compct ws used (4). For comprison, the vlues of P for compcts with reltive density, pr, of 0.85 were used for ll mterils. Plots of log P uersus pr re nerly stright lines nd were used in interpoltion to obtin the 0.85 reltive density vlue. Perhps the rtio of the deformtion pressure, P, divided by the tensile strength is of more interest thn the deformtion pressure lone. If both sher strength nd tensile strength rise from the sme bonded res in given compct, then the rtio P/OT for mterils should hve similr vlues unless the mechnicl structure of the compct influences disproportionlly the mgnitude of these terms. The mgnitude of P should not be influenced by crck propgtion, but tht of UT should be. Thus, if the rtio of P to UT vries over lrge rnge, the pore structure my he ffecting the tensile strength vlues. Crck propgtion occurs Figure 17-Erythromycin bse compct tht frctured when ejected from the die. Strch nd methenmine compcts frctured in similr mnner. l3 Anlogous to P in Eq. 1, except tht Eq. 1 ws mesured t contct points hetween prticles. Here, the men pressure is over mcroscopic re tht my contin pores. Nevertheless, the equtions for nonporous mterils my be used (4). Tble 111-Influence of Mchine Speed nd Precompression Force on the Finl Compression Force tht Produced Frctured Tblets Finl Compression Force, Mchine Precompres- Metric Tons Speed, sion Force, rpm Metric Tons No Lmintion Lmintion Cupped Punched Flt Punches= ~ See footnote 6 in text for the composition of the formuls. b When 11.9-mm flt punches nd die were used with the sme formultion, no lmintion ws observed. C Very little work ws done with the flt punches becuse formul tht produced good bond t lower pressures nd lminted t the highest pressures ws not developed. when the tensile stresses t flw exceed the tensile strength without the sher stresses exceeding the sher strength, i.e., without stress relief occurring by plstic flow. Thus, the rtio of Plq might correlte with the BFP. If true, reltively lrge vlue of P/UT should indicte n incresed propensity for brittle frcture. Fctors tht could ffect this comprison re differences in the surfce energy of the solid, the modulus of elsticity of the compct, nd the internl flw structure tht concentrtes stresses. Tble I1 shows the results of these mesurements. It is obvious from Tble I1 tht the P~UT vlues do not correlte with the BFP vlues. Nor do the PIUT vlues correlte with the tendency to form frctured tblets. It seems more resonble to conclude tht both UT nd P re mesuring different mnifesttions of the strength of the true contct res without gross effects from stress concentrtion t pores controlling the vlues. The impct-rebound method of determining P provides mesurements of both the energy used in the permnent deformtion nd the energy of the elstic recovery from the impct. A high energy of elstic deformtion per unit of plstic deformtion energy, EJE,, could indicte tht lrge elstic stresses develop within the compct. Thus, it is of interest to compre the mgnitude of E,IE,, for the vrious mterils. The lst column of Tble I1 lists the experimentl vlues for severl mterils. Obviously, the mgnitudes of the rtios of E,IE, do not correlte with the brittle frcture properties of the compct. Tblet Mking-Stress relxtion is believed to explin some prcticl problems encountered in tbleting. When lmintion is problem nd the production volume of rotry mchine is needed, mchine tht provides precompression should be selected. The precompressed compct hs time to undergo some stress relxtion before the finl compression is pplied. To mximize the stress relxtion, the precompression pressure should be ner the mximum tht will not by itself introduce lmintion. This will mximize the stress relxtion tht cn occur before the finl compression. A long dwell time under compression lso will increse the time for stress relxtion. Thus, slow operting speed lso increses the time vilble for stress relxtion. The finl compression should use s smll force s possible to obtin n cceptble tblet, since there is less stress cting t smller compression force to cuse the compct to frcture. If the BFP of the formultion is not too high, one should be ble to mke stisfctory product under the conditions described. The use of deep ovl punches is known to engender cpping. Obviously, lrge quntity of mteril in the dome is expnding rdilly s the punch is removed. Since the min body of the tblet cnnot expnd rdilly into the die wll, lrge sher stresses develop. Flt punches void this contribution to the sher stress. Therefore, when possible, tblet shpe selection should be mde to reduce stress grdients during tbleting. Other studies hve demonstrted the effects of precompressioni4. They were repeted in the present study to observe the effects of precom- l4 A. C. Shh, The Upjohn Co., unpublished dt. Vol. 66, No. 4, April 1977 I517

9 Figure 18-Exmples of simple fringe ptterns obtined with nd without hole in compct subjected to trnsverse compression. These photogrphs were mde with white light nd simplp polrizers nd re not suitble for stress nlysis use However, they identify high stress grdient res. pression on finl compression, the influence of mchine speed, nd the influence of punch shpe (Tble 111). The theory predicts the pt.tern of the experimentl results. Of course, quntittive predictions re not possible with the present knowledge. The minimum precompression force for intct compcts ws function of mchine speed, finl compression force, nd punch shpe. Conversely, the mximum finl compression force tht produced intct compcts ws function of the precompression force, the mchine speed, nd the punch shpe. Conditions tht incresed the mount of stress relxtion permitted incresed compression force nd vice vers. If even the best conditions of tbleting still produce lminted tblets, reformultion is necessry. One should then seek n excipient mteril tht hs very low BFP vlue to dd to the high BFP medicment. Of course, in prctice, one must lso consider effects on disintegrtion, etc. Nevertheless, n understnding of the discussed principles provides much guidnce in the formultion of the compressed tblet dosge form. peted recompression nd decompression cycles. In some mterils, the internl sher stresses cuse crck to propgte nd frgmenttion occurs. If the stresses during decompression re not sufficient to produce crck propgtion within the die during decompression, the stress concentrtions developed t the edge of the die my produce crck propgtion (lmintion) s the tblet is ejected. Since sher stresses develop during decompression nd/or ejection, the filure to frcture ppers to be due to the bility of mteril to relieve sher stresses by loclized sher flow, i.e., plstic deformtion. This property cn be mesured by compring the tensile strength of compct tht contins built-in stress concentrtor defect with one tht does not. By using this knowledge, test ws designed tht indictes property of mteril clled the brittle frcture propensity. The brittle frcture propensity vlue indictes whether or not cpping or lmintion my be problem in tbleting the mteril. SUMMARY Under the nonisosttic compression force of tbleting, the powder prticles undergo sufficient plstic deformtion to produce die wll pressure in excess of tht tht cn be relieved by the elstic recovery ccompnying the removl of the punch pressure. This die wll pressure produces internl stress sufficiently high to cuse internl sher in the compct during the decompression. Plstic deformtion occurs in re- z - 4 W v) W W I!- 4 w Figure 19-Specil punch used to mke compcts with smll h,ole in center. Pin is spring loded nd retrctble so tht ny resonble compct thickness cn be used SECONDS Figure 2O-Reltiue punch pressure versus log time. Zero time corresponds to the strt of the stress ppliction. Circles re dt from n in ir mesurement; tringles re dt from n in vcuo mesurement. Mteril with the slowest rte of relxtion frctured upon decompression in the die; erythromycin lminted upon ejection. Mximum pressures (in Nlm2 X were: cetminophen, ir 7.31 nd in vcuo 7.03; erythromycin, ir 7.86 nd in vcuo 8.89; nd modified strch, ir 6.62 nd in vcuo /Journl of Phrmceuticl Sciences

10 \ r - 4 w U 2 v) LLI LT L w 1 i- -I I, I Lu : SECONDS Figure 21-Reltiue punch pressure versus log time. Zero time corresponds to the strt of stress ppliction. Circles nd dimonds re dt from n in ir mesurement; tringles re dt from n in vcuo mesurement. Only mteril with the slowest rte of relxtion frctured upon rpid decompression in the die. Mximum pressures (in Nlm? X were: methenmine, ir 8.34 nd in vcuo 8.41; sucrose, ir 6.96 nd in vcuo 6.52; nd sitosterols, ir 4.62 nd in vcuo The time-dependent nture of plstic flow or stress relxtion lso must be considered nd my ccount for differences in the properties of tblets produced on vrious mchines or t vrious mchine settings. REFERENCES (1) E. L. Knoechel, C. C. Sperry, H. E. Ross, nd C. d. Linter, J. Phrm. Sci., 56, 109 (1967). (2) E. N. Hiestnd nd C. B. Peot, ibid., 63,605 (1974). (3) S. Shlnt nd G. Milosovich, ibid.. 53,562 (1964). (4) E. N. Hiestnd, J. M. Bne, Jr., nd E. P. Strzelinski, ibid., 60, 758 (1971). (5) A. S. Rnkell nd T. Higuchi, ibid., 57,574 (1968). (6) P. York nd N. Pilpel, J. Phrm. Phrmcol., 25, S-1P (1973). (7) E. N. Hiestnd, Phrm. Ind., 34,262 (1972). (8) P. Dychenko, N. Tolkchev, G. Andrew, nd T. Krpov, The Actul Contct Are Between Touching Surfces, Consultnts Bureu, New York, N.Y., (9) F. C. Yip nd J. E. S. Venrt, J. Phys. D., Appl. Phys., 4,1470 (1971). (10) D. Trin, J. Phrm. Phrmcol., 8,745 (1956). (11) E. Shotton nd J. A. Hersey, in Theory nd Prctice of Industril Phrmcy, L. Lchmn, H. Liebermn, nd J. Knig, Eds., Le & Febiger, Phildelphi, P., 1970, chp. 9. (12) E. Nelson, J. Am. Phrm. Assoc., Sci. Ed., 44,494 (1955). (13) S. Leigh, J. E. Crless, nd B. W. Burt, J. Phrm. Sci., 56,888 (1967). (14) J. E. Crless nd S. Leigh, J. Phrm. Phrmcol., 26, 289 (1973). (15) C. Lipson nd R. C. Juvinll, Hndbook of Stress nd Strength, Mcmilln, New York, N.Y., (16) R. Berenbum nd I. Brodie, Br. J. Appl. Phys., 10, 281 (1959). ACKNOWLEDGMENTS AND ADDRESSES Received December 4, 1975, from Phrmcy Reserch, The Upjohn Compny, Klmzoo, MI Accepted for publiction June 8, The uthors thnk the mny people tht ssisted in vrious wys with this reserch. Mr. H. Bllen nd Mr. C. C. Sperry designed the specil pprtuses used. Dr. G. Milosovich nd the University of Michign School of Phrmcy loned the stress relxtion pprtus. Mr. L. H. Mcdonld nd Mr. J. F. Glsscock worked with the phencetin formultions. To whom inquiries should be directed. Solubility Studies of Silver Sulfdizine R. U. NESBITT, Jr. *, nd B. J. SANDMANN Abstrct 0 The solubility of silver sulfdizine s function of ph ws determined in nitric cid-potssium nitrte buffer for ph 2-3 nd in 2-(N-morpho1ino)ethnesulfonic cid buffer for ph 6-7. As the slt of wek orgnic cid, silver sulfdizine exhibits the nticipted increse in solubility with n incresing hydrogen-ion concentrtion. Mesurement of the silver-ion concentrtion ws crried out using silver-ion selective electrode. The methods of known subtrction nd known ddition were utilized to mesure the totl concentrtion of the silver ion in solution. Evidence ws obtined to indicte tht the slt is completely ionized in queous solution. Keyphrses Silver sulfdizine-solubility s function of ph, potentiometric study 0 Solubility-silver suifdizine s function of ph, potentiometric study ph-effect on solubility of silver sulfdizine, potentiometric study 0 Potentiometry-study of solubility of silver sulfdizine s function of ph Anti-infectives, topicl-silver sulfdizine, solubility s function of ph, potentiometric study Silver sulfdizine, substnce with extremely low wter solubility, ws reported to be prticulrly efficcious s topicl ntibcteril gent for the control of Pseudomons infection in burns (1). When pplied loclly to burned skin, silver sulfdizine is climed to offer definite therpeutic dvntges over other similr chemotherpeutic gents used to tret infection. Unlike other drugs tht diffuse rpidly or deplete chloride ions from body fluids, silver sulfdizine remins in the wound exudte for prolonged effect nd ppers to enhnce conditions fvorble for epithelil regenertion. BACKGROUND The mode of ntibcteril ction is different thn tht of sulfonmides, becuse the drug is not ntgonized in uitro by minobenzoic cid. In binding studies using rdioctive silver sulfdizine prepred from rdioctive Ag- nd :%trcers, the silver ion ws found to bind with the Pseudomons cells. No cellulr binding of sulfdizine ws detected (2, 3). The binding of silver to bcteril DNA ws proposed s importnt for inhibiting microbil growth. Silver displces the hydrogen bonds between djcent nitrogens of the purines (denine or gunine) nd pyrimidines (thymine nd cytosine) in the DNA molecule. The nitrogen-silver bonds, once formed, pper to be stronger thn the nitrogen-hydrogen bonds; therefore, bcteri hving this silver-nucleic cid complex presumbly Vol. 66, No. 4, April