SENJU EXHIBIT 2141
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`IPR2015-01105
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`PAGE 1 OF 8
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`PAGE 2 OF 8
`
`Von‘. 65. No. 6. June I976/833
`
`PAGE 2 OF 8
`
`

`
`170
`‘I60
`‘I50
`I40
`pgfml
`.130
`120
`110
`‘I00
`90
`80
`70
`60
`50
`
`
`
`
`
`TOTALBENZOCAINERELEASED
`
`10
`
`40
`30
`20
`
`Table II—Summary of Calculated Statistical Parameters
`
`Procl-
`ucl.
`
`B
`D
`E
`F
`G
`H
`K
`L
`M
`N
`0
`P
`Q
`R
`S
`
`Intercept
`(bu)
`
`-88.9583
`-62.6965
`-90.9342
`-69.2085
`-76.7483
`-81.1662
`-21.1737
`-6.8433
`-8.5915
`-10.7434
`-10.6500
`-8.634‘?
`-18.4070
`-11.9034
`-13.0224
`
`SE of
`Intercept
`
`SE of
`Regression
`Coefficient Regression
`[b,}
`Coefficient
`
`4.2313
`7.3624
`3.1531
`5.8930
`5.5375
`4.4574
`1.3366
`0.5277
`0.3772
`0.5166
`1.3357
`0.6929
`1.0351
`0.5641
`0.8578
`
`113.5101
`76.0611
`96.8973
`74.6488
`87.5097
`86.9697
`27.3889
`11.6569
`14.3776
`15.6600
`17.8333
`14.5876
`23.6619
`16.9296
`18.6843
`
`2.4429
`4.2507
`4.5225
`3.2689
`3.0717
`2.4725
`0.7717
`0.3047
`0.2178
`0.2982
`0.7712
`0.4001
`0.5976
`0.325?
`0.4952
`
`times that of the cocoa butter, and this difference was reflected in the
`variation in the total amount of benzocaine present in suppositories
`containing the same percent of benzocaine but different vehicles.
`The total mass of drug transferred from semisolids under the
`conditions of the in oitro experiment was nearly linear with respect
`to the square root of time for the times investigated (Fig. 2}. The linear
`portions of such benzocaine release curves were used in generating
`a linear least—squares regression line, and comparisons among the
`estimated parameters [Table II) were made [Table Ill} using the usual
`null hypothesis. The data points for Product I) were approximated
`with two linear portions (Fig. 2). and the line for the early time period
`was arbitrarily chosen for statistical comparisons (Tables II and III].
`In vitro testing of suppositories involves many considerations and
`some compromises in simulating conditions operating during rectal
`absorption. The conditions (6) that should be emulated are: lo) an
`average temperature of 36.9“; lb) water not present in the liquid state
`but present in the semisolid feces, which are 77-82% water: (cl rectal
`mucosa acting as a semipermeable membrane, allowing passage of
`water both away from and into the blood, depending on the osmotic
`gradient; (d l practically no peristaltic movement; [e] pressure on
`rectal contents varying from 0 to 50 cm of water, according to posture;
`and ifl possible presence of feces.
`In normal people, fecal material is present in the rectum just prior
`to defecation only (7). Most of the time, this organ is free of solid
`matter which could physically interfere with absorption. Therefore,
`it is not necessary to introduce a material for in ultra testing that
`would simulate the presence of feces. It is necessary, however, to ex-
`pose the dosage form to some fluid so that the drug has an opportunity
`to dissolve. While this exposure may seem to violate Condition b, a
`positive correlation between in cit.-o testing and in viva results would
`indicate that such exposure to fluids is acceptable for testing purposes.
`Testing at body temperature is critical, especially for products that.
`melt in the rectum. Conditions (1 and c are readily satisfied by using
`a temperature-controlled water bath and placing the suppository
`inside a commercially available. semipermeable, dialysis membrane
`tubing. Condition ct can he met by placing the dosage form in an un-
`stirred medium. Although this procedure may allow a buildup of drug
`around the dosage form. which can slow drug release, such a static
`dialysis method may have a closer relationship to the absorption of
`drugs through a biological membrane than dialysis when the bulk
`phase is stirred.
`The data reported here were obtained using a simple dialysis pro-
`cedure, without stirring of the bulk receptor phase, which exposed
`the suppositories tested to a single, uniform pressure and approxi-
`mated to some degree Conditions a, c, and d.
`Examination of the results for the commercial products (Fig. 1]
`reveals less release from the 1 1% preparation than the 10% preparation
`and somewhat greater release from the -1.9% preparation than the 5.4%
`preparation, although the latter difference is not significant. For-
`mulation factors other than concentration that could be playing a role
`include the presence of other ingredients that might interact with the
`benzocaine as well as different vehicle effects. The experimental cocoa
`butter formulations were completely melted within 10 min and the
`polyethylene glycol vehicles were dissolved within 1 hr. There was,
`however, no visible change in any commercial product during the 5-hr
`dialysis period. Each commercial suppository retained its shape, al-
`
`Figure l—E}',fect of suppository vehicle composition on release of
`drug from preparations containing benzocoine. Key: see ’l"able l’.
`
`blood sample collection, and blood analysis methodology were fol-
`lowed as previously reported (4).
`
`RESULTS AND DISCUSSION
`
`Table I shows the composition of suppositories selected for the
`investigation ofvariations in dialysis and rate of release for absorption
`of benzocaine. Figure 1 illustrates the variation in drug release ofsome
`experimental suppository formulations and the commercial products
`investigated. Since the active ingredient content of many commercial
`products is reported as a percentage, rather than an amount, Products
`A—-P were prepared on a percentage weight per weight basis. The
`specific gravity of the polyethylene glycol vehicle used was about 1.4
`
`rnl
`TOTALBENZCICAINEHELEASED,mgr'100
`
`
`
`10
`
`11
`
`I4 15
`13
`12
`MINUTES”
`
`I6
`
`17
`
`13
`
`Figure 2-—Rel'au'onship between. total mass of drug dialyzed and
`timel”. Key: see Table I.
`
`834 I Journal of Pharmaceutical Sciences
`
`PAGE 3 OF 8
`
`PAGE 3 OF 8
`
`

`
`Table III--Individual Comparisons Made“
`
`S
`
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`ns
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`no
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`ns
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`B
`
`_
`
`“Comparisons among rates of benzocaine release from the semisolid as measured by the regression coefficient of the total benzocaine re-
`leased with respect to the square root of time were made. All of these comparisons are not statistically inclependent.'I‘hereforc, when a com-
`parison is noted as significant at the 95% confidence level. it is meant that the rates of release of benzocaine for the two products under com-
`parison are likely to be different but at a confidence level slightiy less than 95%. The result is that some of the differences in release rate noted
`as ~* might not prove to be significantly different under more rigorous testing: I15 -‘= not significant. *-* = barely significant. ‘ = significant,
`and -« ‘~= not tested for significance.
`
`though they all became somewhat more pliable at the end of the ex-
`periment than at the beginning.
`The dialysis of drug from saturated benzocaine solutions was
`studied, and the ratio of total benzocaine to free benzocaine increased
`proportionately as the concentration of a nonionic hydrophilic sur-
`l'actant3 was increased from D to 7%. Addition of the surfactant to a
`solution containing a fixed amount of benzocaine increased the di-
`alysis rate compared to a solution without surfactant (5, 8). Therefore.
`0.05 and 1.0% of aorbitan rnonooleate or polysorbate 80 were incor-
`porated into both the polyethylene glycol and the cocoa butter vehicle
`containing 3% benzocaine.
`Figure 3 shows the effect on the cocoa butter suppositories and the
`increase in the amount and rate of henzocaine released. The greatest
`increase in release was due to the presence of 1% polysorbato 80. Since
`the membrane was not controlling the rate of diffusion (as evidenced
`by increasing diffusion with an increased concentration}, the sur-
`factant must have been increasing the rate of dissolution of the drug.
`This finding is consistent with work showing that an increase in
`benzocaine dialysis from surfactant—containing solutions is due to the
`increased solubilization of the drug because of surfactant-—di-ug in-
`teractions, followed by a rapid release of free drug as dialysis takes
`place (5, 8).
`
`Figure 4 shows the results of dialysis from polyethylene glycol
`suppositories containing surfactants. Between 63 and 80% of the active
`ingredient was released (Table I).
`It is not possible to use the actual amount of drug released from the
`different products [Table I} as a measure of the effect of the vehicle
`on dialysis of drug. since the amount present varies with the product
`considered. The percent of drug released, however, can be used for
`this purpose. The total released from the polyethylene glycol vehicle
`containing 10% benzocaine was almost 2.5 times the total released
`from the corresponding cocoa butter preparation when the percent
`benzocaine diaiysed was considered. The ratio was 2.9 to 4.2 when
`comparing the corresponding preparations containing 3% benzocaine.
`When considering the release from the 3 versus 10% preparations of
`a single vehicle type, it can be seen that the 10% formulation released
`a larger amount of drug but a smaller percent of drug during the di~
`alysis period {Table 1).
`Various concentrations of 3H-benzocaine in suppository dosage
`forms with and without surfactant (Table I) were selected for in viva
`testing and were inserted into the rectum of female Sp-rague—-Dawley
`rats. Blood samples (0.1 ml} were taken from the inferior vcna cava
`at 5. I0, 20, 30, 40. 60. 90, 120, 180, 240. and 300 min, and the total
`
`‘[20
`
`
`
`
`
`TOTALBENZOCAINE_FIELEASED.iu9a"ml
`
`NJ {ll
`
`20
`
`.5 U1
`
`.- 0
`
`on
`
`TD
`
`60
`
`10
`
`50
`
`40
`
`3D
`
`20
`
`
`
`
`
`
`
`TOTALBENZOCAWEFIELEASED.Hgfml
`
`1,0
`
`3.0
`2.0
`HOURS
`
`4.0
`
`5.0
`
`1,0
`
`3.0
`2.0
`HOURS
`
`4.0
`
`5.0
`
`Figure 3—E{f£’t‘t ofsurfoctonts on drug release from cocoa butter
`suppositories. Key: see Table I.
`
`Figure t—Effecl ofsurfactonts on drug release from polyethylene
`glycol suppositories. Key: see Table I.
`
`Vol. 65, No. 6. June 1976 / 835
`
`PAGE 4 OF 8
`
`PAGE 4 OF 8
`
`

`
`
`
`.
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`o
`
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`
`2
`
`3
`HOURS
`
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`
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`
`Figure 6—Blood radioactivity after the application of 3l‘.l-b£.'t'l.-
`zocaine in a cocoa butter suppository vehicle. Key: see Table I. A
`twolue larger than the critical t-value was obtained for all point
`comparisons except corue L versus K at I80 min, curve L versus J
`at 240 min, and come K versus J at 180 and 240 min. (One side of the
`standard error of the mean is shown.)
`
`for the radioactivity to appear, under the conditions of this experi-
`ment the total radioactivity represents several metabolites rather than
`intact drug (4). Therefore, no pharmacokinetic analysis using the
`blood level radioactivity versus time curves was done in the present
`experiment.
`A previous in uitro study (3) found that an increased concentration
`of benzocaine in polyethylene glycol ointment caused a decrease in
`release through a dialysis membrane. That decrease was explained
`on the basis of a decreased solubility and precipitation of the benzen-
`caine in a polyethylene glycol-water solution. which formed under
`the in oitro conditions. This effect was not observed during the cur-
`rent dialysis experiments and is apparently not occurring in viva, as
`evidenced by increasing absorption from an increased concentration
`of drug in this water-soluble vehicle.
`The absorption from a cocoa butter suspension of drug is much less
`in rate and amount when compared to equal concentrations of drug
`in polyethylene glycol (Fig. 6}. The latter vehicle is water soluble and
`can dissolve in the rectum. Benzocaine was dissolved in the polyeth-
`ylene glycol vehicle and. therefore, was available to partition into the
`rectal fluids and the rectal mucosa during liquefaction {dissolution}
`of the polyethylene glycol. Cocoa butter does not dissolve but melts
`in the rectum.
`Before liquefaction, dissolution of drug in rectal fluids is limited
`to the drug located at the surface ofthe suppository. Diffusion through
`the semisolid suppository is probably of little importance, since
`melting occurs readily at body temperature. After liquefaction, the
`~..I O
`
`01O
`
`U’! D
`
`dpmlml B
`BLOODHADIOACTIVITY,X10"’
`
`
`-hD
`
`(JO
`
`M D
`
`0
`
`40
`
`80
`
`160 200 240 280
`120
`MINUTES
`
`Figure 7-—Blood radioactivity alter the application of 3‘? “H-
`henzticcrine and s-ur,foclanfs in a polyellsylene glycol vehicle. Key:
`see Table l. A t—t-aloe larger than the critical t-value was oril_volJ—
`lairiod for-point comparisons on curue D versus E after 240 min, cw-oe
`E! versus C after 240 min, curoe E versus F after 240 min. and curve
`F‘ versus H or 90 min.
`
`450
`400
`
`350
`
`30D
`
`28B
`
`260
`
`240
`
`220
`
`2'00
`
`180
`
`160
`
`‘I40
`
`120
`
`100
`
`B0
`
`60
`
`40
`
`20
`
`
`
`
`
`BLOODRADIOACTIVITY,X10-’dpmlrnl
`
`Figure 5-—Blood radioactivity after the application of i'H—beri—
`zocoine in a polyethylene glycol suppository vehicle. Key: see Table
`l. A t-oolue larger than the critical t-value was obtained for all point
`comparisons except curve I versus B at 5 and it’? min; curve C versus
`8 at 5, I0, 20, and 300 min; and curve 8 versus A at 180 min. {One side
`of the standard error of the mean is sl1o1un_J
`
`radioactivity present was determined. The means of the radioactivity
`detected are shown in Figs. 5-9.
`Statistical analysis using unequal variance techniques indicated
`that weight variation among animals accounted for less than 5% of
`the variation following different dosage formulations. The standard
`error of the mean is included in some figures but not in others due to
`crowding. A point—hy-point comparison of the means obtained at each
`sample time for the nonlinear curves was made using the Student I
`test (95% confidence level). and the results are summarized in the
`figure legends.
`Due to the relatively large dispersion of experimental values. the
`ability to distinguish between mean values, which appear quite dis-
`tinct, is compromised. An example of this situation can be seen when
`comparing the results from Formulation A oersos Formulation B in
`Fig. 5 for the 180-min sample, The mean values for A and B were
`significantly different for each sample time (95% confidence level}
`except at 180 min due to the relatively large variances at that time.
`Increasing the number of animals in the study may have resulted in
`a significant difference in this case.
`The blood level radioactivities from different concentrations of
`“H-bcnzocaine in polyethylene glycol suppositories (1. 3. 5, 10, and
`20%} and cocoa butter suppositories (3, 10, and 20%) are shown in Figs.
`5 and 6. Increasing the concentration of -‘H-benzocaine in both
`polyethylene glycol and cocoa butter suppository bases resulted in
`a higher total radioactivity in the blood. Since the volume of sup-
`positories was equal with every concentration of drug administered,
`the total dose was increased by increasing the drug concentration.
`Both concentration and variation in total dose may be causes for the
`difference in the shape of the blood level curves using the same sup-
`pository vehicle.
`It is clear from Fig. 5 that an increase in the “H-benzocaine in
`polyethylene glycol increased the area under the carve up to 5 hr.
`Although this finding indicates an increase in the amount of drug
`being absorbed from the rectum. since the drug had in be absorbed
`
`836 I Journal of Pharmaceutical Sciences
`
`PAGE 5 OF 8
`
`PAGE 5 OF 8
`
`

`
`P <3
`
`5"o
`
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`
`
`
`BLOODHAOIOACTIVITY,xto"dpmiml
`
`El
`
`40
`
`BO
`
`120 160
`MINUTES
`
`5200 240 280
`
`Figure 8———Blood' radioactivity after the application of 3% “H-
`benzocoine and surfactants in a cocoa butter suppository oehicie.
`Key: see Table l. A t-value larger than the critical t—ualue was found
`for at least half of the points when comparing the curves of L versus
`0. L versus P, M versus P, N versus 0. and N versus P.
`
`suspended drug would be coated with melted cocoa butter, which is
`much less viscous than the original semisolid.
`Some drug may be exposed to the rectal fluids for rapid dissolution,
`but most drug would still have an oleaginous coating in which the drug
`has a very low solubility. The drug would have to diffuse through this
`mating before absorption could occur. Therefore, the slower drug
`absorption from the cocoa butter is not surprising, since the drug
`particles would be coated by a hydrophobic substance in which the
`drug has a low solubility.
`Surfactants were included in the 3% “H-benzocaine in polyethylene
`glycol and cocoa butter suppositories to determine if the presence of
`a nonionic hydrophilic or lipophilic surfactant would affect the rate
`or amount of benraocaine absorption. Incorporation of a 1% lipophilic
`or 0.05 or 1% hydrophilic surfactant in the polyethylene glycol vehicle
`resulted in an apparent increase in total blood radioactivity (Fig. 7)
`for times beyond 180 min. although the range of values was wide
`enough for the differences of the means to be not statistically signif-
`icant at. most times.
`With 3% 31-Lbenzocaine in cocoa butter base, the lipophilic sur-
`factant in both concentrations studied (1 and 0.05%) showed no sig-
`nificant influence on the amount absorbed (Fig. 8). However, the
`hydrophilic surfactant in both concentrations studied decreased the
`total counts in the blood significantly with most times under inves-
`tigation.
`Table III shows that for the products in Fig. 4 the release rates of
`only Formulations D and E were significantly different in uitro. All
`products were essentially the same in oivo with respect to the rate of
`drug release. All products with surfactant in cocoa butter, however,
`demonstrated a significant increase in the rate of drug release in vitro,
`but the only significant effect in viva was a decrease in release with
`1% polysorbate 80. l n some cases the in uitra method did not accu-
`rately predict the in viva effect. In these cases there were relatively
`small actual differences for the in oitro system, although the differ-
`ences were statistically significant.
`In the earlier part of the study, some experiments were run to
`measure the blood level concentration of radioactivity versus time
`using male rats. Female rats showed a total radioactivity in the blood
`about twice that of male rats (Fig. 9} when the same dosage form was
`administered. These differences could be due to differences in the rate
`of absorption, hiotransformation, distribution, or excretion. Ab-
`sorption across rectal membranes is usually considered to be a passive
`diffusion process. In passive diffusion, either the release of drug from
`
`PAGE 6 OF 8
`
`op-rnirnl
`BLOODFlAD|DACT1\r‘|TY_X10"’
`
`
`D
`
`40
`
`80
`
`200 240 280
`120 160
`MINUTES
`
`Figure 9--Comparison of blood radioactivity following 393 “H-
`benzocoine in a polyethylene glycol oehicle in male and female rats.
`Key.‘ see Table I. A t-value larger than the critical t.-value was found
`for point comparisons of male versus female rats receiving the some
`formulation except for the first 66 min for E; versus EM and G;
`versus G”. {The F subscript is for female rats, and the M subscript
`is for male rats.)
`
`the vehicle or drug dissolution in rectal fluids would be the rate-lim-
`iting step for absorption, especially with a drug like benzocaine which
`has a low water solubility.
`The decreased rate of appearance of radioactivity in the blood from
`20% 31-I—benzocaioe in the cocoa butter vehicle compared to 20%
`1'-H-henzocaine in polyethylene glycol indicates that the rate of ab-
`sorption is dependent on the amount of drug released from the vehicle
`and presented to the rectal mucosa, at least for the concentrations of
`drugstudied here. Since the same vehicle and drug concentration were
`administered to males and females. it is unlikely that the observed
`differences were due to differences in absorption. Furthermore, the
`differences probably were not due to differences in excretion half-life
`of the parent drug or of identical amounts of the same metabolites in
`males or females because most drugs are excreted by a first-order
`process in either sex.
`'
`Excretion of total radioactivity and loss from the bloodstream may
`be different in males and females if metabolism is occurring at dif-
`ferent rates and if different amounts of metabolites are available for
`excretion. One possible explanation for the results could be that males
`were metabolizing the drug to more polar products faster than the
`females and the more polar products were being cleared from the
`bloodstream more rapidly than the parent drug. Another possible
`explanation could be that distribution of the molecules containing
`radioactivity was different for male and female rats. Further work
`involving tissue distribution and metabolism is underway in these
`laboratories to determine which possibility is correct.
`'
`
`SUMMARY AND CONCLUSIONS
`
`A simple dialysis method was used to measure the release of hen-
`socaine from various experimental and commercially available sup-
`positories. Wide variations were found in the amount of benzocaine
`dialy-zed. Small differences, which were detectable in oitro, were not
`seen in viva in rats. although substantial differences in oitro were
`correlated well with experimental results obtained in ciao.
`Benzocaine was dialyzed and absorbed rectally in rats more rapidly
`from a polyethylene glycol vehicle than from cocoa butter, and the
`effects of the surfactants tested were variable. Rectal administration
`of the same concentration of “H-benzocaine in the same vehicle to
`male and female rats results in lower blood radioactivity versus time
`curves for the male rats.
`Some formulation factor other than the concentration ofbenzocaine
`affected the relative amounts of benwcaine released in oitro from the
`commercially available products examined. Although the dialysis
`method is useful for evaluating the effects of formulation on drug
`
`Vol. 65, No. 6, June 1976'/837
`
`PAGE 6 OF 8
`
`

`
`release from suppositories, the desirable release rate for the specific
`drug investigated has not been determined since its minimum effec-
`tive concentration is not known. Considerably more research is needed
`in this area.
`
`(7) E. Nasset, in"Medical Physiology," 12th ed., P. Bard, Ed, C.
`V. Mosby, St. Louis, Mo., 1968, p. 559.
`(8) H. Mateumoto, l-I. Matsumura, and S._Iguchi, Chem. Pharm.
`Bull, 14, 39l(1955l.
`
`REFERENCES
`
`(ll W. W. Davis and W. E. Wright, in “Pharmacology and the
`Skin," W. Mantegna, E. J. Vanscott, and R. B. Stoughton. Eds... Ap-
`pleton-Century Crofts, New York, N.‘1’., 1972, pp. 37-39.
`(2) M. Gibaldi and S. Feldman, J. Pharm. Sci, 59, 579(I9?0).
`(3) J. W. Ayres and P. A. Laskar, ibid., 63, I-i.02(197-1).
`H) J. W. Ayres, D. Lorskulsint, and A. Lock, ibid., 84. l;958{19'r'5).
`[5] H. Matsumoto, H. Matsumura, and S. Iguchi, Chem. Pharm.
`Burt, 1-1,3a5(19es}.
`(6) I. Setnilrar and S. Fantelli, J. Pharm. Sci., 5|, 566(1962].
`
`ACKNOWLEDGMENTS AND ADDRESSES
`
`Received February 26, 1975, from the Department of Pharma-
`ceutical Science, School of Pharmacy, Oregon State University,
`Corvallis, OR 97331‘
`Accepted for publication August 11, 1975.
`Abstracted in part from the thesis submitted by D. Lorskulsint to
`the Graduate School, Oregon State University, in partial fulfillment
`of the Master of Science degree requirements.
`Supported in part by Biomedical Sciences Support Grant RP.
`07079.
`* To whom inquiries should be directed.
`
`Attainment of Highly Uniform Solid Drug Dispersions
`Employing Molecular Scale Drug Entrapment in
`Polymeric Latices
`
`A. B. LARSON “ and G. S. BANKER‘
`
`Abstract D'I‘he uniformity of distribution attainable for an amine
`drug in solid dispersions prepared using a molecular scale entrap-
`ment procedure was investigated. Excellent reproducibility of drug
`content throughout the entire entrapment product was demon-
`strated in both flocculated (high drug levels} and deflocculated
`(low drug levels) systems. Drug content and content uniformity
`were found to be predictable for dellocculated systems, even at
`high drug dilution ratios. Milling or particle-size fractionation ap-
`peared to have no effect on the distribution of drug throughout the
`solid dispersion entrapment products. Dry blending was inferior to
`molecular scale drug entrapment in distributing small quantities
`of drug uniformly.
`
`Keyphrases III Dispersions, solSd—amine drugs, uniformity of dis-
`tribution, molecular scale entrapment procedure, flocculated and
`deflocculated systems El Molecular scale drug entrapment—uti-
`lized to prepare solid dispersions of amine drugs, uniformity of dis-
`tribution studied Cl Distribution uniformity—amine drugs in solid
`dispersions studied, molecular scale entrapment procedure, effect
`of milling or particle-size fractionation Ell Amine drugs—-uniformi-
`ty of distribution in solid dispersions, molecular scale drug entrap-
`ment procedure
`
`Safety, efficacy, and reliability are the three basic
`criteria that define the quality of any well-designed
`pharmaceutical dosage form. High standards of drug
`product quality are necessary for the protection of
`the public, and one important facet of quality assur-
`ance is the maintenance of content uniformity. Con-
`tent uniformity directly bcars on each of the three
`criteria defining drug product quality. The impor-
`tance of content uniformity in solid unit dosage
`forms to the consumer’s health, safety, and welfare
`becomes obvious when one considers the potency of
`many drugs in use today.
`
`833 2' Journal of Pharmaceutical Sciences
`
`PAGE 7 OF 8
`
`BACKGROUND
`
`Failure to meet content uniformity specifications in a solid dos-
`age form may be attributed to weight variation between dosage
`units or improper mixing (nonhomogeneity of drug distribution).
`Another factor resulting in inaccuracies of drug content in tablets,
`capsules, or powders is drug segregation. Improper mixing leading
`to nonuniformity can result from the inherent difficulty in setting
`the "ideal mixing time" for high dilution solid dosage forms. Ho-
`mogeneity of a potent active ingredient throughout a powder mix
`is highly dependent on particle size and shape, particle-size distri-
`bution, density, moisture, and charge. Furthermore, the size, effi-
`ciency, and type of mixer can make a difference when choosing a
`mixing time specification.
`A "perfect mix” for a powder formulation would be exemplified
`by a three-dimensional location of drug plus excipient in space, in
`which every drug particle is the same size and is the same distance
`in all planes from every other drug particle. Two miscible liquids
`most closely approach (in practice] a perfect mix, since mixing oc-
`curs at a molecular level and is completely random. This result is
`never attained in powder blending due to the finite number of par-
`ticles involved and the factors previously listed that may contrib-
`ute to unmixing or segregation. However, a reasonable mix is pos-
`sible if there are enough particles per drug dose and if the opti-
`mum mixing time is selected after carrying out adequate testing
`and sampling of the powder blend.
`A high degree of mixedness achieved in a powder mix, however,
`does not necessarily mean the final product will meet content uni-
`formity specifications. Segregation can occur when the mix is re-
`moved from the mixer, transferred to another point in the plant. or
`subsequently treated by other processing procedures. Further-
`more, for capsules and tablets. nonuniform flow and subsequent
`weight variation could hinder unit-to-unit drug content even more.
`In addition to these manufacturing problems, other problems
`concerning the control of content uniformity include analytical
`methods and statistical procedures. To allow content uniformity
`determinations on individual unit dosage forms, the assay methods
`must be accurate, reliable. and specific as well as sufficiently sensi-
`
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