DRUGS AND THE PI-IARMAIJEUTICAI. SCIENCES
`
`VOLUME 40
`
`SEDDND EDITION, REVISED IIND EXPANDED
`
`EDITED 3‘!
`
`REPLACEMENT Mylan Ex. 1015, Page 1
`
`

`
`Library of Congress Cataloging—in~Pub|ication Data
`
`Modern pharmaceutics .
`
`(Drugs and the pharmaceutical sciences ; V. 40)
`Includes bibliographical references.
`1. Drugs——Dosage forms.
`2. Biopharmaceutics.
`3. Pharmacokinetics.
`4.
`Pharmaceutical industry--Quality
`control.
`I. Banker, Gilbert S.
`II. Rhodes,
`Christopher '1‘.
`III. Series.
`RS2UO.M63
`1989
`615’.1
`ISBN 0w8247—7499~X
`
`89~23365
`
`COPYRIGHT o 1990 by MARCEL DEKKER,
`
`INC. ALL RIGHTS RESERVED
`
`Neither this book nor any part may be reproduced or transmitted in any
`form or by any means, electronic or mechanical,
`including photocopying,
`microfilming, and recording, or by any information storage and retrieval
`system, without permission in writing frcm the publisher.
`
`INC.
`MARCEL DEKKER,
`270 Madison Avenue, New York, New York 10016
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`REPLACEMENT Mylan Ex. 1015, Page 2
`
`

`
`Oisperse Systems
`
`EU.
`
`SUSPENSIONS
`
`339
`
`A. Advantages and Disadvantages of Suspension as a Dosage Form
`Even those of use who have 'l1’1'v'€SlE(i considerable time and iabor in the
`l“c.ir1ti1.:iatiot1 of suspensions must. admit
`that the suspension has
`number of
`:'.iis:3td'-:'an1_at_;'es
`a dosage !"m*n1. First, unif'ormity and accuracy of dose.
`even when the prepai‘tit.itm is nurse administered,
`is unlikely to compare
`t‘a\ror'atily with that obtainable by the use or" tablets or capsules.
`Ser.iimen-
`tation and compaction of sergliment. cause problems wiiich are by no means
`always easy to solt-"c.
`Fur-tl'ie'r,
`the product
`is liquid and 1'-elati\»'ely bulky;
`these pr‘-operties are disatlvaritageous to ‘noth pharmacist and patimit.
`Form-
`ulation of an effective and pharmaceutically elegant suspension is usually
`much harder to achieve than of a tablet or capsule of the same drug.
`l-lowevet; suspensions do have some aclv-.mtages which can, under certain
`circtuiistaiices, oiitweigh their disatlvantages.
`sllany of the more rer=.e'ratly developed drugs are basically hydrophobic
`in nature and thus their aqueous solubilitics are low. Thus solutions of
`these drugs, containing an appropriztte dosage, woiild be of an unacceptably
`large volume.
`Suspensions allow the development of a iiqtiid dosage form
`=:‘.cnt:-lining an appropriate quantity of drug in a reasonably small *.-'olume.
`Further,
`resistance to hydrolysis and oxidation is generally good compared
`with that deserved in aqueous solution.
`Suspensions
`also be used to
`mask.
`the taste of drugs. Also,
`there is a significant proportion of the
`population, especially very young children, who have difficulty in swallow-
`ing t..=',tblets or capsules.
`in recent years increasing attention has been
`given to the use of suspensions in intramuscular injection for depot therapy.
`For example, a l’1llll1iJ1’:'l" of research teams are presently developing intra~
`muscular suspensions of contraceptixre steroids that may ;»'_§.i.ve contraceptive
`protectioa*-. for periods in excess of a year.
`
`8.
`
`Physical Stability of Suspensions
`
`Pharmaceutit.-al suspensions are basically unstable systems. Aggregation of
`suspended particles and sedimentation {and possibly impaction of sediment}
`present real prohlt-zms to the pharinaceutical Formulator.
`As has already
`been indicated, much of the theory relevant
`to the formulation of 3.CCE,‘pi.£-ll')lE}
`pharmaceutical suspensions is derived from the findings of colloid scientists
`who have stmlied model systems. There are, however, several important
`differ-ericzes between model coiloidal systems and pharmaceutical suspensions,
`some of the more important. of which are shown in Table 6.
`
`Repulsive and Atti'-rtctfve Forces Between Particles
`
`!‘.—'luch of the present-day theory regarding the chat*._L_fc on suspended particles
`results fromthe work oi’ four scientists: Derjaguin and Landon from the
`Soviet Union, and Verney and Overbeek from the I\iethe.rlands. The theory
`is thus often referred to
`the l.'JLVO theory. This theory allows us to
`t'lB\"ElOl_3 insight
`into the factors responsible for controlling the rate at which
`particles in a suspension will come together, or aggregate.
`to form dupiets
`(two particles],
`triplets (three particles), and so on. The process of‘ ag-
`gregation will accelerate sedimentation and affect redispersibility and thus
`important
`to the pharmaceutical scientist formulating a suspension. The
`total energy of interaction, VT, between two particles is definecl as
`
`REPLACEMENT Mylan Ex. 1015, Page 3
`
`

`
`31:6
`
`Rhodes
`
`‘Fable 5.
`
`l)it‘t'eren<:es Between £_‘.olloit,lal and Pharinaceutical Suspensions
`
`ltltitzlel colloidal. suspensions
`
`E’harmaceutioal suspensions
`
`l-lomotlisperse (Le. , suspended
`particles alinost all the same
`5.:E‘.¢e)
`
`Heteroriisperse (i.e., suspended. parti—
`cles-:. of a (.':tI)l’l2-'$IitTii~‘3i’e'ii)i£:‘ range of
`sizes)
`
`Particles less than about
`in diameter
`
`I ma
`
`Pai:’ti(:1es often very mtioii larger than
`1 pm
`
`Continuous phase simple in
`nature; basically aqueous
`
`Continuous, often complex: containing
`many substances as well as water
`
`Shapes of particles usually close
`to spherical
`
`Shapes often quite nonspherlcal {e.g.,
`needle crystals)
`
`Solids content usually low (e.g. ,
`2%)
`
`Solids content sometimes very high.
`(e.g. , 50%]
`
`V
`
`T
`
`3 V
`
`R
`
`4- V
`
`A
`
`”‘
`("i
`
`where VR and VA represent the repulsive and attractive forces, respectively.
`(It is possible to estimate VR and VA; see Matthews and Rhodes [23]).
`Figure 2 exemplifies some energy-of-interaction curves. Curve A applies
`when VR > VA,
`that is,
`the term VT is aiways positive because of the high
`potential at the double layer.
`In such cases a suspension would exhibit
`very good resistance to aggregation (_i.e., flocculation or coagulation)
`provided that the particles are not sufficiently large to sediment under
`gravity.
`Curve B shows a high potential energy barrier, VM, which must be
`surmounted if the particles are to approach one another sufficiently closely
`to enter the deep primary energy minimum at P.
`If the height of the energy
`barrier VM greatly exceeds the mean thermal energy of the particles,
`they
`will not be able to enter P. The value VM required to just prevent this is
`probably equivalent to a zeta potential of about 50 mV. Thus,
`in formulat-
`ing a pharmaceutical suspension it
`is often useful to aim at a system with
`a zeta potential of more than 50 HIV. Aggregates that do form at P are
`likely to be very tightly bound together since H,
`the interparticulate dis-
`tance,
`is small and the energy well at P is often quite deep. Thus in a
`pharmaceutical preparation very vigorous shaking would be required to
`redisperse the product.
`It should also be noted that there is a secondary
`energy minimum at S.
`If this trough is sufficiently deep,
`loose aggregates
`can form at this point;
`these will usually be easy to re-disperse.
`Curve 0 shows the situation that exists when attractive forces com-
`
`pletely overwhelm ‘repulsive forces {i.e., VA > VR). Under other such
`conditions very rapid aggregation will occur.
`The curve VS shows the stabilizing effect of surfactants adsorbed on
`the surface of suspended particles;
`it shows a quite sharp cutoff point at
`Ed, where d is the thickness of the adsorbed surfactant layer. The strong-
`ly hydrated nature of surfactant head groups impedes particle-particle
`
`REPLACEMENT Mylan Ex. 1015, Page 4
`
`

`
`Disperse Systems
`
`3-'41
`
`
`
`Figure 2 Total energy of interaction curve between suspended particles
`(h is the inte1'-particulate distance).
`
`(.‘.0I1l’.8.Ci, which. would result in aggregation. Thus, even nonionic surfac-
`tants can be used to stabilize suspensions.
`It shouid be noted, however.
`that an excessive quantity of stir-facztant can,
`in some systems, have a
`significantly adverse affect on stability.
`
`:1 ggregotion K inet ice
`
`The aggregation of particles in a suspension can be termed flocculation or
`coagulation. The term coagulation should be used when the forces involved
`are primarily physical due to reduction in the repulsive forces at the double
`layer. The term flocculation is applied to those cases in which “bridging“
`occurs between particles. However, since in many‘ pharmaceutical systems
`the exact nature of the forces is somewhat obscure. we shall restrict our—
`selves here to use of the term aggregation. Using" simple ciiffttsion theory
`[24], Von Smoluchows1<1' derived equations for both. rapid aggregation [when
`all p-article~perticle collisions result in aggregation") and slow aggregation
`fin which only a fraction,
`fit, of all particle—particle collisions result in the
`forination of aggregates).
`Pharmzaceiitical scientists are concerned primarily
`with slow aggregation, sirzee the aggregation in suspensions of drugs is
`mainly slow. The tng,
`time for the initial number of particles {singlets}
`in a suspension to decrease by 50%, because of aggregation is given by
`
`t..=
`H2
`
`'
`'-lD1l7tN0u:1
`
`(5)
`
`REPLACEMENT Mylan Ex. 101 5, Page 5
`
`

`
`an-;-A
`
`3&2
`
`Rhodes
`
`trem-
`the §3;.'.ts
`the saingglet, R is:
`r.:oet‘i'i(.:iea'it {in} ml.‘
`r!il‘i"i.i:-:is.‘m.
`:l'u:-
`is
`where iii
`initial
`i't11li!i.'mt'.‘ of simzltetz ii-.~.1r°t.ie|.e.<;, and -.-is.
`is
`the collision
`ihc-'5.
`st.a'-.ir1t.; N0 is
`it
`is r'-‘.I.IllIiE-,‘.li1'l‘i\’-3{-.‘-
`:':om-'i.\.ni:=ei.1i‘.
`to rietemiine W,
`the st:;il'.>ilit.y raiti-J;
`ei'f.'i<:ier1c:y.
`this is the :‘f.=!(‘:i[.!r'rI}i'.’:':tl of r:olEisir.n'1 r.-:f'a“i.c.rie.iu'.'3,=. This t'£>,lt{ii’.l\”€}ly
`.<;im1.'1le E?i.}_)[.)l"0E\{.‘i'
`to the l<iriet.i<:s oi’ 2tge;re2e;::it.ii:';:i
`ii'lf‘lilt'l£'2i'-‘-
`:1ssi1mptioi'is not always a1j.)pl.i(.:s.l:ie to
`1)iii).t'In:1<:e:.ttit:nl
`L-“a}',=‘E-‘ul'(-‘.lllS [25i.
`in I'JE'i.l"l.l.vi.tlllEt.I‘,
`ri
`iiiixtnr-<-3 of la-1i‘g__>je. entl siliztll
`p2.u’tieles as ‘may ijrt-': u.-_mmi:.mty i:‘o1:n<i
`in :1
`;>l1e.1mii:'ureutit'.:aE 53t1.*'~5pI_—':l1Sl:')t1 will slim
`s c.£iff‘e1'*er1t
`I‘-:'1t'e of’
`-.-1g'g:‘eg=;:it.l:.'nri
`to that. of at Hitililill‘ system oon'r.;-finirig pm“
`tttrles of only one size l‘2il§.
`
`Wetting
`
`i:‘or.'mul.a.tet'.{ En. siispeiisisms ere besitzulty hythopliobic in ne.tu1?e,
`Many rl_r-tags
`and thus in the al'Jsenee of ['1 s;:1it:'.-ihie wetting agent the tlrug particles
`would merely float on the ar[neo1.1s plmse.
`Stirf:-1¢:l.ent.s, p:1r*ti<':uler1y tmionizr-.
`or nonionie, are thei*e['or*e ir1t:l:.t<'.£eri
`in ph-aimnec:eutitrai suspensions. The
`hy<.'11°ocai=bon tail of the ssL:r.*faet-L‘-mt becomes atisorberl onto the sut*f'au::e of
`the particle, with the hyzzlmted he:-'1('l groiip l'"or-ming a link with the :3.f..}_lt(-:¢_'rtl1~‘_«
`ptiase.
`
`Brownian Motion and Desimenttttion
`
`it will experience random motio
`If s Suspender} particle is siiffieiently small,
`due to molecular‘ boinberdiiient, which at
`times will be greater on one facet
`of the particle than on others. The Brownian motion of the pamiele (some-
`times known as the ctr-unken walk) will be sufficient to prexrent sedimenta-
`tion.
`The r,lisplat:ement or distance moved, D1, due to l_:§I‘DV.\r'f1iE!.t1 motion is
`given by
`
`._-3.1‘-_,
`2 ..
`Di. h N3'fir‘,I‘
`
`'7
`L
`
`J
`
`where R is the gas constant, T is the te1npei*atu'r*e in degrees Kelvin, N is
`Avogaclrxfs numl:JeI',
`r:
`is the viscosity,
`t
`is the time, and P is the radius
`of the particle. Note that the larger the value of 1°,
`the smaller the value
`of Di.
`The basic equation controlling settimentation for spherical particles is
`that defineci by Stokes.
`it states that the velocity of sedimentation, V,
`goiter-nett by the formula
`
`is
`
`2
`‘Mel - .00) P 8
`F1.
`
`where {)1 and pg are the density of the particle and eontirtuoils phase,
`respectively, and g is the gr-avit.at.ional constant;
`the other symbols have
`the same meaning as in Eq.
`(7). Of cotarse,
`few,
`if any phe'rme<:ei1tit:ei
`pcawtiers are spherical, and the equation is only i°igor’ouely applicable to
`systems in which the settling particles do not iI1tet‘fer'e with one another.
`Since in many phamiaoettlical suspertsions the solids content is high, hin-
`rlerecl settling can be expected to I’J(_’(Zi.l‘E‘. Thus some wot'l~Let*s
`in this area
`have applied other relationships, such
`the Kozeny eqlietion {la}. How-
`ever, eonsiciet'at.ion of Stokes‘ law does allow an understanding of some of
`the techniques that
`the phai=maceiitic:ai fot'inulatoi:* can use in o':?cler* to pm-
`
`REPLACEMENT Mylan Ex. 1015, Page 6
`
`

`
`..4.:
`
`Disperse Systems
`
`3Li3
`
`Table T Estimated Effect of Percentage Glycerol on
`NSD for Pat-ticitis of" Density 1.3 g.."c':r‘.3
`
`Glyccroi
`( -96 V ii V
`NSJJ
`l_].l’!1l
`
`0
`
`2.2
`
`20
`
`fill
`
`70
`
`Ill!)
`
`3.7
`
`(1.1
`
`8.5
`
`26.9
`
`It can be seen from Stokes” law that both
`dame an at':cept:.tble suspension.
`viscosity and density can affect the velocity of sedimentation.
`A wide
`variety of suspending agents is available for l"ormi:la{.ioi'i.
`Som-:2. such as
`cellulose derix-'atives, have a pronouncecl effect upon viscosity but scarcely
`any on density. Others, such as sorbitol, mod.i.i’y both density and viscosity.
`it can be seen from Eq.
`(8)
`that if the density r;iit'f‘erence between the par-
`ticles and continuous phase can be eliminated sedimentation can be prevented.
`l-lowever,
`it
`is seldom if ever possible to increase vehicle density above
`about 1.3, and acrroimiirigly,
`it
`is not possible to match particle density,
`although it
`is possible to reduce the density difference.
`Examination of Eqs.
`(T) and (8) reveals that as the radius of a suspended
`particle is increased, Brownian motion becomes less important and sedimen-
`tation more important.
`For any given system we can define a "no sedimen-
`tation diameter" (NSD), below which value Brownian motion will be sufficient
`to keep the particle from sedimentation. The value of NSD will obviously
`depend on the density and viscosity values of any given system.
`The data shown in Table 7 were estimated by Matthews and Rhodes [27].
`Calculations of the type made by these workers may prove to be of really
`practical value in Future t‘ormulat.ion work. Thus it can be seen from Table
`7 t.hat
`if one had a powdered drug of less than 7 tun in diameter, a 70%
`glycerol medium would apparently be of sufficierit viscosity and density to
`prevent sedimentation.
`
`Crystal Growth (Ostwald Ripeningl
`
`The surtace free energy for small particles is greater than for large par-
`ticles.
`"in some systems,
`theret'ore. small particles will be appreciably more
`soluble than large ‘particles.
`For such systems small fluctuations in tem-
`perature will result in crystal growth as the small particles dissolve with a
`temperature increase and then or-ystall.i?.e as larger particles or on the sur-
`face of existing particles, with a temperature drop. Thus the large particles
`will grow in size at
`the expense of the smaller ones. The suspension will
`l'JE?(_‘.Ol'1'[e coarser as the mean of the particle size spectrum shifts to higher
`values. Vlariy gums adsorb onto crystal surfaces and thus can be used to
`inhibit crystal growth.
`Free;:e~th-aw as well as more elecated temperature
`cycling tests can provide a useful technique for evaluating crystal growth
`and crystal growth inhibitors.
`
`C. Methods of Evaluating Suspensions
`Sedimentation Volume
`
`'l‘h.<-2 measurement of the ‘volume of sediment produced by a given formula-
`tion of’ a
`suspension has been used by a number of workers in attempts
`
`REPLACEMENT Mylan Ex. 1015. Page 7
`
`

`
`31474
`
`Rhodes
`
`to evaluate suspensions [$18,291. Host commonly sedimentation volume, V3
`is defined as
`
`vs = S x 100
`0
`
`(9)
`
`where H is the ultimate settled height and Hg is the original height of the
`suspension before settling. For example,
`if 100 ml of a well-shaken test
`formulation is placed in a graduate cylinder and it is found that the ultima
`height of the sediment is at the '2D-ml line,
`then V5 is 20. As will be
`IV.
`shown in a later discussion of controlled aggregation formulation (Sec.
`D},
`it is normally found that
`the greater the value of V3 for a given mass
`of drug,
`the more satisfactory the product.
`
`Ease of Redispersibility
`
`if a pharmaceutical suspension does produce a sediment on stor
`Obviously,
`age,
`it
`is essential that it should be readily dispersible so that uniformity.
`of dose is assured. The amount of shaking required to achieve this end
`should be minimal;
`the formulator should consider the problems of an 80-
`year-old, somewhat absentminded arthritic.
`Stanko and DeKay [28] were
`probably the first workers to propose the use of redispersibility tests for
`pharmaceutical suspensions. Various modifications of the basic principle
`have been described.
`For example,
`the suspension may be placed in 100-
`ml graduate cylinders which after storage and sedimentation are routed
`through 360“ at 20 rpm. The endpoint is taken as being when the inside
`of the base of the graduate is clear of sediment [30]. The ultimate test 01
`residpersibility is the uniformity of suspended drug dosage delivered from"
`a suspension product,
`from the first volumetric dose out of the bottle to
`the last, under one or more standard shaking conditions as just described.
`
`Particle Size Measurements
`
`These are useful in that they can allow aggregation or crystal growth to
`be evaluated. Particle size measurements of dispersed systems are often
`employed as fundamental quality control procedures and standards for phat
`maceutical suspensions in ‘particular manufactured in production operations.
`
`Rheological Studies
`
`As indicated in an earlier part of this chapter. rheological evaluations can
`be rapid and simple or detailed and complex, depending on the exact natui
`of the product [31]. They are also an important quality control feature of;
`all dispersed systems. The adequacy of hydration and quality control of
`the gums used as suspension-viscoasity-imparting vehicles is best confirmed-
`by a rheological check. All of the gums, whether natural (acacia,
`traga-=
`canth, etc.), modified natural (cellulose, alginate derivatives, etc.), or
`I
`synthetic (carbcxyl, vinyl, pyrrolidone. etc.), are polymers or contain
`to
`polymer constituents that vary in molecular weight distribution from lot
`lot. This in turn may have a material effect on vehicle viscosity.
`In ad-
`dition,
`the degree of dispersion of emulsions influences viscosity, as does"
`particle size and particle size distribution, providing a usable method of
`quickly verifying dispersion consistency.
`
`REPLACEMENT Mylan Ex. 1015. Page 8
`
`

`
`Disperse Systems
`
`3345
`
`Temperature and Gravitational Stress Tests
`
`Some experts in the field of suspension formulation place great reliance on
`temperature and gravitational stress tests, whereas others have considerable
`reservations about their use based on subjecting systems to forces they
`will never encounter in practice. The use of storage at elevated tempera-
`tures is less popular than temperature cycling, and certainly a freeze-thaw
`type of test {e.g., +40 to -5°C in 24 hr) can be of real value in crystal
`growth studies. Centrifugation at relatively low rates may also be effica-
`cious in predicting in-use stability; however,
`there is a marked paucity of
`published data relative to this point.
`It is possible that testing suspensions
`at relatively low rates of centrifngation may have sound theoretical basis
`{.25}.
`
`Zeta Potential Determinations
`
`As discussed earlier (Sec. II.C), determination of zeta potential can be of
`value in the development of a pharmaceutical suspension, particularly if the
`controlled aggregation approach described immediately hereafter is used.
`
`0'. Controlled Aggregation Formulation of Suspensions
`The application of zeta potential measurements to the formulation of pharma-
`ceutical suspensions is generally attributed to Haines and Martin [32].
`They pointed out that if a suspension were prepared with a high zeta poten-
`tial the mutual repulsion between particles would be strong;
`thus one would
`expect the rate of sedimentation to be slow. One's first reaction might,
`therefore, be to prepare suspensions with as high a zeta potential as pos— '
`sible. However, because the sedimentation rate is slow the particles in the
`sediment will have plenty of time to pack tightly by falling over one another
`to form an impacted bed. The sedimentation volume of such a system is
`low, and the sediment is difficult to redisperse.
`If, however,
`the amount
`of electrolyte, and hence the zeta potential,
`is reduced somewhat,
`the sys-
`tem may still have sufficient physical stability for the patient to obtain a
`uniform close after shaking; but the sedimentation will be comparatively
`rapid, and the aggregates would not have time to impact at the base of the
`container. The sedimentation volume is high, and redispersion is relatively
`easy. Basically,
`therefore,
`the controlled aggregation theory produces
`pharmaceutically elegant products as far as ease of redispersion is concerned,
`by control of zeta potential "not
`too little, not too much" [33].
`Such sys-
`tems may develop some region of clear supernatant solution above the loose
`sediment and may accordingly look less uniform on standing, even though
`they provide the greatest ease of redispersion and best dose uniformity.
`
`Guidelines for Suspension Formulation Using the Controlled
`Aggregation Technique
`
`1.
`
`2.
`
`3.
`
`Select a nontoxic surfactant for wetting the drug. Normally an
`anionic material might be preferred, but nonionics may also be used.
`If necessary, add a suspending agent (e.g. , sodium carboxymethyl-
`cellulose). Care should be taken to ensure that there is no chemical
`or physicochemical interaction among surfactant, suspending agent,
`and any electrolyte that may be used.
`Add just sufficient nontoxic electrolyte to produce aggregation.
`
`REPLACEMENT Mylan Ex. 1015, Page 9
`
`
`
`

`
`346
`
`Rhodes
`
`{)5
`
`4. Check that additional components, such as flavors, colors, homec-
`tants {to prevent the closure and the bottle form locking or stick-
`intj, or preservatives, do not substantially modify the properties
`of the system.
`Evaluate the product after storage for, say,
`Redispersibility tests
`b. Sedimentation volume tests
`:1. Particle size measurements before and after temperature stress
`tests
`
`1 month by:
`
`«:1. Rheological tests
`e. Cyclic stability tests
`
`it will often be found that
`if the controlled aggregation approach is used,
`storage for long periods, say, a year or more, will make little if any dif-
`ference to the results.
`
`6. Check the suspension stability in the final package.
`
`Recently, optimization techniques (see Chapter 17) have been applied
`to suspension formulation {33a].
`
`E. Preparation of Suspensions
`
`the
`Once a satisfactory laboratory-scale formulation has been developed,
`In
`problem of pilot- and manufacturing-scale production must be solved.
`the research and development
`(R&D)
`laboratory we will probably be produt
`ing quantities in the region of 200 ml (or less) up to a liter or two, where
`in industry much larger quantities will be produced {several decaliters up
`to kiloliters}. At this scale-up point we may well meet problems of mixing
`and dispersion not met in small-scale production [34}. Thus the new form
`ulation is often taken to a pilot-scale plant, where larger quantities are
`produced and scale-up problems investigated.
`It is then taken to the pro-
`duction. line, where further problems may become evident as an additional
`quantum jump in scale-up is met.
`In many pharmaceutical companies,
`ther
`fore,
`it is normal for the RSLD department to maintain control and respon-
`sibility until three or four full production batches have been produced.
`Suspensions can be prepared by either dispersing finely divided powds
`in an appropriate vehicle or by causing precipitation within the vehicle.
`The precipitation method is somewhat complex and may involve a controlled
`pl-I charge of the solvent. Double decomposition has also been used (e.g.,
`preparation of White Lotion). The community or hospital pharmacist has Ell’
`important role in preparing antibiotic suspensions for individual patients.
`This is a relatively simple operation that may just involve adding a premix:
`vehicle to the powdered drug and then dispersing by vigorous shaking.
`This technique helps to reduce stability problems. However,
`the pharmaci:
`filling such a prescription has a special responsibility for ensuring that ill:
`product is used correctly. Study of the earlier chapters in this book will
`reveal the importance of adhering to the appropriate dosage regimen, but
`also the patient should be advised about the necessity of shaking the bottl
`in order to obtain uniformity of dose. Further, for some products storage
`in a refrigerator is required. The practice of hoarding unused quantities
`of such preparations is, of course,
`to be discouraged because of their
`short shelf life.
`Time taken to explain the reason for this advice is always
`well spent.
`
`REPLACEMENT Mylan Ex. 1015, Page 10
`
`

`
`Disperse Systems
`
`31‘-l?
`
`On the industrial scale, production batches of 300 liters or more of
`
`If the suspension is prepared by the disper-
`suspension may be produced.
`sion process,
`the milling of the solid is often effected by a micronization
`technique. This method can reduce particle sizes to values significantly
`less than 10 um [35}. Basically, rnicronization is achieved by forcing a
`coarse powder into a turbulent. air chamber where collision between particles
`results in particle fragmentation.
`If the suspension is to be prepared by
`controlled crystallization, a supersaturated solution is prepared and then
`quickly cooled by rapid stirring; by this method we obtain a large number
`of small crystals. Homogenization of the suspension will normally be re-
`quired when I;he various other components are added. On the laboratory
`scale, an ultrasonic generator can be used; for industrial production, a
`conventional colloid mill may be suitable. Fuller details of industria1—scale
`production and equipment are provided in Ref. 34.
`
`V.
`
`EMULSIONS
`
`A. Uses of Emulsions in Pharmacy
`
`The emulsion is a dosage form that has had considerable traditional usage
`in pharmacy.
`Indeed,
`there are numerous advances in emulsion technology
`that are directly attributable to pharmaceutical scientists. Although emul-
`sions can be designed for the oral route of administration (e.g., cod liver
`oil emulsion),
`their major use in present—day pharmaceutical practice is in
`topical preparations. Radiopaque emulsions can be used as diagnostic agents
`for X-ray examinations. The technology of simple emulsions,
`that is, oil
`in water (olwl or water in oil (wlo),
`is reasonably clearly established.
`in recent years, however,
`increasing attention has been given to multiple
`emulsions such as water in oil in water,
`in which water droplets are dis-
`persed in oil droplets, which are in turn dispersed in water. There are
`considerable technical difficulties in the preparation of such systems; how-
`ever, a series of patents covering such products has recently been issued,
`and it
`is known that several groups are considering the use of such systems
`for pharmaceutical purposes.
`It
`is possible that such multiple emulsions
`may be used for oral pro1onged—action products or intramuscular depot
`therapy. Release of drug from the central aqueous phase can be controlled
`by a number of‘ factors,
`including pH and the nature and thickness of the
`oil phase.
`
`l*‘ormula'tion of many cosmetic products is basically similar to formulation
`of topical pharmaceutical products, and thus the data presented in this
`chapter and Chapter 8 are of some relevance to cosmetic products. Cos-
`metic products and creams may contain various natural and synthetic waxes
`as the oil phase,
`in which case the products are made at an elevated tem-
`perature that must exceed the melting point of the ingretlient with the
`liighest melting temperature.
`
`B. Major" Factors Affecting the Formulation of Emulsions
`
`A good deal of the ‘research discussed in earlier sections of this chapter is
`also of relevance to emulsions.
`in general,
`the globules in an emulsion
`have diameters ranging from about 0.2 to 50 um. Thus their properties
`can overlap the colloidal and supracolloidal areas. Because of their very
`large interfacial area, emulsions are basically unstable. The forniulator
`
`REPLACEMENT Mylan Ex. 1015, Page 11
`
`
`
`
`
`3i:'<0'6<5\‘-‘~34w4~:<5'a-a:9;$<hsw—.-'ava.ss¢s3v:s«-rv
`
`
`
`
`=::2.s(é'-s<-'-y=«';«>=-29:.-.w.r..:.m:'.'-'»sy2;.s,'r..mw.y.s'.u-;.§-.:2a~<-:».-.-,
`
`
`
`
`xxx-r,-.i:merm.<«cmu.slm-r-'z2:;2:;<~»3¢:=&>e«>x/4:4wm\v,e::w=r':~:~.'9'.§'a~<'...'.5-;‘.I:*?-I\'»es<r1“_?~>..-2.4
`
`
`2:_-.z
`
`
`
`52 E
`
`:
`i2‘ST
`
`'
`
`.3z.
`91‘
`it
`2.
`
`atit:
`é.
`
`
`
`
`
`..\.—....w-M..-V.-...,,,.-,.....-.:w.w_\-...w,._.._N,,.,.,.,,{,,,',._.,;,N_,,._._,,,’;,_.
`
`

`
`Disperse Systems
`
`351
`
`tJnt'o:r'ti.:iia.te£y,
`tot‘ emziisiozi si..=1biii‘ty tests ['1{j,-£7].
`‘:1:-we also heeri user]
`tliere is at ‘present he gr-_-rieral agireement on the design of .‘5".1t.‘1’l tests.
`"L"l1t>.s
`in one ta:-\bor.eto1’y I-.1 een:.r’ifi.:g:atiou test may in\=‘olve it 5-min test ‘using
`-_-"1
`'.*1igli~speet'i <:e=_'H.1*'ig!_:ge, whei*e-as in eeothe.r- a EU-miri test using
`iow—.~::peeti
`.'.?'{'1'['L’
`e Ill‘.-1y’ he Lised.
`The i_'it=etlieti\.'e vaiiie of 311011 tests
`hy no 1119:-_'i.I'lS
`
`;-.i.lw-.:ys
`2-.l.}."1.'_\r'
`:.1p;m.'r-eiit.
`Si-milat'ly_.
`t.empei‘*:2itt\'r=e stress tests var-e,
`like t'm>se
`tiseti
`tot" :~sLispe:i.=:ioi'is, vawitihie in.
`Ili-1tL11"E!.
`in one h‘-.tbor=-ator-y -5 to +riE}°C
`oi‘;
`.2-1
`'.3'=‘+~h':* cycle is es:-zti foe 24 eyoies, wherests in e.noi.li.ei° 5
`to 35°C on :1
`l.'2~ht’
`f.‘._\/{‘;1{? for it} eycies is used.
`ii:=t=adiati::m to tie-
`Pett‘ows1<:i
`[-18'} has described the use of l’Il1C‘£‘0WaV'E‘
`termiiie emtilsion stability. This t.ec‘mr1iqL1e HIJEJQBFS to merit for-the't* inves~
`<;i.gat‘ion. After’ tI*eaI.1t1ent by microwave ii"-mcliatiori,
`the stirfatze teniperer
`t1.U.“E} of
`the emulsion tends to be highest and the temperate:-e gradient be-
`tween the Sli}I‘fEl:.’3E-? am! bottom of
`the emulsion to be smallest for the more
`:~;te.hle ezmzlsioris. Those iiiterested in ttetailetl stuciies of ezmzlsion sta'hility
`we r*et'ei:*r-t—;cl
`to pL1i:»lic:etirm;~:. by r-t'.=;~';earr.~.h e;m1.1ps such as itiet
`led by Groves
`[-$9-51.].
`iisua-ally he r-ea‘-actily seen by eye. Howet-‘er. other
`lI’lt-ase inversion ('.';'-tI’1
`
`::
`at-.-._1il-.a.l_'ile ineltlde COE‘lF1l’.C[iOl1‘I(-31Py.
`(if water is the eorii.'in=.1ot1s phase,
`=.'l1e emulsion will mmdm.-t eleetrir_'ity.) Aiteicmttively, a few tit-ops of Et
`w:—tt.e'r--soitible (lye £?'.':1I’1 be p1:;1CE‘.II1. on the s=.t.1t*Face of the emulsion: of the
`-::inu|.sior1 is olw,
`the dye will rapidly rliffuse T.1'1L"(.}1.1g'h()1JT. the system;
`if it
`is wxie,
`the ("lye will not disperse.
`.\-iieroeleetr-ophoretie uieasur-ements have
`also sometimes been used to aid in the e\-'ii11.1Etti0t'l of emulsions.
`_--\s with siispeiisioiis,
`it is useful
`to pE‘I'f0T"Tl1 some of the tests for the
`eiiiulsioii
`in the final contair1et*.
`Als.:e as with suspensions,
`the type of
`r*heo|og;ioai tests neetled can x-‘airy with the I"l3.1’1,Il"E of
`the it-'r=oc1iir_:t.
`
`0.
`
`Preparation of" Emulsions
`
`to
`is rather‘ i"a1°e for the present-tiay community or hospital phat-niacist
`it
`have to prepare an eniulsion, although c.-o1ii1JoL1nded demiiatologmal emulsions
`=.=.ir-e still preset-ibed and the 1:-hei:=1nac.i.st still
`recgtiir-es some knowledge of
`emuls-;iori pr7e;.)eI=atior1. The phamiiatzist can use the English or the C0‘I‘.[iI'1EI1‘*
`ml method for‘ the &'.T{E€‘]11D(.II‘L1ne{1LJS preparation of eimilsioris [52}. Large-
`seale pi:-ocluetiori methotls show eninsiclemble variation. The oil and water
`phases containing the hydrophobic and liyctrophilir; r:omponenls.,
`r*esper:ti\rely,
`are often heated separately in large tanks. when waxes are present, both
`pliases must be heated abo‘.-‘e the :emper'etL13=e oi’ the highest
`ineltihg point
`of any c'.oziipoheht present. One phase is then pumped into the tank eon-
`mixiing; the second,
`::oiis1.ai'1t eagit.-.'ai.ioii being provided ’Eh'£’r.)L|'gh0‘tlF. the time
`of ar_td.if..iort.
`.i\€'ter=
`cooling,
`the prodtiet
`is packagecl.
`with s-suspei1si_or1s,
`.=.sr.*:-ale-I.1_r_a
`['J‘E‘0b1e['l1S quite possibly may arise ha-rtweean the 1-abor:r4.to'r-y and
`
`.-ale pt*or.'iut:‘~I.ion.
`irwge-sci
`
`REFERENCES
`
`l.
`
`En.
`
`2.
`
`'.[‘e_\:tbool< of Colloid
`5:: Short
`Start-iiimanis,
`.liz*g;ehso1is C-3.‘£1E.1 Vt.
`B.
`_Clie1iiistr*y, Pergainon Press,
`'.?_Ilii1sford, Z\I.Y., 1962.
`-_\". A. ?vlat’tin, J. Swairht-icli,
`.-3.11:1 P. C.='-irrima1=at.a,
`_.1jhysi<'::1L Ph-ar'macy‘,
`End e<i., Lee S; Fehigt-er‘, Philadelphia,
`.1869.
`P. M. Eihort,
`V. Lirieolri,
`a-mti
`(.1. T. Rhodes, Pheraiittzie Q, 319
`(1985) _l .
`
`REPLACEMENT Mylan Ex. 1015, Page 12
`
`

`
`352
`
`Rhodes
`
`.:—\dv. Pliarnl. Sc;-L, g, 1100 (1367).
`1. C. Eciinumlson,
`(1.968).
`'_5_Z, 55’?
`B. A. Matthews and C.
`'1‘. Rhodes, J. Pharm. Sr.:i.,
`P. Kl. Short, E. T. Abbe, and C. T. Rhodes, Can. J. Ph.arm. Sci.,
`1, 8 (15369).
`
`B. A. Matthews and C.
`(1970).
`
`‘F. Rhodes, J. Colloid lraterf-ace Sci.,
`
`'_g, 339
`
`A. P. Bl