REPLACEMENT Mylan Ex. 1015, Page 1
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`Library sf Cangress {Zataicging-§n~Pubiietatian Data
`
`Modern pharmaceutics .
`
`(Drugs and the yharmaceutieai sciences ; V. 4(3)
`Includes biblicgtraphical references.
`1. Drugs--Dosage forms.
`2. Biopharmaceutics.
`3. Pharmacokinetics.
`4. Pharmaceutical industry~~Quality
`control.
`I. Banker, Gilbert S.
`11. Rhodes,
`Christopher T.
`III. Series.
`RS200,M63
`1989
`615.}.
`ISBN OM8247~7499~X
`
`89453365
`
`{TOPYRIGHT © 1890 by MARCEL DEKKER,
`
`INC. ALL REGHTS RESERVES
`
`Neither this book nsr any gar: may be reprsduceri er transmitted in any
`form or by any means, eiectronic er mechanical,
`including photocopying?
`microfilming, and recording, or by any information stcrage and rzstréevai
`system, without permission in wriéing from the pubiishezn
`
`MARCEL DEKKER, ENC.
`270 Madiscn Avenue, New Yark,
`
`flew ‘Kerk 1i}01t3
`
`PRINTED IN THE UNETEB STATES OF AMERICA
`
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`Qieperee Syeiezee
`
`Sl.§SiP§%‘é$§Q§‘éS
`
`339
`
`e“?‘\.
`
`edveetages anti Sieeeveeiegee of Sueoeasioa ee 3 Ciesege Form
`
`lam-’es;te::l {:omel<le':°a‘ole time and labo:= in :he
`use wee
`Ezree ifeoee
`eeepezzeéoes mzzeé eiizeéé {eel the :‘st;%,S§%f:S‘§<}1":
`e ouezber of
`§o':°:eele"ilo::
`e doeege
`Reel,
`:m’l§o:*::“9;§j; and
`of close,
`iileaéizrenéeejee
`the p":*epe‘eetlon ifs ‘ezmse eilseinisteeeil,
`e23l";l«:elf; to oompaee
`§at;o:°e%3.§§; aviélz ’§l”:e'i o‘o:e§;:1e’:>le by ‘me
`of iebleie or eegssulee.
`S8€}.lE‘{‘;€'l‘:‘“
`éetlon end compaction of eeéimeni Cease p:*o'§:>lems zvlqioh e1‘-e by eo means
`
`releiively bl:-_ll<.y;
`ihe proéizzct is liquid
`Furtlzee,
`solve.
`elwegre
`iézese peopertiee eye ol§eedvan%_iageo2.:s :0 both pharmacist and petiem.
`Fo1:>m-
`‘elation of 21;: effective
`jg1“:e1°:ee£-eutioelly elegant suepeneion ls; ueueily
`§llUECh ha1:°de:° to aollleve than of a ‘aablei or capsule of :he eeme drug.
`Erlmxievey-, Suepeneions {lo have some ecévemeges wllleh can, under Certain
`<:i:*::z121:st2meee, ouiweigl: them clieesivantages.
`
`‘oy of the more eeeemly developed drugs are basically hydrophobic
`in nemre email
`‘Elms their aqueous solubilitles are low. Thus eolutlone of
`Eheee d:=ue;e, <:onte.ining an appropriate dosage, would be of an unaccept-e.bly
`
`volt ne.
`Suspezleiozzs allow the development of a liquid dosage form
`(remaining an :1pp:=opz*ia‘{e quantity of (leug in e Feasonaéfly small volume.
`Fmfiller, reeietance to hydvolysls and oxiclation is generally good oompared
`with that observed in aqueous solution.
`Suspensions can also be used to
`mes}: the 2-aste of e:%;:°ugs. Also,
`there is a significant proportion of the
`population, especially very young children, who have difficulty in Swallow-
`log zableés or Capsules.
`in recent years incveaeing attention has been
`given to the use of suspensions in intratxlusolllar injection for depot therapy.
`For example,
`21 number of eeseaych teams ax’-e presently developing int:*a~
`mueeuler suegensions. of <:o’ntz=:aeeptive steroids that may give contraceptive
`preteetioe for periods
`exceee of 21 year;
`
`B.
`
`Phyeécal Stability of Suspensions
`
`?harma<:eu’iieal suspensions, are basically unstable Systems. Aggregation of
`euspended ‘particles and eedimematloo {and possibly impaction of sediment}
`presem real problems to {he pharmaceutical forznulator. As has al1“e-arly
`been indicated, much of the theory relevant lo the fot*mula?;ion of acceptable
`pharmaceutical susspeosions is derived from the findings of colloid scientists
`who have studied model Systems. There ere, however, several important
`allffeeenoes between moclel Colloidal systems and pharmaceutical suspensions,
`some of éhe more ‘important of which
`shown in Table 6.
`
`Repulsive Q2152 Ail:/nzzciéve Forces Between. Particles
`
`on euependecl particles
`Slush of {he ptr*esent-day’ iheory regaeding the
`‘results feomtlle wo1°l<: of four eelentists: Eieljlaguin and Lanclon from the
`Soviet Union, and Verne}? and Ovefoeek from the Netherlands The theory
`is {has often referred éo
`the BLJVG theory. This theory allows us ‘Lo
`ilearelop insight into ihe “actors responsible for- <?or1‘{z*olli:og the rate aé whieh
`';i,7:?iI‘ilCl€S
`in a Suspension will come together, or aggregate,
`to form duplets
`{two particles),
`triplets (three particles), and so on. The process of ag~
`geegetiozl will accelerate sedimentation and affect redispersibility and thus
`is leaportalxt
`to the pham:'lace11fi.oal scientist formtilaiing a suspension. The
`mtal ene1“gy of inieracétion, VT, between two particles is defined as
`
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`REPLACEMENT Mylan EX. 1015, Page 4
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`REPLACEMENT Mylan Ex. 1015, Page 4
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`
`fééseerse Sxgsiems
`
`35$’?
`
` E
`
`/
`
`2
`
`U)
`
`N
`
`<
`
`Tet-al energy of interaction cu.*z*ve between suspended particles
`Figwce
`(h is the interperticuiate distance).
`
`in aggeegetien. Thus, earee eenienie su:Pfe<:-
`eonfiacl, which would scesult
`Earns can be used 1:9 stabfiéze suspensions‘
`it should be neied, hewever,
`that an excessive quantity of surfactant ean,
`in some systems, have a
`significantly adverse affeci on stability.
`
`A ggregation Kinetics
`
`The aggregation of particles in a susrpensioe. Can be termed f'l<:»eeulatien or
`coagulation. The term eoegjilatien should be used when the forces involved
`are pr-imerily physical due to reducéion in the repulsive forces at the double
`layer. The term flocculation is applied to these cases in which ”bI*idging“
`<>ee1ix’s between particles. However, since in many phermaeeiziieal syete-ms
`éihe exact nature of the forces is somewhat obscure, We shell restrict cur-~
`selves here ‘go use of the term aggregation. Using simple diffusion theory
`€24];
`V011 Smoluchewskl derived equations 50:“ both zepid aggregation {when
`all §>e:*tiele~pet*ficle collisions asesult in aggregation} and slow aggregation
`{fin which only a fraction, a, of all pez’tiele—per€£ele
`collisions resulé:
`in the
`§e:*me*:iee of eggregazes),
`Pharmaceutical scientists are eeneereed p:*ie1ex*ilԤ,f
`with slow aggregation, since the aggregation in suspensions of drugs is
`mainly slew. The ‘E-ling,
`iime fer fhe initial m;m‘ber* of particles {singlets}
`in a suspension ‘Le decrease by 59%, because of eggregatien is given by
`
`1
`‘as: “ 4l}1RNGe
`
`(5)
`
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`':§s’>1?i*!:
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`Bésserse Sxgséesss
`
`35.33
`
`’§e.fe§.e 2" Estlleaieil Effeet ef §e‘:-eetrgtege éilyeerel
`NEE}
`Elertleles ef Sensity
`gfeseg
`
`§§;ja;'QZE‘i3§
`‘»'?’<’}
`
`JSE:
`{ll-:11}
`
`2%
`
`39
`
`$9
`
`lléfi
`
`2 ’{
`
`ill
`
`28.3%
`
`It can be seen free: Stokes’ law that both
`{lees an acceptable suspension.
`wiscesitgz and dettséty est: effect the veleeity sf setlltnetttetlen. A wide
`variety of suspending agents is available for feesetzletlen.
`S0333; such as
`cellulose derivatives, have a peeneuneed effect upen Vlseesity but seereel
`eny en tieesity. Sthees, such as serbitel, medtify eeth (tensity end vlseeslty.
`it can be seen from Eq.
`(8)
`that if the density élffeeerlee between the per»
`tieles and eentinuous phase can be eliminated sedimentation can be prevented.
`llewever,
`it
`is seldom if ever possible to increase vehicle density above
`zafeeut L3, and accordingly,
`it is net possible to match particle density,
`elthettgh it
`is possible to reduce the density difference.
`Exalnlnation of Eqs.
`(7) and (8) reveals that as the radius of a suspended
`particle is increased, Brewnlan motion becomes less important and sedimen-
`tetien more important.
`For any given system we can define a "no sedimelrr
`tetlon diameter" (NSD), below which value Brownian metien will be sufficient
`te keep the particle from sedimentation. The value of NSD will obviously
`depend en the density and vlseeslty values of any given system.
`The date shown in Table 7 were estimated by Matthews and Rhodes {Z7},
`Calculations ef the type made by these workers may prove to be at’ really
`practical value in future fer-mulatien work. Thus it can be seen from Table
`7 that if ens had a pewdered drug of less than 7 pm in diameter, a ?O%
`glyeerel medium would apparently be of sufficient viseesity and density to
`mgevent sedimentation.
`
`Crystal Growth (Osw/aid Rtpening}
`
`"E‘he surface free energy for small particles is geeater than fer large par“-
`téeles.
`En some systems,
`theeefore, small particles will be appreciably more
`seluble than large pastieles.
`Fer such systems smell fluctuations in term
`perattme will eesellt in crystal growth as the small particles cllseelve with e.
`temperature increase and thee eeystellize as large? particles or en the sure
`face ef existing garticles, with e temperetuzrfe drep. Thus the large particles
`*:—:'£ll geew in size at the expense of the smaller canes. The suspenslen will
`‘tleetzeze eoeeser as the mean of the Igertiele size spectrum shifts to higher
`veltzes. Many gums edseeb ante eeystel stmfeees and thus can be used to
`inhibit crystal growth,
`l’+‘reeze~tlte.w as well as mere eleeeted teltlperature
`<::3;ellt§g tests can previde a useful technique fee evaluating crystal grewth
`and crystal growth inhibitors.
`
`it/Eetlfiocis ef Evaéttaténg Suspensions
`C.
`Sedimentation Volume
`
`The measurement of the volume cf sediment produced by a given formula‘
`tier: 9%? a
`suspensien has been used by a number of W0‘.f‘k€1“S
`in attempts
`
`
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`35$;
`
`Rtzooes
`
`to eeelzzate soseensioss lf28..2§}.
`is defined as
`
`Retest cotesiosiy sedimentation voltage, V3
`
`VS 2
`
`><
`
`too
`
`6
`
`{8}
`
`where ii is the uitiieete settled height and ag is the original height of the
`suspension before settling.
`For example? if 130 ml of a Well-shaken test l
`formulation is pieced in a graduate cylinder and it is found that the uitime
`height of the sedimeztt is at the 2G~rnl line,
`then V5 is 20. As will he
`shows in a later discussion of controlled eggregation formutation {S1-‘ac. EV.
`B},
`it is normally found that the greater the Value of V3 for a given mass
`sf drug,
`the more satisfactory the prooltict.
`
`Ease of Redispersibility
`
`if a pharmaceutical suspension does produce a sediment on stor
`Ghviously,
`age,
`it is essential that it should be readily dispersible so that tmiformity;
`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 ebsentminded 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 100-4
`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 {$0}. The ultimate test oi
`residpersibility is the uniformity of suspended drug dosage delivered from‘
`a suspension product, from the first volumetric close 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 ieontrol 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,“-1
`be rapid and simple or detailed and complex, depending on the exact nets:
`of the product {.31}. They are also an important quality control feature of
`ail dispersed systems. The adequacy of hydration and quality control of
`I
`the gums used as suspensionsViscosity-imparting vehicles is best confirmed?
`by a rheological check. Ail of the gums, whether naturai éacacia,
`tragaw:
`oanth, etc.), modified natural (cellulose, alginate derivatives, etc.), or
`V
`synthetic {cerboxyl, vinyl, pyrrolidone, etc), are polymers or contain
`polymer constituents that vary in molecular weight distribution from lot to;
`lot. This in turn may have a material effect on vehicle viscosity.
`In ad-l
`ciitéon,
`the degree of dispersion of emulsions influences viscosity, as doesij
`particle size and particle size distribution, providing a usable method of
`‘
`quickly verifying dispersion consistency.
`
`
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`
`;.w
`":§§p€f”S€
`
`Systems
`
`’E"eez:2er*e2:;e“e seal Grexeizeééenei Sézeess Fests
`
`32:5
`
`ii’: the fleleé ef szsspensioe §€3E‘i:§11§:fi‘{3:?§‘i place geee: eelieeee en
`Seine
`iempe:=a:e;“e and geaviteiieeal stress tesis, wheeees e?:he“es have eerisiéleztable
`:’§3S€}:‘V8.i§@}”:S
`ebexsz ‘ilieie use based er: sizbfieeiing systeels to feeees
`nevez‘ eeeeuzziee in preeiieel The use ef eierege es: eieveseé tempere-
`{$34933
`fess pO§>‘L€l8E‘
`iéian temjeeeeiure cycling, eed eeeiainly e f’:*eeze~iheW
`i:\/we ef test {eggs +453 :0 =-5°C in 24 he}: can be of real value in ezystal
`siedies. Ceéiteifizgetien at releiiirely lew ‘fates may also be effieae
`in peedioting izeruse stability;
`l*1ewever,
`there is a anerked paucity of
`€252.13
`j;31ii}liSl3e€3 deia relative to Ellis point.
`li is eessible that testing suspensiene
`eele Krely low “gazes ef eentrifugatien may haiie Selma‘ iheeretieel basis
`g."(“H
`
`Ze fie Po temtiel De iermineziens
`
`iietemeineiiezz ef zeta peiemiai can be of
`As dlszzussed eeelier {Secs ELC},
`value in the development ef a pliarmaeeutieal suspensien, particularly if the
`oozitrelleci aggzsegetien eppmeeh described immediately hereafter is used.
`
`0. Centrolleci Aggregation Formulation ef Suspensiens
`
`The application of zeta potential measurements to the formulation of pharma-
`eemieal suspensions is genersally attributed to Haines and Martin {S2}.
`They pointed out that if a suspension were prepared with a high zeta poten-
`tial {he mutual repulsion between particles weulcl be strong‘;
`thus one would
`expect the rate of sedimentatien to be slow. One‘s first reaction might,
`therefore, be to prepare saspensions with as high a zeta potential as pos- '
`sible.
`lrlowever, because the sedimentation rate is slow the particles in the
`sedimerzi 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 ihe sediment is difficult to vedisperse.
`If; howevez=,
`the amount
`of elec:i:*olyte, and hence the zeta potential,
`is reduced somewhat,
`the sys~
`zen: may sill have sufficient physical stability E01‘ 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
`eoelainer. The sedirnentatioe Volume is high, and redisgersion is relatively
`Basically’,
`iherefore,
`the controlled aggregation theory produces
`phemiaeeutlcally elegant products as far as ease of I-eciispersion is concerned,
`by eonlmi of zeta psjteniial "net
`too litile, not :00 much" {E3}.
`Such sys-
`iems may ole*—;ele3‘p some regien ef clear supernatent selution above the loese
`sediment and may accordingly look less uniform on standing, even though
`they picevicle {he greezest ease of redispersien and best dose unifermiiy.
`
`Guidelines for Suspension Fermulazien Using the ifenirolied
`faggregazien fechnique
`
`ll
`
`2.
`
`Select .3 neeiexic suefaciant for’ wettine“ the drug. Normally an
`anionic material might be preferred, bet nonionies may also be used.
`if necessary, add 8. suspending agent {e.g., sodium oarboxymethyl-
`eellulose). Care should be taken to ensure that there is no chemical
`or physieochemieal interaction among surfactant, suspending agent,
`and any electrolyte that may be used.
`Add just sufficient nentoxic electrolyte to produce aggregation.
`
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`3:5
`
`5?‘: iaeaes
`
`e, Cheek that aétiitieaai eezsgaeneats, 31283: as téavers, eaters, mamas»
`tents {ta prevent the etesure and the bettie foes: teasing as site}?
`Eat),
`es? gareaeriratives, eta act substaatéaééy taedifjag the gsrapeeties
`if the system;
`Evaéuate the pesiitict a§tee starage tee, say;
`a. Reaisyersibitity tests
`33, Sedimentation velume tests
`
`i iaetzth ‘by:
`
`MK
`
`as
`
`Paaatieie size measusezaents ‘eefere and aftee temperature stress
`tests
`
`.51?»
`
`Rheologieai tests
`a. Cyclic stability tests
`
`if the eentraiteci aggregaticm appmaeh is useég it will often be fauna teat
`atewsage for tong yesiads, say, a year G1“ more, W111 make iittte if any difw
`t’e1=e:1ee ta the resutts.
`
`§. Check the suspension stsbfiity in the final package.
`
`Recentty, optimization techniques {see Chapter 1'2} have been applied
`to suspension fofmnulation [33a].
`
`E. Preparaticn of Suspensions
`
`the
`Once a satisfactory labaratory-scale formulation has been developed,
`In
`pfmblem of pilot—- and manufactu:*ing-sca1e praduction must be solved.
`the research and development {R&D) laboratory we will probably be produc
`ing quantities in the regien of 200 ml {er less) up to a liter or two, where
`313 industry much larger quantities will be produced (severai deealiters up
`tea kiloiiters}. At this sca1e~up point we may W211 meet problems sf mixing
`and dispersion not met in small-scale production {34}. Thus the new form
`uiation is often taken to a piiot-scale plant, where Iarger quantities are
`pmduced and scaie-up probiems investigated.
`It is then taken to the gre-
`duction. line, where further problems may become evident as an additienai
`quantum jump in scalemp is met.
`In many pharmaceutical eampanies,
`ther-
`fere,
`it is net-ma} fer the RM} department ‘:9 maintain control and respon-
`sibility anti} three er four full production batches have been produced.
`Suspensions can be yrepared by either dispersing finely divided pewde
`in an appropriate vehicle or by causing precipitation within the vehicle.
`The precipitation methed is semewhat complex and may involve a controfied
`pH charge of the soivent. Double decomposition has also been used {e.g;§
`prepaeatien of White Lotion). The community er hospital pharmacist has 81
`impot-taut rate in preparing antibietic suspensions for individual yatients.
`This is a relatively simple eperatien that may just involve adding a premix;
`szehieée ta the pewdered drug and then dispersing by vigereus shaking.
`This technique heips ta reduce stability problems. Hewever,
`the pharmaci:
`fitting‘ such a prescription has a speeiai responsibility for ensuring that tlm
`gcoduct is used earreetly. Study of the earlier chapters in this book will
`‘retreat the importance sf adhering t0 the appropriate dosage regimen, but
`alas the patient should be advised about the necessity of shaking the bottl
`in arder to obtain uniformity of dose. Further, for some products storage
`in a refrigerator is required. The practice of hoarding unused quantities
`of such preparations :3, of course,
`to be discouraged because ef their
`short shelf life.
`Time taken to explain the reason for this advice is ahvay:
`well spent.
`
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`Sisperse Systems
`
`Bit?
`
`more of
`3:: the irsiostcial scalel production batches of 3&9 lizecs
`sospeosion may be pcodsced;
`ii‘ the suspension is prepaeed by the dispatc-
`sioo process? the milling‘ of tiae solid is often eifecteé by a zaicroaiaatioo
`éecheiqae. This method can eeaisce particle sizes to sraises significantly
`‘areas than l8 toe £35}; Basically? lsiccooizatioo is achieves ‘oi; foccirgg a
`coarse goowder into a tucbuleoe are chamber where coliisioo between particles
`sesulis to pae’sicle isagmestation.
`if the suspension is to ‘ca prepared ‘of;
`cosisolied crystallisation, a supecsaiusaied solution is prepared sod ‘titer;
`Quickly cooled by capi-:3. stirring; by ‘this method we obtain a large number
`of small crystals. Homogenization of the suspensioo will normally be ce-
`quiced wash the vacious other components are added,
`{)2 too laboratory
`scale, an ultrasonic genecator can be used; for isdsstsiai production, a
`coaveotioaal colloid mill may be ssitabie. Fuller details of :Endustcial~scale
`psoclaction and equipment are provided in Ref. 34.
`
`V.
`
`EMULSlONS
`
`A. Uses of Emuisioos in Pharmacy
`
`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 ptcesenhday 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 {o/W} or water in oi} (WHO),
`is reasonably clearly established.
`in recent years, however,
`increasing attention has been given to multiple
`esmisions such as waier in oil is water,
`in which water clroplets are dis-
`persed in oil olcoplets, which are in turn dispersed is 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
`€oc pharmaceutical purposes.
`It is possible that such multiple emulsions
`may be used for oral prolonged-action products or intramuscular depot
`zherapy. Release of drug from the central aqueous phase can be controlled
`by a number of factors,
`inciuding pH and the nature and thickness of the
`oil phase.
`
`Formulation of many cosmetic pcoeiocts is basically similar ‘:0 formulation
`of topical pharmaceutical products, and thus the data presented in this
`chapter and Chapter 8 also of some relevance to cosmetic products. Cos-
`metic pcoducts and creams may cootain Various natucal and synthetic waxes
`as the oil phase,
`in which case the products are made at an elevates ten/:-
`peratuee that must exceed the melting point of me ingredient with the
`highest meitiog temperatuce.
`
`8; 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 pm. Thus their properties
`can overlap the colloidal and supracolloidal areas. Because of their very
`large interfacial area, emuisioos are basically unstable. The formulaic?
`
`REPLACEMENT Mylan EX. 1015, Page 11
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`REPLACEMENT Mylan Ex. 1015, Page 11
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`

`
`Qieeeree ‘Esgsieées
`
`35%
`
`ifiefezazzmziieigfg
`‘eeen Listed for sazaazieiezz e<;a‘ab:‘£;'g teete [<‘:£3g%':"§,,
`
`
`3.: peeserzi
`see geaezsai
`am {he deeégn ef s':;.€:§:
`tests.
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`of mierovave §:‘:“'€*;{ii8.E"§QEi
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`§>e'—* ezssséii E483
`Eerteiee eexuieéee etebiliiy. This éecizifique epgaeare to ezerilt further énvee-
`éiga‘éi_ez1. Afier i;z:*eetme:r1i: by :::}lei*02~:ave i:s:*:°ae:iia:i0n§ ihe eurfaee tempera
`éime of {he emuisien teeds to be highest ané. me tempeeaiere geadient be-9
`‘iween fine em”-face
`bemem of ihe enmlsien to be smafiesit $02“
`the meee
`<at;eb1e eemleiene. These interested £31 de$z:iEe<i
`s€2,zc1_§es ef eznekaien stabiiiiiy
`we :°efe‘:°::=e<i
`‘ie pueéiztedciens 133* feseariéh grémps such
`led by Gzexree
`E43-31.1};
`Eiewevetg other
`usualify be readiifg seen by eye.
`Phase i'nve1°sien
`
`2: gééabie ineiucie eendxzetieizxewy.
`(E1? weier
`the centimzeue phases
`{es
`the emulfirsn wiil e<>nciuet electricity.) Aiternatively, a few dug’-zaps of
`weJ:,e1>—ee1uk>1e dye
`be placed on the emeface of the emulsion: ef the
`emuieion is efw,
`the dye will rapiciigr diffuse thmugh01.1t the system;
`if it
`is w,/0,
`the dye win my: disperse.
`:\Eie150e1eetr*0ph<3r*e<:éC measurements have
`aése sometimes been used to aid in the evamation of ezmflsions.
`As with suspensions,
`it is useful to perform some 0%’ the tests fer the
`emulsien in the final container.
`A139 as with suspensions,
`the type 91:”
`:'Vnee'ieg*ica1 tests needed
`very with the nature ef the product.
`
`E).
`
`?reparat§en ef Emzdséens
`
`is I=a‘ihe1* rare fee the pI*esent-day eemmunity er hospiiai pharmacist to
`it
`have ta peepare em enmlsion, aitheaigh «::empeunded dermatological emuésiens
`:3:‘:"€: SUB preeeribed and the phermacést still requires same knowiedge of
`emulsion p‘:‘epa1r=at,irm. The phamiacisi: can use the Engiish er the Cominezrr
`iai method fer
`externperzmeeézs }3E‘€Dé1f’é3.‘£iO§’1 ef emuieiens {$2}. Large~
`seaée pmcfiuetéon methods shew eorxeiderabie variatien, The oil anti water
`pheases eentairairzg; the hydr*<3phe‘:3ie and hycimphilie eemp<>r:em;s, respectively,
`are eften heated sepaeaéeiy in éecege tanks. when waxes are present, been
`> zeees. must be heated e.§3e’~Je the 1CE!3§p€1”8.tEl}”'€
`ef the highest melting point
`:" eny eozzipenetzt present. One phase
`‘men pumped into the tank COR‘
`mining the seeondg ee:r:e‘{am egitaiien being 'pt‘Q§?’id€(i
`ihrezzghetit the time
`if eéidiiéen. After <:<3»3h'ng,
`ihe peeémei
`is packaged, As with suspensiene,
`
`:5 ’§e-up pz:=e‘e’:eres qtzéie pessibéy mag?
`‘eetween ihe ‘:abere’Ee“ey and
`§e.“zég>;e~ss<:e2e prociuctionv
`
`
`
`REFERENCES
`
`5.
`
`"2.
`
`E). SI:<’a.1:z’na:1ie, A $73201’: Tezztbeek sf Cafleéd
`B. Jirgensons ‘<}.E1(i M,
`Chernistrjg, Pergamen ?\:'es-as, Eihnsford, <.\f.Y,, 1962.
`N. A. Martin, J. Swarbrick,
`P. {Temsx3arata, Pievsicei Pharmaeg,
`‘End ed.5 Lea
`Febiger, Phiieeisaipizia,
`19939.
`5
`3
`3
`__a
`P
`Shaw:
`8. V. Liraezaén
`and C. T. Rhodes Phemzazie 5
`{£969}.
`
`319
`
`REPLACEMENT Mylan EX. 1015, Page 12
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`REPLACEMENT Mylan Ex. 1015, Page 12
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`

`
`
`
`rxmwz,
`
`(?<;E§:">i:‘i
`
`REPLACEMENT Mylan EX. 1015, Page 13
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`REPLACEMENT Mylan Ex. 1015, Page 13
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`

`
`353
`
`
`
`1:3
`
`e{i., V01,
`Wiiey-E:‘;ie*c~
`
`6
`
`:1-‘iL1s‘:afa, J.
`
`?ha1:=m. E3‘}12'n~2naco1.,
`
`‘_;_§, 8?1
`
`
`
`
`
`’
`e<i.},
`E}
`
`féze iétét
`Proeeesiirzosz <3?
`1r’azE::=i§
`"s>"b;‘:3%>se1*i}I3 aim,
`:?;he::<:%::(,
`Ef?}€;i5‘
`:1a‘:£<;:‘:eE {jez3'*ress en €§::2:*'faee A 1:ix«'ii‘y’, Efeéa 33 1;. E,
`i:*i2Es::z; am} '8. F.
`Eezazieéens (£3. Shem2a;2§
`
`Y<3:=é{, 196?.
`:‘s=1:aa:m.ii2a:'1,
`(388 {18£34f:;.
`Weci:ie:='buz“::, sldt. Phazrm. Sci, ;_5
`E13. (hiffing in E;:1eV<:2e*e{iia <3? Chemise} '§‘echn<3T.em;5
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`
`
`E‘v'1a‘r‘:«:, anti 3‘, F. {}:hs:':e:"-,
` R. Sfiiiidéfig E. E‘.
`flee: New ‘:’<3z*k, £365.
`":}35
`:33?
`E7. T‘i.ngs{a<i3 :3} P‘§:::::*m. S«Ci,,
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`22:11. Oi} Chem. 306., EL 120 (1,§}?¢%
`G, E.
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`?‘e.>;2r=x11. Sci, 5?? 1273 {E68}.
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`€}23i>ves, R. M. Eiizxstafa, and 5; E. Cafless, J.
`; arm. Pharnxaeoh,
`_‘3_{S_,
`2234 (19%),
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`(1974).
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`
`élé,
`1:23;!
`
`3
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`influence of lipid composition and iemlc strength
`er‘: the physical siability of Eéposomes, J. Pharm. Sci., 3, 1559 (198191
`§f‘&{1k3§,7€:3
`"E2 3%., and N, Piilgeh Simpie, rapid method €01‘ comparing the
`seiffiemuiséfiabiiéiy ef h'ffdPOC31"bGI1 efls, J. }3'harm.
`23:21.3 1%, 1261’ {198'§~_);
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`iechneiegy for eosmeiic applieatians, J. Soc. Cosmet. Chem.,
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`{Egg
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`REPLACEMENT Mylan EX. 1015, Page 14
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`
`355:
`
`Rhoées
`
`3333231 3,, Ssha 3.. 393:9}, Mam C; Eiaggis, Virgafi E’. Sham Vadlamazzi
`Fateg,
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`K.
`ehiorsthiaziée fmm ":a%::§ei:s and 31131393232023? 3. Fharm. Sci; Z3335 33$
`{E384}.
`
`jgammeter 331$; hgzérsphiiichipaghéiic ijaianca sf na:3:rz~
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`actizm betwaen peiyérs and aimrzrina Edyéroxide gel, J. Pharm, S83. , 3:9,
`11$} (1383.
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