oe
`
`“a
`-
`"Bie
`
`.
`
`eeeeCRCoie
`CTOOTe
`
`Page 001
`
`“Dy
`>. a
`
`ag
`
`rma
`
`eau
`
`Fo
`
`tT 7
`
`-
`
`en
`
`“.we
`AS 5
`~
`PComy
`
`_—
`
`Par Pharm., Inc.
`Exhibit 1028
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 001
`
`

`

`4 Pharmaceutical Technology JANUARY 1993
`
`The New
`KL2000 Multitrack
`Counter
`* New Electronics
`* New Dust Removal
`* Faster Throughput
`* Exceptional Accuracy
`* Simpler Operation.
`The new KL2000 counts
`up to 4,500 tablets
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`
`System
`
`For more information contact:
`
`!KO!Ri!EJWLESTER
`
`Kirby Lester Inc., 470 West Avenue,
`Stamford, CT 06902 USA
`
`Tel: (203) 323-1499 Fax: (203) 353-9718
`Call toll free outside Connecticut: (BOO) 243-2465
`
`Cirde 3
`
`Pharmaceutical
`ingredients
`& Technical Service Expertise
`For All Applications ...
`0 Tableting 0 Coating Systems
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`0 Colorants (FD&C, D&C & Naturals)
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`CROMPTON & KNOWLES
`CORPORATION
`Ingredient Technology Division
`1595 MacArthur Boulevard, Mahwah NJ 07430
`Telephone (800) 343-4680 Telefax (201) 818-2231
`Alto: Clayton J. Bridges, Jr.
`
`Circle 46
`
`PHARMACEUTICAL
`TECHNOLOGY®
`
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`
`Par Pharm., Inc.
`Exhibit 1028
`Page 002
`
`

`

`32 Pharmaceutical Technology JANUARY 1993
`
`A Survey of
`Current Industrial
`Practices in the
`Fonnulation and
`Manufacture of
`Tablets and
`Capsules
`
`Ralph F. Shangraw• and
`Dudley A . Demarest Jr.
`
`Dramatic changes in the formulation and manufacture of pharmaceutical
`dosage forms have occurred during the 15 years of Pharmaceutical Technol(cid:173)
`ogy's existence. Many of these changes have been motivated by the introduc(cid:173)
`tion of new processing equipment and new pharmaceutical excipients. Al(cid:173)
`though marketing surveys by equipment and excipient suppliers have been
`conducted, most of the results are unpublished. In order to obtain a better un(cid:173)
`derstanding of industry attitudes toward both excipients and manufacturing
`processes, the authors designed a questionnaire to assess current industrial
`practices. The results of our survey are described in this article.
`
`Ralph F. Shangraw, PhD, cmd Dudley A. De·
`marest Jr., PhD, are professors ar rhe Universiry
`of' Maryland, School of Pharmacv, Balrimore, MD
`21201. USA. Dr Shangral\' iJ a member of rhe
`Pharmaceutical Technology Edirorial Ach·isor_1
`Board.
`
`*To whom all correspondence should be
`addressed
`
`MIKE DEAN
`
`Questionnaires were mailed to one per(cid:173)
`
`son at each of 68 different companies.
`gh an attempt was made to identify a
`A
`person who would most likely be able to
`complete the questionnaire, addressees were
`asked to forward it to a more appropriate per(cid:173)
`son if necessary. Questions were generally
`posed in the context of what recipients or.
`their companies were doing at present, thus
`attempting to determine current attitudes of
`formu lators rather than what had been done
`in the past. A total of 58 questionnaires were
`returned, representing 30 innovator pharma(cid:173)
`ceutical companies, 14 generic companies, 8
`nonprescription drug companies, and 6 vita(cid:173)
`min and nutritional supplement companies.
`The questionnaire was divtded into several
`sections. The first two sections asked form u(cid:173)
`lators about their use of excipients in tablets
`and capsules The last two sections inquired
`about their companies' current formulation
`pohc1es and general excip1ent use.
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 003
`
`

`

`No matter where your pharmaceuticals travel
`Klockner rigid films provide the perfect packaging climate.
`
`Packaging pharmaceuticals for
`today's expanding markets can be a
`major headache. Geography, humidity
`and changing climatic conditions all
`pose a serious challenge to product
`integrity and efficacy.
`To meet that challenge, Klockner
`is the only U.S. manufacturer of vinyl or
`polyester thermo form films that meet or
`surpass all international barrier property
`standards. Klockner rigid films give you
`better MVfR properties (virtually 15%
`better than comparable U.S. made films);
`better shelf life; better product protection.
`You get the perfect packaging cli(cid:173)
`mate. Rigid films that can be used "as
`is"- or as a substrate
`for higher barrier
`laminates and
`coated films.
`
`Pentaphann® Rigid Films - High
`performance mono-films with better
`barrier-qualities. You save testing time
`for NDA's. Ideal for 70% to 80% of your
`blister requirements.
`
`Pentaphann Alfoil P-Rigid film with
`customized PVDC coating for increased
`hygroscopic protection.
`
`PentaphannAifoil T - Multi-layer
`(PVC/PE/PVDC) high barrier protection
`for products that are extremely moisture
`and gas sensitive.
`
`Pentaphann Customized Films(cid:173)
`Klockner R&D will develop custom(cid:173)
`designed films- in a full range of formu(cid:173)
`lations and thicknesses-to meet any
`specific product or market requirement.
`
`No matter how far your products
`travel, we can provide the packaging
`films you need to take them there. The
`formulations, thicknesses and combina(cid:173)
`tions you want. So let it rain in Rio or stay
`dry in Tucson-we've got you covered.
`Discover the unsurpassed quality(cid:173)
`and superior barrier protection of
`Klockner rigid films. Call (703) 832-3600.
`Klockner Pentaplast, Gordonsville,
`Virginia 22942.
`
`I{LUCKNER
`PENTAPLAST
`Rigid film, machinery and service. Worldwide.
`
`Cirde 26
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 004
`
`

`

`34 Pharmaceutical Technology JANUARY 1993
`
`TABLETS
`The first question asked respondents to rank
`filler binders in terms of first, second, third,
`etc. , choices. The results in Figure 1 show
`that lactose and microcrystalline cellulose
`were preferred. The reasm1s for this prefer(cid:173)
`ence are shown in Table I. Lactose was cho(cid:173)
`sen because of its solubility and compatibil(cid:173)
`ity and microcrystalline cellulose because of
`its compactibility, compatibility, and unifor(cid:173)
`mity of supply. In contrast, dicalcium phos(cid:173)
`phate was chosen mainly because of compat(cid:173)
`ibility with no perceived benefit from
`solubility.
`The different types of filler binders pre(cid:173)
`ferred are shown in Figures 2a-c. Modified
`lactose (alpha monohydrate) was preferred
`over other types of lactose, which may indi(cid:173)
`cate a preference for its utility in direct com(cid:173)
`pression. Those using starch preferred the
`pregelatinized form. For calcium phosphate,
`the preference (in descending order) was
`
`(a)
`
`NF and
`
`NF
`
`Lactose
`Microcrystalline cellulose
`o Starch
`• Calcium phosphate
`Sucrose
`
`(/) 30
`
`Q)
`(/)
`c
`0 fr 20
`~
`0
`Qj 10
`.0
`E
`::J
`z o~~~~.u~~~~~~
`1st 2nd 3rd 4th 5th
`6th
`Preferences
`
`Figure 1: Preference for tablet filler(cid:173)
`binders (58 responses).
`
`NF
`Anhydrous Modified
`and modified
`40.0% and modified
`7.3%
`5.5%
`
`(b)
`Maltodextrins
`1.8%
`
`Plain
`
`Table 1: Reasons for preferences of filler-binders .
`
`Reasons
`
`Lactose
`
`Starch
`
`Microcrystalline
`Cellulose
`
`Calcium
`Phosphate
`
`Solubility
`Cost
`Tradition
`Compatibility
`Uniformity of supply
`Compactibility
`Handling
`Physiological inertness
`
`Total selections
`
`. 19
`15
`21
`20
`14
`17
`8
`8
`41
`
`4
`6
`9
`7
`4
`6
`3
`
`12
`
`9
`, 3
`18
`33
`26
`46
`11
`16
`
`52
`
`1
`2
`4
`3
`3
`8
`0
`2
`
`8
`
`Pregelatinized
`62.5%
`
`(c)
`Dibasic
`anhydrous
`20.4%
`
`pregelatinized
`16.1 %
`
`Tribasic
`2.0%
`
`Regular
`dibasic
`
`Table II: Reasons for preferences of disintegrating agents.
`
`Reason
`
`Starch
`
`Sodium Starch
`Glycolate
`
`Croscarmellose
`
`Crospovidone
`
`Disintegration/
`dissolution
`Cost
`Tradition
`Compatibility
`Uniformity of supply
`
`Common
`Range
`Total selections
`
`11
`9
`12
`6
`3
`
`10%
`5-20
`20
`
`27
`2
`16
`12
`13
`
`40
`0
`8
`12
`23
`Concentrations
`
`5%
`0.5-15
`34
`
`2%
`0.5-8
`44
`
`17
`1
`3
`7
`8
`
`0.5-4
`18
`
`Regular
`Anhydrous Dibasic
`and unmilled unmilled and unmilled
`4.1%
`30.6%
`2.0%
`
`Figure 2: (a ) Filler-binder p reference: (a )
`lactose (55 responses), (b) starch (56 re-
`sponses), (c) ca lcium phosphate (49 re-
`sponses).
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 005
`
`

`

`OUR SENTRY®SIMETHICOME CiS PUTS
`YOUR PRODUCT IN A BmER POSITION.
`
`Finally, higher profits are easier to reach.
`Count on SENTRY® Simethicone GS to lower
`production costs and give you greater marketing
`flexibility.
`Only SENTRY Simethicone GS is in a new .
`granular form, so now you can add simethicone
`gracefully to solid mixtures, such as cold medica(cid:173)
`tions, buffered aspirins, vitamins and more.
`Plus, our new granules dry-mix easily with other
`
`components for more cost-effective processing.
`To find out more about SENTRY Simethicone
`GS, call us at 1-800-523-5862. Or write to Union
`Carbide, OrganoSilicon Products, Systems and
`Services, Department H2375, 39 •
`Old Ridgebury Road, Danbury,
`Connecticut 06817-0001.
`Ana let your profits tum-
`ble easily into your pocket.
`
`1
`• • = 1
`ORGANOSILICON PRODUCTS,
`SYSTEMS, SERVICES
`
`Copyright© 1991 Union Carbide Chemicals&: Plastics Technology Corporation. SENTRY is a registered trademark of Union Carbide Chemicals&: Plastics Technology Corporation.
`Union Carbide Chemicals and Plastics Company Inc.
`Cirfle 27
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 006
`
`

`

`• Starch
`Sodium starch glycolate
`D Croscarmellose
`• Crospovidone
`30
`
`(/)
`Q)
`(/)
`c
`0
`fir 20
`~
`0
`w 10
`
`.0
`
`~ 0 I ~
`
`1st
`
`I
`4th
`3rd
`2nd
`Preferences
`
`.Ill
`sth
`
`Figure 3: Preference for dis integrating
`agents in tablets (58 responses).
`
`• Hydroxypropyl cellulose
`Hydroxypropyl methylcellulose
`D Povidone
`• Starch paste
`• Pregelatinized starch
`(/) 30
`Q)
`(/) c
`0 fir 20
`~
`0
`w 10
`.0
`E
`::0 z Q.jll..l.,. . . li,IL~MJI-..n:.i,....IU"'-,-Il...,
`
`Preferences
`
`36 Pharmaceutical Technology JANUARY 1993
`
`milled dibasic, unmilled dibasic, and anhy(cid:173)
`drous dibasic. Almost 50% of respondents
`preferred modified sucrose over other su(cid:173)
`crose products (data not shown).
`Although preferences for filler-binders
`were somewhat predictable, this. was not true
`for disintegrating agents (Figure 3). There(cid:173)
`placement of starch with superdisintegrants
`is evident: Croscarmellose NF was preferred
`by 26 respondents, and sodium starch glyco(cid:173)
`late NF was preferred by 22. This trend can
`be attributed to the need for faster dissolu(cid:173)
`tion. The reasons for use and concentrations
`commonly used are given in Table II. The
`most common concentration of croscarmel(cid:173)
`lose (2%) seems a litt le low, whereas the
`upper range of both starch and sodi um starch
`
`glycolate seemed a little high. Although the
`use of we~ting agents in capsules has been
`advocated for some time, the use of surface(cid:173)
`active agents in tablet formulations by 76%
`of the respondents is somewhat surprising
`(Figure 4). This no doubt reflects the increas(cid:173)
`ing use of direct compression and the need
`for lowering surface tension in the matrices
`and tablets not wetted during the granulation
`process. The wetting agent of choi ce was
`clearly sodium Laury! sulfate.
`By comparison with the choices of agents
`as filler-binder or disintegrants, povidone
`NF was clearly preferred as the wet binder of
`choice (Figure 5). Twenty-nine of 58 respon(cid:173)
`dents chose povidone NF based on its com(cid:173)
`patibility and compactibility and its sol ubil-
`
`100
`
`80
`
`60
`~
`
`Q)
`(/)
`
`:J 40
`
`20
`
`0
`
`Sodium Dioctyl Tween
`lauryl
`sod ium
`su lfate
`sulfa-
`succinate
`
`Poly(cid:173)
`ethylene
`glycol
`
`Other
`
`Figure 5: Use of wet binders in tablets (58
`responses).
`
`Figure4: Use of wetting agents in capsules (58 responses).
`
`• Magnesium stearate
`Stearic acid
`D Hydrogenated vegetable oils
`• Talc
`(/) 60
`Q)
`[!! 50
`0 fir 40
`~ 30
`0 w 20
`
`.0
`E 10
`::0
`z
`0 +--ioo-,,..-..E...,,.......L.A.._,.....LL-r---011..&-~
`1St
`
`Preference£
`
`Figure 6: Preference for lubrican ts in
`tablets (58 responses).
`
`Table Ill: Reasons for preferences of wet binders.
`
`Reason
`
`Cost
`Dissolution
`Handling
`Compatibility
`Cornpactibility
`Effact
`Total select1ons
`
`Pregelatinized
`Starch
`
`Starch
`
`Povidone
`
`Hydroxypropyl Hydroxypropyl
`Cellulose
`Methylcellulose
`
`4
`4
`0
`2
`2
`6
`8
`
`3
`6
`8
`6
`12
`10
`20
`
`0
`14
`11
`18
`24
`14
`45
`
`0
`5
`2
`4
`6
`3
`11
`
`1
`9
`3
`7
`14
`8
`26
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 007
`
`

`

`
`
`
`Mo oe OG geo oh ae ON tle a ee
`
`ED Be ae
`
`ea i ae
`
`
`
`ATyas2) G60) On czaroeOm Bal BS a Bh aED DTPA 4/9 Ss a Ses Cre EX CELLEN GE
`
`EMCOCEL
`
`Page 008
`
`
`
`
`
`daVIENDELL
`A PENWEST Company
`
`Lonsdale House,7-11
`treet, Reigate,
`Corporate Headquarters: 2981 Route 22, Patterson, New York 12563-9970 (914) 878-3414 + (800) 431-2457 + (914) 878-3484 Fax * 497-1034 Telex European O
`9-4122-92530 + Fax
`122-925314
`CMW eeeeeniconry
`Surrey RH2 GAAEngland Tel 44-737-222323 + Fax; 44-737-222545 GermanOffice: Edward Mendell GmbH, Répeke
`American Manufacturing Plant: Cedar Rapids, lowa
`iolWINE EteslateRaelMiNelelc Mate)Elle|
`
`Circle Pr
`
`Par Pharm., Inc.
`Exhibit 1028
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 008
`
`

`

`38 Pharmaceutical Technology JANUARY 1993
`
`ity and reproducibility of effect (Table ill).
`Little preference was shown for either acacia
`or gelatin. For those formulators who still
`used starch, pregelatinized starch was clearly
`preferred over starch paste. Hydroxypropyl
`methylcellulose was preferred over hydroxy(cid:173)
`propyl cellulose, although both were used be(cid:173)
`cause of compactibility and dissolution char(cid:173)
`acteristics.
`The almost unanimous choice of magne(cid:173)
`sium stearate is somewhat surprising, consid(cid:173)
`ering the multitude of problems that it can
`cause (Figure 6). The preference for magne(cid:173)
`sium stearate certainly is a testament to its
`functionality. A total of 54 out of 58 formu(cid:173)
`lators selected magnesium stearate as first
`choice, two others selected calcium stearate,
`and one each selected stearic acid and hydro(cid:173)
`genated vegetable oil (data not shown). The
`averages and ranges of choices are shown in
`Table IV. The relatively low concentration of
`stearic acid is probably due to its wide use in
`combination with magnesium stearate to re(cid:173)
`duce dissolution and compatibility problems.
`The extent of the use of such combinations is
`shown in Figure 7, which also indicates that
`talc also is often combined with magnesium
`stearate.
`Given the problem s with ma gne sium
`stearate, the respondents were asked whether
`their company specified an exclusive source
`and type of magnesium stearate. The results
`are shown in Figure 8. Eighty percent said
`that their company did specify a specific
`source and type, and almost 50% of those in(cid:173)
`dicated a specific supplier - Mallinckrodt.
`Others indicated that they selected magne(cid:173)
`sium stearate on the basis of a functional test
`or compendia! standards. The latter response
`IS interesting because compendia! standards
`do not provide functionality tests. The results
`shown in Figure 9 reflect which raw material
`tests are routinely conducted by the various
`populations identified in the previous ques(cid:173)
`tion. In general, the same level of testing was
`used by all three groups- and those who in(cid:173)
`dicated a single supplier tested as much as or
`more than the other companies.
`The most surprising res ult was that ap(cid:173)
`proximately 50% indicated that they perform
`particle-size testing on magnesium stearate,
`and 33% conduct a bulk density test, al(cid:173)
`though neither of these is a compendia! test.
`Respondents were also asked why they
`used lubricants other than magnesium
`stearate; 50% indicatetl stability and 30% in(cid:173)
`dicated compatibility and dissolution.
`Seventy-five percent of respondents said
`that they used glidants. and 80% of that
`
`Use
`
`Never
`
`Most of
`time 17.2%
`
`Magnesium stearate
`
`100
`
`Rarely
`5.2%
`
`c
`~50
`Q) a..
`
`Without
`
`With I Stearic
`
`50
`
`acid
`
`Talc
`
`o+-~~~rL--~~ o~~~~~,
`~ Hydro-
`genated
`vegetable
`oils
`
`Other
`
`Figure 7: Use of combinations of lubricants in tablets (58 responses).
`
`No
`
`Yes
`80.4%
`
`Did not specify
`which source
`22 .6%
`
`~
`
`Mallinckrodt
`47
`
`a functional test
`13.6%
`
`Those that meet /'
`Both Witco and
`compendia! standards 9.1% Mallinckrodt 2.3%
`
`Figure 8: Exclusivity of magnesiwn stearate source (56 responses).
`
`Table IV: Lubricant levels used in tablet manufacture.
`
`Excipient
`
`No. of Responses
`
`Average
`
`No. of Responses
`
`Range
`
`Magnesium stearate
`Stearic acid
`Hydrogenated
`vegetable oil
`Talc
`
`19
`18
`
`15
`10
`
`0.6%
`1.9%
`
`2.3%
`2.6%
`
`14
`10
`
`5
`6
`
`0.25-2%
`0.5-10%
`
`0.5-3%
`1-15%
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 009
`
`

`

`Let I<arlshamns
`Focus On Your
`Formulation
`Needs With
`Lipid Solutions.
`
`Karlshamns is a world leader with over 200 years of collective experience in the development
`
`and application of lipid based technologies in the USA and Europe.
`
`We offer you well characterized lipid based materials which are essential
`
`to a vast array of health, personal care and sophisticated drug delivery systems
`
`worldwide. Our lipid systems range in application as carriers and solubilizers for
`
`active substances to tablet lubricants, suppository bases, emulsifiers and emollients
`
`for creams, lotions and ointments. Karlshamns tailor produces lipids for parenteral
`
`and enteral nutritional emulsions and is a recognized leader in the production of
`
`medium chain triglycerides (MCT oils), structured lipids and specialty oils.
`
`Karlshamns creates pro-active solutions for a growing number of demands
`
`for "natural" and environmentally friendly products. As lipid specialists we focus on-
`
`and solve-your formulation problems. Producers
`
`of sensitive health, cosmetic and personal care
`
`products turn to Karlshamns for technical
`
`assistance and an assortment of sophisticated
`
`systems derived from renewable natural resources.
`
`Call us today for our
`
`colorful new "Lipids for Care"
`
`brochure.
`
`<? Karlshamns
`
`Karlsharnns USA lnc.,Lipids for Care • P.O. Box 569 • Columbus, OH 43216-0569 • (614)299-3131 or 1-800-526-4547 • TELEX: 245494 • FAX: (614) 299-8279
`
`Karlshamns AB, Lipids for Care • S-37482 • Karlshamn, Sweden • Call: +46-454 82 300 • TELEX: 4510 FOPART-S •.fAX: +46-45412 911
`
`Circle 28
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 010
`
`

`

`40 Pharmaceutical Technology JANUARY 1993
`
`group indicated that they preferred colloidal
`silica.
`
`CAPSULES
`The survey was designed to elicit informa(cid:173)
`tion about the use of excipients in capsules
`and in tablets. Forty of 58 respondents manu(cid:173)
`fac tured capsules. The preference for fillers
`in capsules is shown in Figure 10, and lac(cid:173)
`tose monohydrate in various form s clearly
`was the top choice of most companies (22 re(cid:173)
`sponses). When lactose monohydrate is com(cid:173)
`bined with anhydrous lactose, tbe preference
`for lactose as a filler in capsules was over(cid:173)
`whelming. Again, this no doubt reflected the
`superiority of lactose in dissolution. Both mi(cid:173)
`crocrystalline cellulose and pregelatinzed
`starch were preferred over starch. One of the
`most surprising responses was that more than
`60% of the respondents indicated that they
`used other di sintegrating agents, with a clear
`preference for either starch or sodium glyco(cid:173)
`late or croscannellose (Figure I 1 ). Likewise,
`almost 60% indicated that they used wetting
`agents in capsules, again demonstrating the
`current emphasis on dissolution (Figure 12).
`Of those wetting agents used, sodium lauryl
`sulfate was the most preferred.
`
`NEW EXCIPIENT$
`For each type of excipient, respondents were
`asked if they had a need for new materials
`and why. These results are shown in Figure
`13. Considering the breadth of the question,
`there was a surprisi ng comfort level with
`what is already in existence. The major ex(cid:173)
`ceptions to this were the desire for a soluble
`fi JJer with the properties of microcrystalline
`cellulose and a soluble or at least more hy(cid:173)
`drophilic material with lubricant properties
`equivalent to magnesium stearate.
`
`PHARMACEUTICAL PROCESSING
`In addition to questions about excipients, the
`survey asked about the types of tablet manu(cid:173)
`facturi ng processes that currently were pre(cid:173)
`ferred. These results are shown in Figure 14.
`When all of the responses were taken to(cid:173)
`gether, the overwhelming choice of tablet
`manufacture was direct compression fo l(cid:173)
`lowed by wet massing-fluid bed drying fol(cid:173)
`lowed by wet massing-tray drying. However,
`when the responses are segmented into inno(cid:173)
`vator companies vs. generic companies, this
`preference for direct compression is not in(cid:173)
`dustry-wide (Tables V and VI). Because of
`the long lead time from discovery to market
`and the uncertainty of drug properties. the in(cid:173)
`novator industry may be more likely to prefer
`granulation of one type or another. This is
`
`• No exclusivity (11)
`Exlusivity (45)
`D Mallinckrodt (21)
`
`• Starch
`Lactose NF
`D Anhydrous lactose
`• Pregelatin ized starch
`Microcrystalline cellulose
`
`100
`
`80
`
`Q)
`
`g' 60
`c
`Q)
`~ 40
`Q)
`a_
`
`20
`
`a ~~~~~~~~~~~
`10
`
`t Particle t su rtacel Bul k
`I s1ze
`I area
`dens1ty
`Chemical Fluidity Moisture
`content
`composition
`
`Figure 9: Raw material testing on magne (cid:173)
`sium stearate (58 responses).
`
`Preferences
`
`Figure 10: Preference for fillers in capsules
`( 40 responses).
`
`Table V: Tablet manufacturing preference in innovator companies.
`
`Process
`
`Direct compression
`Roll compaction
`Wet massing
`-fluid bed drying
`Wet massing
`-tray drying
`All-in-ane processing
`
`No. of Responses Average
`24
`1.9
`17
`3.6
`
`26
`
`21
`16
`
`1.7
`
`2.5
`3.7
`
`Preference
`3
`7
`2
`
`3
`
`9
`2
`
`2
`5
`3
`
`8
`
`4
`2
`
`4
`1
`7
`
`0
`
`2
`7
`
`5
`0
`4
`
`4
`
`11
`1
`
`14
`
`5
`
`Soduim
`
`Use
`
`100
`
`80
`
`-60
`c
`Q)
`~
`Q)
`a_ 40
`
`20
`
`0
`
`Pregelatinized
`starch
`
`Croscarmellose
`
`Others
`
`Figure 11: Use ofdisilltegrating agents (other than starch) in capsules (40 responses).
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 011
`
`

`

`We specialize in
`fabrication at
`your facility:
`A New tanks up to 750,000
`gallons
`Repair and modification of
`existing tanks
`Stainless Steel
`and aluminum materials
`Erected inside your existing facility
`ASME code pressure vessels or
`non-code tanks
`Insulation &
`sheathing
`Heat transfer
`surface
`
`P R ECI S I ON
`STA I N LE SS
`
`3300 E. Pythian, P.O. Box 668
`Springfield, Missouri 6580 1
`Telephon e: (4 17) 865-2990
`FAX: (4 17) 865-0906
`
`Agitators
`Manways & special fittings
`Variety of material finishes,
`including electropolish
`
`Cirde 29
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 012
`
`

`

`42 Pharmaceutical Technology JANUARY 1993
`
`not true of the generic industry. Furthermore,
`data not shown indicate that both the vitamin
`industry and the nonprescription drug indus(cid:173)
`try are heavily committed to direct compres(cid:173)
`sion ( 13 out of 14 companies indicated it was
`their preferred method of manufacturing).
`In spite of its relatively recent introduction
`into the industry, ali-in-one processing was
`preferred by 14 companies that rated it either
`
`first, second, or third. In contrast, 5 out of 30
`innovator companies still listed tray drying
`as their first choice.
`In an attempt to validate the opinions of
`respondents relative to direct compression,
`respondents were asked about their com(cid:173)
`pany 's overall policy on direct compres(cid:173)
`sion. These responses are indicated in Fig(cid:173)
`ure 15 . Support for direct compression was
`
`Use
`
`100
`
`(!)
`
`c
`E
`(!)
`0..
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Sodium
`lauryl
`sulfate
`
`Dioctyl
`sodium
`sulfa(cid:173)
`succinate
`
`Tween Pluronic F Poly(cid:173)
`ethylene
`glycol
`
`Figure 12: Use of wetting agents in capsules (39 responses).
`
`Filler-binder
`
`No
`43.9%
`
`Yes
`56.1%
`
`Wet binder
`
`Yes
`41 .1%
`
`No
`58.9%
`
`Yes
`43.1%
`
`No
`56.9%
`
`Lubricant
`
`Yes
`70.2%
`
`No
`29.8%
`
`Not
`recommended
`
`Never used
`,-----1 .7%
`
`• Direct compression
`Roll compaction
`D Wet mass- fluid bed drying
`• Wet mass - tray drying
`Ail-in-one
`
`en 35
`~ 30
`c 8.. 25
`~ 20
`0 15
`2 10
`§ 5
`z
`o ~~~.u~~u.~~~--~
`4th
`5th
`Preferences
`
`Figure 14: Preference for method of tab let
`manufacture (58 response.\).
`
`Use both
`wet granulation
`and direct
`compression
`41.4%
`
`Method
`of choice
`41.4%
`
`Figure 15: Company policy on direct com(cid:173)
`pression (58 responses).
`
`Figure 13: Perceived need for better excipi(cid:173)
`ents (58 responses).
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 013
`
`

`

`“When you compare aL ya
`Rae erm eee
`AMM ee mee ee
`z=
`comments about their performance...”
`“Their engineering concepts
`aa
`“Our producttesting at
`a Piediaoveal
`i
`;
`Vector’s Laboratory
`a Deeee
`ReeRae
`OUTstne
`3
`y
`Nak
`P
`Oem tata 1 ee
`Be ae ==: ae WEease
`advanced computer
`iin the U.S...”
`control technology
`they've developed...”
`“Look at the
`“They providea
`ORseeeer
`| ST)ea ORea
`
`Page 014
`
`2
`;
`ee
`Manufacturers offluid bed systems, perforated coating pan coating systems,
`process control systems, laboratory and production sized equipment.
`
`Vector Corporation ™@ 675 44th Street m™ Marion, lowa 52302 m Telephone319-377-8263 ™ Fax 319-377-5574
`Circle 31
`
`Par Pharm., Inc.
`Exhibit 1028
`
`When you compare
`eT pan systems,
`Vector's is the ae TiC
`
`|
`
`yo
`
`- AFELE
`
`Cd
`
`a,
`
`th
`
`LALACAC
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 014
`
`

`

`44 Pharmaceutical Technology JANUARY 1993
`
`still strong. But in data not shown, almost
`one-third of the innovator companies indi(cid:173)
`cated that it was not recommended or never
`used; however, it was the method of choice
`of 60% of the combined generic, vitamin,
`and nonprescription drug industries. The
`overall acceptance of direct compression ap(cid:173)
`pears to be greater than the authors would
`have predicted.
`Finally, companies were asked some gen(cid:173)
`eral questions. The response on policy to(cid:173)
`ward noncompendial excipients indicated
`an aversion to their use. Twenty-five percent
`of the companies, mostly innovators, indi(cid:173)
`cated they would never be used (Figure 16).
`In response to a question on the use of com(cid:173)
`puter optimization for formulation devel(cid:173)
`opment, 50% of the companies indicated
`that they always or occasionally used it and
`50% said they rarely or never used it (Fig(cid:173)
`ure 17). These results indicate that the ben(cid:173)
`efits of computer optimization are begin(cid:173)
`ning to be realized. The trend toward interna-
`
`tiona! harmonization of formul ations is
`shown in Figure 18. Forty companies indi(cid:173)
`cated that they manufactured products in
`more than one country. Of those, 62% (n =
`25) indicated that they used the same excipi(cid:173)
`ents in each country, and almost all of the re(cid:173)
`maining acknowledged that they were mov(cid:173)
`ing in that direction.
`
`CONCLUSIONS
`The following general conclusions can be
`drawn from this survey:
`The industry has adopted rational ap(cid:173)
`proaches to selection of pharmaceutical ex(cid:173)
`cipients.
`Trends in tablet and capsule formu lation
`seem to be
`• phasing-out natural ingredients as binders
`and disintegrating agents
`• increasing use of wetting agents and gli(cid:173)
`dants
`• simplifying formulations as much as possi(cid:173)
`ble.
`
`Table VI: Tablet manufacturing preference in generic companies.
`
`Process
`
`No. of Responses
`
`Average
`
`Preference
`3
`
`2
`
`Direct compression
`Roll compaction
`Wet massing
`- fluid bed drying
`Wet massing
`-
`tray drying
`Ali-in-one processing
`
`13
`4
`
`7
`
`12
`5
`
`1 2
`3 .8
`
`2.3
`
`2.5
`2.4
`
`11
`0
`
`2
`
`3
`
`5
`2
`
`1
`0
`
`3
`
`2
`
`4
`
`0
`2
`
`0
`
`3
`
`5
`
`0
`
`0
`
`0
`0
`
`Direct compression is the method of
`choice for tablet manufacture in all but the
`innovator drug industry.
`There is a general satisfaction with pres(cid:173)
`ent pharmaceutical excipients but a gen(cid:173)
`eral desire for those that would accelerate
`dissolution.
`
`ACKNOWLEDGMENTS
`The authors would like to thank the respon(cid:173)
`dents and companies who participated in the
`survey. •
`
`If they give a
`market advantage
`12.5%
`
`As a
`last resort
`
`34.6% )
`
`Never
`25%
`
`If they meet
`other standards
`22.9%
`
`Figure 16: Company policy on use of non-
`compendia/ excipients (48 responses).
`
`International
`market
`
`formulations
`
`Movement
`
`Figure 18: Company policy on worldwide uniformity oftahlet formulations (58 responses).
`
`Rarely
`5.2%
`
`Occasionally
`34.5%
`
`Figure 17: Use of computer optimization in
`formulution del·eloplllellt (58 responses).
`
`Par Pharm., Inc.
`Exhibit 1028
`Page 015
`
`