Journal of
`Pharmaceuucal
`S Cienoe s0,
`
`SEPTEMBER 1970
`
`VOLUME 59 NUMBER 9
`
`Coden: JPMSA
`
`_ Mylan v. Qualicaps, |PR2017—OO203
`_
`_
`Thlsmaterlalwastupled
`_
`atthe NLM and may be
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2010 - 1/5
`
`

`

`Journal of
`Pharmaceutical
`Sciences
`
`SEPTEMBER 1970
`
`VOLUME 59 NUMBER 9
`
`EDWARD G. FELDMANN
`Editor
`
`MARY HUDSON FERGUSON
`A-5'-Yociate Editor
`
`SHELL‘! ELLIOTT
`Pfoduction Editor
`
`L- I-UAN CORRIGAN
`Contributing Editor
`
`SAMUEL W. GOLDSTEIN
`C°’”'ibmr'ng Editor
`
`LINDA A. LAFONTAINE
`C°"mb“”"&’ Editor
`
`EDITORIAL ADVISORY BOARD
`
`“CK COOPER
`EDWARD R. GARRETT
`GERHARD LEVY
`
`W. LEWIS NOBLES
`G. VICTOR ROSSI
`GORDON H. SVOBODA
`
`COMMITTEE ON PUBLICATIONS
`
`ROBERT c. JOHNSON,
`Cha irman
`
`WILLIAM 5. APPLE
`
`GROVER c. BOWLES7 JR-
`CLIFTON J. LATioLAis
`JOHN H. NEUMANN
`
`urrial of Pharmaceutical Sciences is Publwlled
`by the American Pharmaceutical Association
`at 20
`lb & Northampton Sts. Easton, PA 18042. Second
`cla
`ces.
`'
`’
`'
`ingsigiosmge Paid at Easter)’ Pa , and at additional mall-
`f All expmfiflions of 0 inion and statements of suPl’°5‘3d
`‘act al’1‘e‘11'i!1i:
`in artIicles or editorials carried in this
`'::1‘]"“3 are published on the authority of the writer over
`n ose “€‘m9 they appear and are not to be regarded 3.5
`cgiieiflgruy exPT°.55inK the policies or views of the Ameri-
`. armaceutical Association.
`,
`.
`f
`ces-—Editoi-ial, Advortisiiiiz, and Subscrlvtlon O '
`215 Constitution Ave. N. W., Wasliiniltonv DC
`blicntion Offices: 2o’ih & Northamllw“ Streets’
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`Subseriptions—Unil.'ed States and foreigfli
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`individuals for pL’I‘S0Tlal use ‘miy 35“
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`F,}'l‘:l';F"~:: without notice. Members of
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`raw or‘?iL..i§Z’2‘:§‘3§;‘}“.céE‘.;3%ef'Z3‘ or men
`(“£1181 $40 ABBA membership dues.
`_
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`ah“?-‘Missing numbers will not be sulllllled 1f dues
`.
`ns are in arrears for more than 60 days, °‘
`m".‘3 are received more than 60 days after thejlate
`'3 Issue, or if loss was due to failure to give notice
`'
`-°.°f address.
`'l‘he Association cannot accellt re‘
`- nslbllll-Y for foreign delivery when its records indlcnw
`lament has been made.
`.
`h M
`notif ange Of Address-—Members and subscribers S 9“
`ph 3’ at once both the Post Office and the _American
`N armaceutical Association
`2215 Constitution AV9-r
`‘ W" Washmflton, DC 20057, of any change of address-
`Y1'1Kht 1970 American Pharmaceutical AS8001-""
`a l Tlfirlits reserved.
`21-15 Consfitiition Ave., N. W., Washington. DC
`
`ADVANCING THE CAUSE OF
`THERAPEUTIC ORPHANS
`
`The problems associated with prescribing drugs for children
`were discussed previously on this page (see .[une 1968,.“Thera-
`peutic Orphans”). While knowledge concerning the actions and
`mechanisms of drugs is slowly unraveling, only a relatively few
`steps have been taken in a process that ultimately will require
`much study and research for a full iinderstanding. _
`.
`Determining drug actions and mechanisms in children IS often
`coiiiplicated by different rates of inetabolisni, partially developed
`7 enzyme systems, and other factors associated with growth and
`V maturation which are difllcult to characterize and control under
`experimental conditions. In addition, for drugsnot developed
`specifically for children and possibly having limited use in that
`age group, industry often may. consider the expense of _deter-
`mining dosages and effects
`in children diflicult
`to. _]11Stlfy.
`Moreover, the legal problems andsocial ramifications involved
`with using children and infants in clinical trials further complicate
`the development of suitable criteria for children’s doses.
`_
`Nevertheless, drugs are and must _be used for children.
`Therefore, the most up-to-date information available 1S needed in
`a form that is easily used. For these reasons, the 197i Pediatric
`Dosage Handbook: Usual Doses for Infants and Cliildi'eii has
`been compiled by Dr. Harry C: Shirkey and published by the
`American Pharmaceutical Association.
`_
`The reliability or credibilityof a reference source of this ‘na-
`ture is associated priniarilywith the individuals and organiza-
`tions involved with its compilation and publication. Dr. Shirkey,
`who earned his pharmacy and medical degrees from the Uni-
`Versity of Cincinnati, has practiced as a pediatrician since 1948;
`currently, he serves on the staff of several_hospitals and also
`as a medical school faculty member, teaching courses in both
`ph1arT(zj1:{(i)tli(:)Ei1y
`S1i)lii{il:1ety1::rves as a member of the NF Board
`andnChairman of the NF Committee on Admissions. He is also
`Chairman of the Pediatric Panel of the USP and is a member of
`the Revision Committee. His American Medical Association
`activities include chairing the Drug Utilization Committee and
`serving as Vice-Chairman of the Council on Drugs.
`_
`The major feature of the Hondbook is the comprehensive
`“Table of Pediatric Drugs, Their Dosage, Cautions and Con-
`t1‘z1ir1CllC2ltl0IlS for Use, and Their Available Dosage For1ns.”
`The material in this table reflects the most current and accurate
`information available concerning dosages for children and in-
`fd]l7tVSl1SlIl)€eCtllf1i;’d11l1g6d persists for more breadth and depth in re-
`search designed to elucidate drug niechanisms in adults as well
`as children, the publication of the Pediatric Dosage Handbook
`helps bridge the gap between research and practice as well as
`between research and consumer. Hopefully, this Handbook will
`aid in the effective and safe use of drugs with children and make
`them less “therapeutic Orphans” and more like “foster children”
`at least.
`
`This material was copied
`at the N Llvl a nid may live
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2010 — 2/5
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2010 - 2/5
`
`

`

`
`
`Journal of
`Pharmaceutical
`Sciences
`
`
`
`SEPTEMBER 1970
`
`VOLUME 59 NUMBER 9
`
`
`1205
`
`1234
`
`1243
`
`1246
`
`1249
`
`1252
`
`1255
`
`1258
`
`1261
`
`1265
`
`1267
`
`1271
`
`1276
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`1281
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`1286
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`1290
`
`1295
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`1300
`
`1306
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`1313
`
`EDITORIAL
`
`Advancing the Cause of Therapeutic Orphans
`
`REVIEW ARTICLE
`
`P. N. Patil, J. B. LaPidus, A. Tye
`Steric Aspects of Adrenergic Drugs
`
`RESEARCH ARTICLES
`
`ystems VI: Water—Tetramethylurea
`
`Wen-Hung Wu, Ting-Fong Chin, John L. Lach
`Interaction of Isoniazid with Magnesium Oxide and Lactose
`Donald E. Cadwallader, Janis R. Phillips
`ehavior of Erythrocytes in Various Solvent S
`Harold L. Newmark, Julius Berger
`Coumermycin A;-—-Biopharmaceutical Studies I
`Harold L. Newmark, Julius Berger, J. Thur¢ Carstensen
`Coumermycin A1—Biopharmaceutical Studies II
`M. David MacFarlane, Theodore Koppanyi
`Acetylcholine Tachyphylaxis in Isolated Rabbit Atrium and Its Relation to Norepinephrine Stores
`John W. Poole
`‘
`Effect of Sex on Penicillin Blood Levels in Dogs
`Robert A. 0’Reilly, Gerhard Levy
`.
`'
`Pharma_col<inetic Analysis of Potentiating Effect of Phenylbutazone on Anticoagu1afltA°“°n 0
`John L. Lach, Lyle D. Bighley
`Diffuse Reflectance Studies of Solid-Solid Interactions
`John W. Poole, C. Kanta Bahal
`Dissolution Behavior and Solubility of Anhydrous and Dihydrate Forms of Wy-4503: an Ammo-
`alicyclic Penicillin
`Harald G. O. Holck, Paul M. Lisli, David W. Sjogren, W. W. Westerfeld, Marvin H. Malone
`Effects of Disulfiram on Growth, Longevity, and Reproduction of the Albino Rat
`Jordan L. Cohen, Kenneth A. Connors
`Stability and Structure ofSome Organic Molecular Complexes in Aqueous Solution
`Gerald J. Kelliher, Joseph P. Buckley
`Central Hypotensive Activity of dl- and d-Propranolol
`K. S. Murthy, George Zografi
`vOil—Water Partitioning of Chlorpromazine and Other Phenothiazine Derivatives Using Dodecane
`and n-Octanol
`
`f
`
`Interaction of Bishydroxycoumarm’
`Diffuse Reflectance Studies of Solid-Solid Interactions IV:
`Furosemide, and Other Medicinal Agents with Various Adjuvants
`Louis J. Ravin, Elie G. Shami, Elisabeth Rattie
`Physical—Chemical Evaluation of 3-(3-Hydroxy-3-methylbutylamino)-5-methyl-HS, Triazino
`[5,6~b] Indole (SK&F 30097)
`Ian H. Pitman, Mark A. Ziser
`_
`‘
`Thermodynamics and Kinetics ofCovalent Addition ofBisulfite Ion to Pyrimidimum Tons
`Ping-Hong Chung, Ting-Fong Chin, John L. Lach
`Kinetics of the Hydrolysis of Pilocarpine in Aqueous Solution
`T. L. Breon, A. N. Paruta
`Solubility Profiles for Several Barbiturates in
`Yvonne C. Martin, Ronald Wiegand
`Metabolism and Excretion of Chromonar and Its Metabolite in Dog and Man
`
`Hydroalcoholic Mixtures
`
`
`
`Contents continued on inside back cover
`
`mmerialwafiimd Mylan v. Qualicaps, |PR2017—OO203
`attire NLiv1.and maybe
`‘
`Subject US Ca pzwighti LEWS
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2010 - 3/5
`
`

`

`Contents continuedfrom outside back cover
`
`
`
`DRUG STANDARDS
`
`1319
`
`1324
`
`1328
`
`1331
`
`1333
`
`Ivo Setnikar, Febo Fontani
`Content Uniformity in Rectal Suppositories
`_
`Lee T. Grady, Rupert 0. Zimmerer, Jr.
`USP Collaborative Study of the Assay of Atropine and Scopolamine Dosage Forms
`Harris I. Tarlin, Martin Batchelder
`Determination of Total Iron in I-Iematinics by Atomic Absorption Spectrophotomelry
`M. S. Karawya, M. G. Ghourab
`Assay of Chloramphenicol and Its Esters in Formulations
`M. J. Clio, M. Pernarowski
`Application of Absorbance Ratios to Analysis of Pharmaceuticals VI: Analysis of Binary
`Mixture Using a Reference Spectrum
`
`TECHNICAL ARTICLES
`
`. 1336
`
`1341
`
`N. L. Henderson, A. J. Bruno
`Lactose USP (Beadlets) and Dextrose (PAF 2011): Two New Agents fol‘ Direct C0mPF955i°n
`Tsuneto Kuriyama, Michiharu Nobutoki, Michio Nakanishi
`Permeability of Double-Layer Films I
`
`NOTES
`
`1344
`
`1346
`1348
`
`1350
`
`1353
`
`1356
`_
`1357
`
`1358
`
`1360
`
`1362
`
`1364
`
`Tsuneto Kuriyama, Michiharu Nobutoki, Michio Nakanislii
`Permeability of Double-Layer Films 11
`_
`vWilliam R. Maynard, Jr., Robert B. Bruce
`GLC Determination of Guaiacol Glyceryl Ether in Blood
`_
`_
`William O. Foye, James Mickles, Gerard M. Boyce
`Antiradiation Compounds XIV: Dithiocarbamates of Aminothiophenes
`F. 1. Carroll, Monroe Wall
`N-Substituted Aminoethanethiols and N-Substituted Aminoethanetliiol S-Sulfonic Acids as
`Radioprotective Agents
`_
`_
`_
`_
`Werner Lowenthal, Joseph F. Borzelleca, Charles D. Corder, Jr.
`Drug Absorption from the Rectum III: Aspirin and Some Aspirin Derivatives
`
`1 COMMUNICATIONS
`
`p
`_
`_
`Hansen, _L. J. Hanka
`Robert E. Harmon, S. K. Gupta,’ J.
`Preparation and Biological Activity of Substituted 1,3-Distyryl-4,6-dmltrobenzenes
`Richard J. Warren, R. John Stedman, Elie_ G. Shami, Elisabeth S. Rattie, Louis_J. Ravin
`Observations on the Micelle Formation of 2-Butyl-3-benzofuranyl-4-[2-(diethy1amino)ethoxy]-
`3,5-diiodophenyl Ketone Hydrochloride (SK&F 33134-A) by NMR Spectroscopy
`Y. Fulmer Shealy, C. Allen 0’_Dell
`_
`Imidazole and Pyrazole Bis(2-fluoroetliyl)triazenes
`_
`B. A. Matthews, C. T. Rhodes ;
`_
`Aggregation Mechanisms in Pharmaceutical Suspensions
`Devendra K. Madan, Donald E. Cadwallader
`_
`.
`Effect of Macromolecules on Aqueous Solubility of Cholesterol
`J. C. Stone
`Objective Visual Evaluation of the Relative Content of Major and Minor Defects in Tablets and
`Capsules
`
`1365
`
`BOOKS
`
`This rnatieriaIi.vasci3~péiéd
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`Mylan v. Qualicaps, IPR2017-00203
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`

`

`Objective Visual Evaluation of the Relative
`
`Content of Major and Minor Defects
`in Tablets and Capsules
`
`
`Keyplirases [:1 Tablets, capsules —relative defect determination D
`Defects, tablets and capsules—visual determination method
`
`
`Sfr.‘
`
`Recently, it became desirable for our Quality Control
`Department to develop and subsequently implement a
`reasonably objective analysis for
`the evaluation of
`major and minor physical defects in tablets and capsules.
`The results would then be used to determine if ad-
`ditional processing was required prior to packaging.
`Even though major and minor physical defects are
`routinely monitored by most pharmaceutical manu-
`facturers, we were unable to find a reference regarding
`a test method in the literature. Consequently, a visual
`method has been developed which allows for the mon-
`itoring of major and minor physical defects in tablets
`and capsules.
`Basically, the method consists of filling a rectangular
`plastic (Plexiglas) tray, a inonolayer in depth, with the
`LCeS§Ct}';ll?letS or capsules. The tray is placed on a work-
`Watt _ and positioned under a lamp containirig a 100-
`incandescent lightbulb. The tray’s width 1S placed
`parallel to the front bench edge about 7.62—l5.24 cm.
`(3“6 173-) from the edge. The lamp is connected to a
`'
`i
`.
`.
`,
`°
`,
`-
`.
`.
`,
`timer
`that activates‘illumination of the lightbulb for a
`required amount of time.
`
`.
`-
`'
`‘
`T5!‘ I_ A
`q ) e
`D“fi“'“°“ Of M€U0r and Minor Defects
`
`Minor Defects
`Major Defects
` _
`.
`,
`_
`Surfac
`.
`6 Spots
`Polishing not unilorm
`Breaks or an k
`Comled basectilbslel exposed
`giaggered edges
`Fore
`-
`'
`,,
`.
`.
`,
`Llgn particulate matter
`Pitting or pimples
`Atypical mottling
`Nonuniform color
`Nonuniform size or shape
`Not smooth
`Smeared printing
`Thin-coated edges
`
`(1 Detection of this m
`3Jor defect results in rejection of the lot until it is
`freed Ofany heal
`th hazard resulting from this defect
`
`the start button of the timer is de-
`Subsequently,
`PF_€SS€d
`and the tablets are scanned for both major and
`ddfjfsifltf '(;‘;l_’l‘? 1);
`the defective tablets are
`maticanay thegfilyhe t_-tipped pen (or equivalent). Auto-
`the analysis Ti
`is tutrned off, signifying the end of
`sorted '1:/Id t.h
`e nuin er and types of defects are
`,
`c
`e results are recorded on an assay report
` T
`1 M
`-
`.
`-.
`-
`.
`.
`“M M “VI. Industrial Timer Corporation, Parsippany, N. J.
`
`form. The report is designed so that the number and
`types of defects are identified.
`An empty tray is superimposed over the tablet-
`containing tray, and the two trays are rotated 180°
`around the x- or y-axis so that the reverse side of the
`tablets are exposed. The original tray is removed, and
`the assay is performed on the new exposed side of the
`samples. The procedure is repeated until
`the total
`number of tablets or capsules required in the evaluation
`is assayed, and the results are recorded accuinulatively.
`The total number of units assayed is related to batch
`size and based on Military Standard 105D. Using the
`average tablet or capsule weight, the number of units
`to be tested are weighed into a beaker for subsequent
`transfer to the testing tray. A double sampling plan is
`used in which the acceptable quality level (A. Q. L.)
`is 0.65 and 4.0%, respectively, for major and minor
`defects.
`
`Two sets of trays (two identical trays per set) are
`required to accommodate capsules, capsule-shaped
`tablets, and the conventional standard-shaped tablets.
`All the trays are 22.86 X 15.24 cm. (9 X 6 in.); however,
`the trays used for capsules and capsule-sliaped tablets
`have an inner depth of 0.32 cm. (0.125 in.), and the
`trays used for the standard-shaped tablets have an inner
`depth of 0.16 cm. (0.062 in.).
`Since the size of the tablet or capsule being assayed
`dictates the number of units in each tray load,
`the
`time interval (length of time light
`is illuminated) is
`correspondingly adjusted.
`In effect,
`the illumination
`duration is longest
`for the smallest
`tablet assayed.
`After a year of using this technique, we have developed
`the following formula for determining the time interval
`for a given sample:
`
`I’ seconds/tablet X
`
`total number of tablets to be assayed =
`number of filled trays
`seconds/tray (Eq. I)
`
`The value of P chosen should rellect the desired rigidity
`of the inspection. In our laboratory, P has an average
`value of 0.035 sec./tablet. If 1000 tablets were to be
`tested and five filled trays were involved,
`the time
`interval would be 7 sec./tray. If the last tray is less than
`half a tray, half the time interval is used. Otherwise, the
`tray is considered a full tray.
`We found that the number of tablets scanned per
`tray varies between analysts, and the formula attempts
`to compromise these differences. Otherwise, the natural
`tendency of the analyst is to become overcritical of the
`sample appearance.
`
`J. C. STONE
`Quality Control Laboratories
`Warren-Teed Pharmaceuticals Inc.
`Columbus, OH 43215
`
`Received April 13, 1970.
`Accepted for publication May 27, 1970.
`The author thanks Mr. Frank Blackett for his advice and counsel
`during the assemblement of the testing equipment, and the in-
`valuable assistance provided by the Quality Control Department.
`
`1364 B Journal of1’/imvnaceuticul Sciences
`
`This material was -:5-piad
`at‘ the Nuwl and may be
`SL2 brjzect US {>::-pejright.‘ Laws
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2010 — 5/5
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2010 - 5/5
`
`