HANDBOOK OF
`
`Pharmaceutical
`Manufacturing
`Formulations
`
`Over-the-Counter Products
`VOLUME 5
`Sarfaraz K. Niazi
`
`CRC PRESS
`
`Boca Raton London New York Washington, D.C.
`
`EXHIBIT
`
`I
`
`Apotex (IPR2019-00400) Ex. 1036 p. 001
`
`

`

`Library of Congress Cataloging-in-Publication Data
`
`Niazi, Sarfaraz, 1949-
`Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi.
`p. cm.
`Includes index.
`Contents: — v.5. Over-the-Counter Products
`ISBN 0-8493-1750-9 (alk. paper)
`1. Drugs—Dosage forms—Handbooks, manuals, etc. 1. Title
`
`RS2OO.N53 2004
`615T9—dc21
`
`2003051451
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are
`indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the
`publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
`
`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 or retrieval system, without prior permission in writing from the publisher.
`
`The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific
`permission must be obtained in writing from CRC Press LLC for such copying.
`
`Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd.. Boca Raton, Florida 33431.
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation,
`without intent to infringe.
`
`Visit the CRC Press Web site at www.crcpress.com
`
`© 2004 by CRC Press LLC
`
`No claim to original U.S. Government works
`International Standard Book Number 0-8493-1750-9
`Library of Congress Card Number 2003051451
`Printed in the United States of America 1 234 5 6789 0
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`UNIVERSITY OF ALBFRTA
`
`Apotex (IPR2019-00400) Ex. 1036 p. 002
`
`

`

`Dedication
`
`Dedicated to the memory of Dean Allen I. White
`
`Apotex (IPR2019-00400) Ex. 1036 p. 003
`
`

`

`Preface to the Series
`
`No industry in the world is more highly regulated than
`the pharmaceutical industry because of the potential threat
`to a patient’s life from the use of pharmaceutical products.
`The cost of taking a new chemical entity to final regulatory
`approval is a staggering $800 million, making the phar­
`maceutical industry one of the most research-intensive
`industries in the world. It is anticipated that the industry
`will spend about $20 billion on research and development
`in 2004. Because patent protection on a number of drugs
`is expiring, the generic drug market is becoming one of
`the fastest growing segments of the pharmaceutical indus­
`try with every major multinational company having a sig­
`nificant presence in this field.
`Many stages of new drug development are inherently
`constrained by time, but the formulation of drugs into
`desirable dosage forms remains an area where expediency
`can be practiced by those who have mastered the skills of
`pharmaceutical formulations. The Handbook of Pharma­
`ceutical Manufacturing Formulations is the first major
`attempt to consolidate the available knowledge about for­
`mulations into a comprehensive and, by nature, rather
`voluminous presentation.
`The book is divided into six volumes based strictly on
`the type of formulation science involved in the develop­
`ment of these dosage forms: sterile products, compressed
`solids, uncompressed solids, liquid products, semisolid
`products, and over-the-counter (OTC) products. Although
`they may easily fall into one of the other five categories,
`OTC products are considered separately to comply with
`the industry norms of separate research divisions for OTC
`
`products. Sterile products require skills related to steril­
`ization of the product; of less importance is the bioavail­
`ability issue, which is an inherent problem of compressed
`dosage forms. These types of considerations have led to
`the classification of pharmaceutical products into these six
`categories. Each volume includes a description of regula­
`tory filing techniques for the formulations described. Also
`included are regulatory guidelines on complying with Cur­
`rent Good Manufacturing Practices (cGMPs) specific to
`the dosage form and advice is offered on how to scale-up
`the production batches.
`It is expected that formulation scientists will use this
`information to benchmark their internal development pro­
`tocols and reduce the time required to file by adopting
`formulae that have survived the test of time. Many of us
`who have worked in the pharmaceutical industry suffer
`from a fixed paradigm when it comes to selecting formu­
`lations: “Not invented here” perhaps is kept in the back
`of the minds of many seasoned formulations scientists
`when they prefer certain platforms for development. It is
`expected that with a quick review of the formulation pos­
`sibilities that are made available in this book such scien­
`tists would benefit from the experience of others. For
`teachers of formulation sciences this series offers a wealth
`of information. Whether it is selection of a preservative
`system or the choice of a disintegrant, the series offers
`many choices to study and consider.
`
`Sarfaraz K. Niazi, Ph.D.
`Deerfield, Illinois
`
`Apotex (IPR2019-00400) Ex. 1036 p. 004
`
`

`

`Preface to the Volume
`
`The Handbook of Pharmaceutical Manufacturing Formu­
`lations: Over-the-Counter Products is written for the phar­
`maceutical scientist and others involved in the regulatory
`filing and manufacturing of new OTC products. Because
`of the wide variety of products involved, from those bor­
`dering on cosmetics to proton pump inhibitors, the OTC
`products are manufactured by the most sophisticated glo­
`bal manufacturers as well as small one-room makeshift
`manufacturing houses.
`The OTC products comprise a special category of
`healthcare products in that they can be dispensed without
`prescription, the rationale being that the use of these prod­
`ucts does not expose patients to serious risks associated
`with side effects even if some misuse or overuse of these
`products occurs. The OTC category includes three types
`of products:
`
`• Products that require full filing with the U.S.
`Food and Drug Administration (FDA) for mar­
`keting approval (the NDA/NADA or
`aNDA/aNADA process) including products or
`compositions not included in the monographs
`(see below) or administered in controlled
`release formulations
`• Products that do not require filing with the U.S.
`FDA because they comply with the monographs
`issued by the U.S. FDA in its Code of Federal
`Regulations (CFR)
`• Products that fall under the category of grand­
`father products which have been in use prior to
`the 1960s and have not been specifically
`excluded by the FDA; not all grandfather prod­
`ucts fall under the OTC category — only those
`that are Generally Regarded As Safe (GRAS)
`
`The U.S. FDA provides excellent support through its OTC
`website (http://www.fda.gov/cder/otc/index.htm) and for-
`mulators are highly encouraged to make use of the infor­
`mation available, particularly the updates in the mono­
`graph label requirements and withdrawal of approvals of
`formulations.
`With the safety of consumers in mind, the U.S. FDA
`is in the process of establishing guidelines for all OTC
`products. Although the U.S. FDA began this work over
`three decades ago, much remains to be done. The U.S.
`FDA process begins with the issuance of Proposed Rules;
`this notification is like a warning (or advice) to the industry
`
`that this category of products is now under U.S. FDA
`watch. Often years go by before Proposed Rules are pub­
`lished in the Code of Federal Regulations. The Proposed
`Rules include not only identification of approved active
`ingredients but also inactive ingredients that are deemed
`compatible with the active ingredients and safe for con­
`sumers. The Proposed Rules are subject to criticism by
`the industry healthcare practitioners and consumers. After
`receiving these comments over what can be a period of
`several years, the U.S. FDA issues Final Rules on a spe­
`cific category of products; these become official on the
`date of publication in the Code of Federal Regulations. In
`many cases, however, the U.S. FDA issues subsequent
`rules either to delay application of Final Rules or to mod­
`ify the Final Rules if new information has become avail­
`able.
`The Final Rule requirements have primarily been
`applied to products on the market and a newcomer is well
`advised to study competitor products for market leaders
`as ample opportunities are available to innovate these
`products. Examples include the Tylenol® Hot Therapy
`products and loratidine tablets that dissolve in the mouth
`and do not require water. 1 foresee more such products
`entering into the ever-competitive OTC market.
`It is imperative that any prospective entry into the OTC
`market should begin with a thorough consultation of the
`Final Rules; an examination of Proposed Rules and noti­
`fications to issue Proposed Rules is also helpful in deter­
`mining what rules are about to become Final Rules.
`Reviewing the discussions about Proposed Rules that have
`affected their finalization can be very helpful in under­
`standing the relevant issues of safety, efficacy and label­
`ing. Because the marketing of OTC products requires a
`large investment in marketing efforts, it is prudent to
`develop a clear understanding of the legality of formula­
`tions and claims made in the initial phases of product
`development.
`A large number of products on the market today are
`not covered by the U.S. FDA monographs but does that
`make them legitimate? This is the often-asked question.
`The U.S. FDA has limited resources to tackle everything
`that is out there on the market. When emergencies arise,
`however, the U.S. FDA reacts immediately as it did in the
`case of phenylpropanolamine, pseudoephedrine and
`recently, kava kava. Here are some broad guidelines
`adopted by the U.S. FDA for the most commonly abused
`categories of products:
`
`Apotex (IPR2019-00400) Ex. 1036 p. 005
`
`

`

`1. No treatments are approved for hair growth
`except for minoxidil.
`2. No treatments are approved for enhancing sex­
`ual performance except for sildenafil citrate
`(and that only in MED).
`3. The few treatments approved for weight loss
`include olristat phentermine and sibutramine
`(phenylpropanolamine is no longer a recom­
`mended compound).
`
`It is noteworthy that the U.S. FDA does not differentiate
`between botanical products and chemical-based products.
`If a product bears an efficacy claim it must be governed
`by U.S. FDA rules; however a product that falls into a
`drug category that makes nutritional claims falls under a
`food category with its own set of detailed rules. Vitamins
`and minerals fall under food labeling guidelines; however
`a single-entity vitamin product with specific claims to treat
`or ameliorate a disease is a drug product. These definitions
`do not necessarily coincide with the rulings of regulatory
`authorities worldwide. In many countries nutritional prod­
`ucts are controlled as drugs and require prescriptions;
`these same products would be considered non-prescription
`items in the United States. On the other hand a number
`of highly active drugs are available without prescription
`in many countries such as the Traditional Chinese Medi­
`cine (TCM) in China and Ayurvedic and Unani medicines
`in South Asia.
`A reclassification of a drug to OTC status can be
`requested by drug manufacturers. Recent examples of
`such a prescription-to-OTC switch include ibuprofen (200
`mg), ranitidine hydrochloride (75 mg), and loratidine (10
`mg). Note that specific strengths, not necessarily the
`chemical entity itself, are made OTC. In other words it is
`not necessary to have an official monograph to secure OTC
`status for a drug. The decision to request reclassification
`of a drug as OTC is always a well-calculated business
`decision. Generally drugs with an OTC status will not
`qualify for medical reimbursement by insurance compa­
`nies or federal assistance programs in the United States.
`This can substantially reduce sales of the product; on the
`other hand, ease of availability to a greater number of
`patients can easily compensate for this loss. The most
`lucrative opportunities arise when one strength is made
`OTC while other strengths remain available by prescrip­
`tion only.
`It is noteworthy that the decision to allow a switch from
`prescription to OTC by the U.S. FDA is primarily driven by
`the side effects or toxicity of the drug. For example, in
`Australia a Roche request for a prescription-to-OTC switch
`for its weight-loss drug orlistat (XenicaU) was recently
`turned down because of extensive side effects associated
`with the use of Xenical. The drug itself is very safe as it
`does not enter the body and acts only locally to partially
`block absorption of fat. The unabsorbed fat produces many
`
`gastrointestinal symptoms which although temporary
`were sufficient to disallow the status switch. Obviously
`Roche would have been best advised to develop an OTC
`formulation with fewer side effects before requesting this
`switch. (In the case of orlistat, the solution was simple as
`described in U.S. Patent No. 6,251,421 by this author
`wherein combining orlistat with a natural fiber reduced
`the side effects by 70%.)
`The OTC category of products represents a wide range
`of dosage forms. These formulations have much in com­
`mon with their prescription counterparts but are presented
`in this volume of the Handbook of Pharmaceutical Man­
`ufacturing Formulations because of the development
`approach taken, labeling considerations, and support
`available from suppliers of ingredients in designing these
`products. Because the consumer is inevitably involved in
`the selection of these products, packaging considerations
`are much more important than in the prescription category
`of products. Additional considerations include ease of
`administration, palatability. and stability in storage as con­
`sumers are likely to keep leftovers around for a long time.
`Additionally, price constraints often make it difficult to
`enjoy some freedom of choice in formulations especially
`if the innovator company faces the competition of house
`brands. All of these considerations taken together make
`the OTC category one that should be presented in a single
`volume of this series of books.
`Formulating OTC products is generally easier than
`formulating prescription products if the product is
`described in U.S. FDA monographs (either as Proposed
`Rules or Final Rules); such formulations become merely
`an exercise in mechanics. Whereas a manufacturer is not
`bound by these rules, complying with them reduces the
`costs and time involved securing approval from regulatory
`authorities. The multibillion-dollar market of OTC prod­
`ucts has attracted major chemical suppliers to develop
`support ingredients that are much easier to use; they have
`also developed typical formulations for hundreds of these
`products.
`The most notable industry leaders include:
`
`• Amerchol
`• American Colloid
`• Aquaion
`• BASF
`• BF Goodrich
`• Calgon
`• Colorcon
`• Croda
`• Dow Corning
`• FMC
`• Gattefose
`• General Electric
`• Henkel
`• Hormel
`
`Apotex (IPR2019-00400) Ex. 1036 p. 006
`
`

`

`• Huis America
`ICI Americas
`•
`•
`Inolex
`International Sourcing
`•
`International Specialty
`•
`• Laboratoires Serobioligique
`• Lonza
`• NIPA
`• PPG Industries
`• R.I.T.A.
`• Reheis
`• Rheox
`• Rhone-Poulenc
`• Rohm and Haas
`• Southern Clay
`• Sutton
`• Vanderbilt
`
`The formulations recommended by these and other com­
`panies have acquired almost a universal appeal; through­
`out this book you will find formulations recommended by
`these laboratories, as acknowledged by the listing of a
`brand name in the formula. The best way to connect to
`these companies is to search the Internet for contact infor­
`mation; it is no longer necessary to reproduce such infor­
`mation here. Whereas many companies prefer to use
`generic components in the dosage form, it has been found
`that the use of proprietary components can indeed reduce
`costs in the long run.
`The choice of color is a highly sensitive issue in the
`formulation of OTC products; only FD&C colors are
`allowed. Whereas there is a great need to make the prod­
`ucts attractive and appealing, the choices of safe colors
`are dwindling quickly, such as for red colors. The formu-
`lator is encouraged to review the status of approved colors
`around the world before committing to a specific color.
`Manj' OTC solid dosage forms are available in coated
`form. Sugar coatings have yielded to film coatings, and
`this book contains a large number of sugar-coating, seal­
`coating, subcoating, film-coating, and polish-coaling for­
`mulations that can be easily adapted to various dosage
`form sizes. The use of organic solvent-based coatings has
`become prohibitive because of environment consider­
`ations, but in those cases where formulations are
`extremely sensitive to moisture, organic coatings may still
`offer a valid choice. A few companies offer ready-made
`coating formulations, and these are worth considering.
`The Appendix to this book includes a large number of
`formulations of coatings of solid dosage forms. A keen
`formulator will have no difficulty based on these formu­
`lations in adopting a coating system that will provide the
`necessary protection and offer esthetic appeal as well.
`Solid dosage forms are coated for many reasons, including
`masking the taste, making them easier to swallow, and
`providing protection against the environment.
`
`Stability considerations remain paramount, and the
`data in the final packaging must be evaluated carefully
`before adjusting formulae for excesses; in this book, most
`formulations are provided without this consideration. A
`strip or blister dosage form is more popular around the
`world, but the plastic bottle is the most popular final form
`in the United States.
`The development of OTC products is similar to the
`development of prescription dosage forms; as a result.
`cGMP and Good Laboratory Practice (GLP) consider­
`ations apply equally. The first chapter describes in greater
`detail the cGMP considerations. An Appendix to Chapter
`1 provides a comprehensive checklist of items to review
`to ensure that a manufacturing facility is in compliance
`with cGMP standards. Appropriate identification is made
`in this checklist of those items that comply with EC guide­
`lines. The U.S. FDA guidelines are available from the U.S.
`FDA website: http://www.fda.gov. The World Health
`Organization (WHO) provides GMP guidelines that are
`less stringent than those of the U.S. FDA and EC, and
`formulators should be aware of the fact that all of these
`are simply guidelines. One should be fully cognizant of
`the fact that no agencies are bound by these guidelines,
`particularly the U.S. FDA. Manufacturers cannot take ref­
`uge in the defense that they have complied with these
`guidelines. It is further worthwhile remembering that all
`of these guidelines are continuously revised, and the “c”
`in the cGMP does refer to current.
`The second chapter deals with the most popular cat­
`egory of dosage forms encountered in OTC offerings —
`solids. Issues specific to manufacturing of these dosage
`forms are described from a practical viewpoint, indicating
`the problem areas frequently encountered in manufactur­
`ing practice.
`The third chapter deals with liquids and suspensions
`and includes, like the chapter above, practical advice on
`how to bring manufacturing practices into compliance
`with regulatory requirements.
`The fourth chapter offers highlights of cleaning vali­
`dation, a topic often ignored by OTC manufacturers as not
`being significant because of the safety of ingredients used.
`It is true that the same stringent standards may not apply,
`but compliance with cleaning standards and validation of
`processes go a long way toward ensuring overall compli­
`ance.
`The first four chapters were drawn from advice the
`U.S. FDA gives to its inspectors before they inspect a
`manufacturer. The CFR includes complete details of what
`is considered acceptable by the U.S. FDA: this advice is
`of a practical nature, and I find it to be extremely helpful
`in enhancing awareness of the guidelines of regulatory
`authorities. It is noteworthy that EC guidelines, particu­
`larly in light of the harmonization of specifications, are
`somewhat identical to the U.S. FDA guidelines; in chapter
`1, specific references are made to EC guidelines. The
`
`Apotex (IPR2019-00400) Ex. 1036 p. 007
`
`

`

`Appendix includes formulations of coating solutions;
`these should prove useful for the pharmaceutical formu­
`lation teams.
`The formulations in this book generally fall into three
`categories. Some formulations are presented in greater
`detail, including indications of where quality assurance
`(QA)/quality control (QC) sampling is to be done and
`describing the tooling and in-process and finished product
`specifications. The other extreme is a mere listing of com­
`ponents with a bare minimum of manufacturing methods.
`This was necessary for two reasons: first, to contain the
`size of this book, and, second, to keep from presenting
`superfluous information, as formulators would eventually
`adopt such a formula to their own delivery forms. Also,
`at times the various strengths are merely achieved through
`adjustment of dosage size, so it was considered unneces­
`sary to reproduce manufacturing steps where they are
`obvious.
`The primary source of these formulations is publicly
`available knowledge about formulae that have proven to
`provide stable products. No representation is made that these
`formulations meet U.S. FDA monographs or any other reg­
`ulatory guidelines for safety of inert ingredients. The formu-
`lator is advised to determine guideline compliance before
`adopting any of the formulations given in this book. Those
`interested in obtaining detailed information about these
`formulations are encouraged to contact the author at
`
`http://www.pharmsci.com. Because of the wide variety of
`sources from which the information has been gathered in
`the book, the format of formulations also varies. For exam­
`ple, in some instances scale is provided, whereas in others
`a percentage by weight is described. In still other
`instances, quantities for a specific batch size are provided.
`Obviously, it would be desirable to convert these formu­
`lations into a uniform format, but the task would be daunt­
`ing and inevitably would lead to inclusion of errors. Pro­
`fessional formulators should not encounter any difficulty
`in adapting these formulations to their own system.
`As mentioned before, not all formulations contain the
`required overages for stability considerations and losses
`during manufacturing; formulators are expected to
`develop these based on the final packaging chosen for the
`product. The author would appreciate being notified of
`any special problems encountered in adopting these for­
`mulations or of any errors (niazi@pharmsci.com). Whereas
`much care has gone into ensuring the accuracy of quan­
`tities and proper identification of ingredients, such errors
`shall remain in a work as large as that presented here.
`
`Sarfaraz K. Niazi, Ph.D.
`Pharmaceutical Scientist, Inc.
`20 Riverside Drive
`Deerfield. Illinois 60015
`
`Apotex (IPR2019-00400) Ex. 1036 p. 008
`
`

`

`About the Author
`
`Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharma­
`ceutical industry for over 30 years. He has authored hundreds of scientific papers,
`textbooks, and presentations on the topics of pharmaceutical formulation, biophar­
`maceutics, and pharmacokinetics of drugs. He is also an inventor with scores of
`patents and is licensed to practice law before the U.S. Patent and Trademark Office.
`Having formulated hundreds of products from consumer products to complex bio­
`technology-derived products, he has accumulated a wealth of knowledge in the
`science of formulations and regulatory filings of Investigational New Drugs (INDs)
`and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry
`internationally on issues related to formulations, pharmacokinetics and bioequivalence
`evaluation, and intellectual property issues (http://www.pharmsci.com).
`
`Apotex (IPR2019-00400) Ex. 1036 p. 009
`
`

`

`Acknowledgments
`
`Many have assisted me in the development of this work
`that has taken years to compile, and I am thankful to scores
`of my graduate students and colleagues for their help.
`The diligent and ardent editorial support offered by
`CRC Press was exemplary; nevertheless, any remaining
`errors are altogether mine. 1 am grateful to CRC Press for
`taking this lead in publishing what is possibly the largest
`such work in the field of OTC products. It has been a
`distinct privilege to have known Stephen Zollo, a Senior
`Editor at CRC Press, for many years. The editorial assis­
`tance provided by CRC Press staff was indeed exemplary,
`particularly the help given by Erika Dery, Susan Fox, and
`others.
`
`1 have dedicated this book to Dean Allen 1. White,
`whom I met in 1970 when 1 began my graduate work at
`the Washington State University (WSU) in Pullman. Until
`his death last December, we stayed in touch, and I con­
`tinued to benefit from his advice and kindness. He served
`as Dean of the WSU College of Pharmacy for 19 years.
`With a distinct lean disposition and straightforward
`approach to the profession he loved and the life he cher­
`ished, he taught us many things. I am so fortunate to have
`had this opportunity to know such a great educator, sci­
`entist, and leader.
`
`Apotex (IPR2019-00400) Ex. 1036 p. 010
`
`

`

`Over-the-Counter Product Formulations
`
`121
`
`Calamine Cream
`
`Bill of Materials
`Scale (mg/g)
`Item Material Name
`80.00
`1
`Polawax GP200
`2
`10.00
`Polysorbate 60
`50.00
`3
`Caprylic/capric triglyceride
`4
`QS
`Deionized water
`100.00
`5 Witch hazel distillate
`50.00
`6
`Glycerin
`20.00
`7
`Zinc oxide
`8
`20.00
`Calamine
`Preservative, color
`9
`QS
`
`Quantity/kg (g)
`80.00
`10.00
`50.00
`QS to 1 kg
`100.00
`50.00
`20.00
`20.00
`QS
`
`MANUFACTURING DIRECTIONS
`Heat oil and water phases separately to 65 to 70°C. Add
`water phase to oil phase while stirring. Add zinc oxide
`and calamine under high shear. Stir to cool.
`
`Calamine Cream
`
`Bill of Materials
`Item Material Name
`Scale (mg/g)
`Cellulose (microcrystalline) (Avicel™ RC-591)
`1
`20.00
`Glycerin
`2
`100.00
`Methylparaben
`3
`1.80
`Propylparaben
`0.20
`4
`Glyceryl stearate and PEG-100 stearate
`100.00
`5
`Cetyl alcohol
`25.00
`6
`Zinc oxide
`50.00
`7
`Calamine
`50.00
`8
`Distilled water
`9
`653.00
`
`Quantity/kg (g)
`20.00
`100.00
`1.80
`0.20
`100.00
`25.00
`50.00
`50.00
`653.00
`
`MANUFACTURING DIRECTIONS
`Mix item 2 with item 9. and heat to 75°C. Add items 3
`and 4; mix until dissolved using a shearing mixer. Main­
`tain temperature at 75°C. and gradually add item 1, con­
`tinue mixing at 75°C for 15 minutes, or until item 1 is
`homogeneously dispersed. Mix well. When temperature
`
`drops to 60 to 65°C, gradually add items 7 and 8; mix
`well until powders are homogeneously dispersed. Pass
`through homogenizer, if necessary; adjust theoretical
`weight with warm distilled water, and continue mixing
`until the cream congeals.
`
`Apotex (IPR2019-00400) Ex. 1036 p. 011
`
`

`

`Over-the-Counter Product Formulations
`
`131
`
`Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and
`Balsam Tolu Syrup
`
`Bill of Materials
`Scale (mg/tablet)
`0.001 mL
`5.00
`1.32
`8.80
`0.80
`0.90
`0.10
`6.25
`2.66
`319.22
`238.33
`83.93
`40.00
`166.67
`0.80
`100.00
`QS
`QS
`
`Item Material Name
`1
`Ipecac fluid extract
`Chlophedianol hydrochloride
`2
`Ephedrine hydrochloride (powder)
`3
`Ammonium chloride (reagent-grade granules )
`4
`Carbinoxamine maleate
`5
`Methyl paraben
`6
`7
`Propyl paraben
`Balsam of Tolu (eq. aqueous extract)
`8
`Saccharin sodium (dihydrate powder)
`9
`10
`Sucrose (granulated sugar)
`Glucose liquid (com syrup)
`II
`Sorbitol solution (calculate as 70% sorbitol crystals)
`12
`13
`Alcohol
`FD&C Red Dye (Amaranth El23)
`14
`Raspberry flavor
`15
`Propylene glycol
`16
`HyFlo filter aid
`17
`18 Water purified
`
`Quantity/L (g)
`1.00 mL
`5.00
`1.32
`8.80
`0.80
`0.90
`0.10
`6.25
`2.66
`319.22
`238.33
`83.93
`40.00
`166.67 mg
`0.80
`100.00
`0.50
`-450.00 mL
`
`MANUFACTURING DIRECTIONS
`Charge Balsam of Tolu and 25 mL of water in a steam
`bath. Raise the temperature, stirring continuously in order
`to mix water with the balsam. Boil for half an hour, and
`allow to decant while cooling. Discard extracted Balsam
`of Tolu. Filter the supernatant liquid through filter paper,
`and store apart. Charge 150 mL water in a jacketed mixing
`tank, and heat to boiling. Add and dissolve parabens with
`mixing. Add and dissolve sugar with constant mixing.
`Heat to 70 to 75°C. Once sugar is dissolved, add glucose,
`sorbitol, and saccharin sodium. Mix well until dissolved.
`Dissolve ammonium chloride in 28 mL water. Add to
`mixing tank. Add extract Balsam of Tolu from first step
`
`with mixing. Mix well and cool to 25 to 30°C. Add and
`dissolve ephedrine and carbinoxamine in 20 mL water,
`and add to mixing tank. Mix well. Add and dissolve chlo­
`phedianol in 50 g of propylene glycol, and add to mixing
`tank. Add balance of propylene glycol to mixng tank. Add
`and dissolve Ipecac fluid extract and raspberry flavor in
`alcohol. Add to mixing tank. Dissolve dye in 5 mL water,
`and add to tank with continuous mixing. Rinse container
`with 5 mL of water, and add rinsing. Adjust to volume
`with purified water. Add HyFlo filter aid to syrup, and mix
`well. Recirculate through filter press or equivalent until
`sparkling clear.
`
`Chlorhexidine Gel
`
`Bill of Materials
`Item Material Name
`Scale (mg/g)
`Chlorhexidin diacetate
`20.00
`1
`1,2-Propylene glycol (Pharma)
`2
`300.00
`Lutrol F 127
`3
`220.00
`4 Water
`460.00
`
`Quantity/kg (g)
`20.00
`300.00
`220.00
`460.00
`
`MANUFACTURING DIRECTIONS
`Dissolve chlorhexidin diacetate in propylene glycol at Maintain the temperature until the air bubbles escape. A
`>70°C. Stir well, and slowly add Lutrol F 127 and water.
`clear, colorless gel is obtained.
`
`Apotex (IPR2019-00400) Ex. 1036 p. 012
`
`

`

`Over-the-Counter Product Formulations
`
`157
`
`Iron Polystyrene and Vitamin C Syrup
`
`Bill of Materials
`Scale (rng/ml)
`Item Material Name
`1
`125.00
`Glycerin
`1.40
`2
`Methyl paraben
`3
`0.16
`Propyl paraben
`4
`79.61
`Sorbitol; use sorbitol solution
`Xanthan gum
`5
`3.30
`Sucrose (granulated)
`6
`10.00
`7
`0.20
`Saccharin (insoluble)
`105.00
`Elemental iron; use iron polystyrene sulfonate
`8
`50.00
`9
`Ascorbic acid, USP (35% excess)
`0.10
`Flavor
`10
`Flavor (artificial guarana)
`0.10
`11
`Sodium hydroxide
`12
`QS
`Dye
`13
`QS
`14
`Distilled purified water
`9.50
`Sorbitol solution
`10.00
`15
`
`Quantity/L (g)
`125.00
`1.40
`0.16
`364.33
`3.30
`100.00
`2.00
`530.31
`61.95
`1.00 mL
`1.00 mL
`12. 1.0
`2.00
`-95.00 mL
`-10.00
`
`MANUFACTURING DIRECTIONS
`Add glycerin (item 1) to the tank. Commence heating with
`agitation. Add and disperse parabens. Continue heating to
`70 to 80°C and mix until solution is complete. Force cool
`to 30°C then add and disperse xanthan gum (item 5). Add
`sorbitol solution (item 4) and 80 mL of purified water
`(item 14), and heat with mixing to 60 to 70°C until the
`xanthan gum is fully dissolved. Add and disperse saccha­
`rin and sugar (items 7 and 6). Mix at 60 to 70cC until
`dispersion is complete. Force cool to 25 to 30°C with
`continuous mixing. Commence N, gas protection and
`maintain for the remainder of the manufacturing process.
`Add and disperse ascorbic acid. Continue mixing for 30
`mins at 25 to 30°C. {Note: Use suitable SS high-powered
`stirrer). Mix the iron polystyrene sulfonate milled slurry
`in the original epoxy-lined drums under N2 gas protection
`until uniform. Add the slurry to the main batch and mix
`for 30 minutes at 25 to 30"C. {Note: Avoid scraping the
`
`epoxy lining of the steel drum while mixing and use a
`plastic or rubber scraper to assist in complete transfer of
`the mixed slurry.) Add and disperse the flavors. Mix well.
`Check and record pH. Adjust pH using a 20% sodium
`hydroxide solution (1 g in 5 mL water) to a value of 3
`(range, 2.8 to 3.2). Dissolve the dye in 5 to 7 mL of water
`at 40 to 45°C by stirring for 10 minutes. Add this solution
`to the main batch through a 420-pm screen with mixing.
`Rinse container with 2 to 3 mL water at 40 to 45°C and
`add to bulk through a 420-pm screen. Continue to mix
`under vacuum until mixture is uniform. Pass the suspen­
`sion through the colloid mill at a gap setting of 100 to
`150 pm. Adjust the flow rate such that the temperature
`rise of the suspension does not exceed 10°C. Collect the
`m