HANDBOOK OF
`Pharmaceutical
`Manufacturing
`Formulations
`Liquid Products
`VOLUME 3
`Sarfaraz K. Niazi
`
`CRC PRESS
`
`Boca Raton London New York Washington, D.C.
`
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`

`

`Library of Congress Cataloging-in-Publication Data
`
`Niazi. Sarfaraz. 1949-
`Handbook of pharmaceutical manufacturing formulations: liquid products/ Sarfaraz K. Niazi.
`p. cm.
`Includes index.
`Contents: — v.3. Liquid products
`ISBN 0-8493-1748-9 (alk. paper)
`1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title
`
`RS2OO.N53 2004
`615'19—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 die
`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 0-8493-1748-9
`Library of Congress Card Number 2003051451
`Printed in the United States of America 1 234567890
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`UNIVERSITY OF ALBERTA
`
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`

`

`Dedication
`
`To August P. Lemberger
`
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`

`

`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
`
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`Preface to the Volume
`
`Liquid products, for the purpose of inclusion in this vol­
`ume, include nonsterile drugs administered by any route
`in the form of solutions (monomeric and multimeric),
`suspensions (powder and liquid), drops, extracts, elixirs,
`tinctures, paints, sprays, colloidons, emulsions, aerosols,
`and other fluid preparations. Sterile liquid products are
`presented in another volume. Whereas liquid drugs do not
`share the compression problems of solid dosage forms,
`the filling problems of powder dosage forms, and the
`consistency problems of semisolid dosage forms, they do
`have their own set of considerations in the formulation
`and manufacturing stages. The considerations of prime
`importance for liquid drugs include solubility of active
`drugs, preservation, taste masking, viscosity, flavoring,
`appearance, and stability (chemical, physical, and micro­
`biological), raw materials, equipment, the compounding
`procedures (often the order of mixing), and finally the
`packaging (to allow a stable product to reach patients).
`Suspensions present a special situation in which even the
`powder for reconstitution needs to be formulated such that
`it can be stable after reconstitution; therefore, limited
`examples are included here.
`Chapter 1 in Section I (Regulatory and Manufacturing
`Guidance) describes the practical details in complying
`with the current good manufacturing practice (cGMP)
`requirements in liquid manufacturing. This chapter does
`not address the specific cGMP parameters but deals with
`the practical aspects as may arise during a U.S. Food and
`Drug Administration (FDA) inspection. This includes
`what an FDA inspector would be looking into when audit­
`ing a liquid manufacturing facility.
`Chapter 2 describes the stability testing of new drugs
`and dosage forms. Drawn from the most current Interna­
`tional Conference on Harmonization (ICH) guidelines,
`this chapter describes in detail the protocols used for sta­
`bility testing not only for new drugs but also for new
`dosage forms. The chapter is placed in this volume
`because stability studies are of greater concern in liquid
`dosage forms; however, keeping in mind the overall per­
`spective of the series of this title, this chapter would apply
`to all dosage forms. Again, emphasis is placed on the
`practical aspects, and the reader is referred to official
`guidelines for the development of complete testing proto­
`cols. It is noteworthy that the ICH guidelines divide the
`world into four zones; the discussion given in this chapter
`mainly refers to the U.S. and European regions, and again
`the formulator is referred to the original guideline for full
`guidance. Stability studies constitute one of the most
`
`expensive phases of product development because of their
`essential time investment. As a result, formulators often
`prepare a matrix of formulations to condense the devel­
`opment phase, particularly where there are known issues
`in compatibility, drug interactions, and packaging interac­
`tions. The FDA is always very helpful in this phase of
`study protocols, particularly where a generic drug is
`involved. It is also a good idea to benchmark the product
`against the innovator product. However, one should under­
`stand clearly that the FDA is not bound to accept stability
`data even though it might match that of the innovator
`product. The reason for this may lie in the improvements
`made since the innovator product was approved. For
`example, if a better packaging material that imparts
`greater safety and shelf life is available, the FDA would
`like this to be used (not for the purpose of shelf life, but
`for the safety factors). In recent years, the FDA has placed
`greater emphasis on the control of Active Pharmaceutical
`Ingredient (API), particularly if it is sourced from a new
`manufacturer with a fresh DMF Obviously, this is one
`way how the innovator controls the proliferation of generic
`equivalents. The original patents that pertain to synthesis
`or manufacturing of the active raw material may have been
`superseded by improved processes that are not likely to
`be a part of a later patent application (to protect the trade
`secret because of double-patenting issues). The innovator
`often goes on to revise the specifications of the active
`pharmaceutical ingredient to the detriment of the generic
`manufacturer. However, my experience tells me that such
`changes are not necessarily binding on the generic man­
`ufacturer, and as long as cGMP compliance in the API is
`demonstrated and the impurities do not exceed the refer­
`ence standard (if one is available), there is no need to be
`concerned about this aspect. However, manufacturers are
`advised to seek a conference with the FDA should this be
`a serious concern. At times, the manufacturer changes the
`finished product specification as the patents expire or
`reformulates the product under a new patent. A good
`example of this practice was the reformulation of calcitriol
`injection by Abbott as its patent came to expiry. The new
`specifications include a tighter level of heavy metals, but
`a generic manufacturer should have no problem if the
`original specifications are met because the product was
`approvable with those specifications.
`Chapter 3 describes the container closure systems;
`again, this discussion would apply to all dosage forms. It
`is noteworthy that the regulatory agencies consider con­
`tainers and packaging systems, all those components that
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`come in contact with the product, protect the product from
`environment, or are instrumental in the delivery of the
`product as part of the product definition. Whereas the
`industry is much attuned to studies of the effects of the
`API and dosage formulation components, the study of
`container or closure systems is often left to the end of the
`study trials. This is an imprudent practice, as it might
`result in loss of valuable time. The packaging industry
`generally undergoes faster changes than do the chemical
`or pharmaceutical industries. New materials, better toler­
`ances, more environmentally friendly materials, and now,
`with the use of mechanical devices in many dosage forms,
`appropriate dosing systems emerge routinely. As a rule of
`thumb, the closure system for a product should be the first
`criterion selected before development of the dosage form.
`Switching between a glass and a plastic bottle at a later
`stage can be a very expensive exercise. Because many of
`these considerations are drawn by marketing teams, who
`may change their product positioning, the formulation
`team must be appropriately represented in marketing deci­
`sion conferences. Once a decision has been made about
`the presentation of a product, the product development
`team should prepare several alternatives, based on the ease
`of formulation and the cost of the finished product
`involved. It should be emphasized at all stages of devel­
`opment that packaging scale-ups require just as much
`work as does a formulation scale-up or changes. As a
`result, the FDA provides the scale-up and post-approval
`change (SUPAC) guidelines for packaging components.
`Changes in the dimensions of a bottle may expose a large
`surface of liquid to the gaseous phase in the bottle and
`thus require a new stability testing exercise. This chapter
`forms an important reminder to formulators on the need
`to give consideration to every aspect of the container clo­
`sure system as part of routine development.
`Chapter 4 introduces the area of preapproval inspec­
`tions, a process initiated by the FDA in the wake of the
`grand scandals in the generic pharmaceutical industry a
`few years ago. The FDA guidelines now allow “profiling"
`of companies and list the requirements of preapproval
`inspections when an application has been filed. Whereas
`the emphasis in this chapter is on “preapproval,” the advice
`provided here applies to all regulatory inspections. A reg­
`ulatory inspection can be an arduous exercise if the com­
`pany has not prepared for it continuously. Preparedness
`for inspection is not something that can be achieved
`through a last-minute crash program. This chapter goes
`into considerable detail on how to create a cGMP culture,
`how to examine the documentary needs, assignment of
`responsibility, preparation of validation plan, and above
`all, the art of presenting the data to the FDA. Also dis­
`cussed are the analyses of the outcome of inspection.
`Advice is provided on how to respond to Form 483 issued
`by the FDA, and the manufacturer is warned of the con­
`sequences of failing an inspection. Insight is also provided
`
`for foreign manufacturers, for whom a different set of
`rules may be applied because of the physical constraints
`of inspection. The inspection guidelines provided apply
`to both the manufacturers of API as well as to the finished
`products.
`Chapter 5 includes highlights of topics of importance
`in the formulation of liquid products. However, this chap­
`ter is not an all-inclusive guide to formulation. Only high­
`lights of points of concern are presented here, and the
`formulator is referred to several excellent treatises avail­
`able on the subject.
`Section II contains formulations of liquid products and
`lists a wide range of products that fall under this classifi­
`cation, as interpreted in the volume. There are three levels
`at which these formulations are described. First, the Bill
`of Materials is accompanied by detailed manufacturing
`directions; second, the manufacturing directions are
`abbreviated because they are already described in another
`product of similar nature; and third, only the composition
`is provided as supplied by the manufacturer. With the wide
`range of formulations included in this volume, it should
`be a simple matter for an experienced formulator to con­
`vert these formulations into quantitative Bills of Materials
`and then to benchmark it against similar formulations to
`come up with a working formula. The problems incum­
`bent in the formulation of liquid products are highlighted
`in Chapter 5, but these are generic problems, and the
`formulator should be aware of any specific situations or
`problems that may arise from time to time. I would like
`to hear from the formulators about these problems so that
`they could be included in future editions of this book.
`Again, the emphasis in this series is on a practical reso­
`lution of problems; the theoretical teachings are left to
`other, more comprehensive works on this topic. The key
`application of the data provided herein is to allow the
`formulator to select the ingredients that are reportedly
`compatible, avoiding need for long-term studies to estab­
`lish compatibilities.
`I am grateful to CRC Press for taking this lead in
`publishing what is possibility the largest such work in the
`field of pharmaceutical products. It has been a distinct
`privilege to know Mr. Stephen Zollo, senior editor at CRC
`Press. Stephen has done more than any editor can do to
`encourage an author into completing this work on a timely
`basis. The editorial assistance provided by CRC Press staff
`was indeed exemplary, particularly the help given by Erika
`Dery, Amy Rodriguez, and others. Though much care has
`gone into correcting errors, any errors remaining are alto­
`gether mine. I shall appreciate the readers bringing these
`to my attention for correction in future editions of this
`volume (niazi@pharmsci.com).
`This volume is dedicated to one of the great educators
`and a leader in the pharmaceutical profession. August P.
`Lemberger, who is truly a Wisconsin man. At the Univer­
`sity of Wisconsin in Madison, he was an undergraduate
`
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`and graduate student. He was then a professor, and twice
`Dean of the School of Pharmacy (1943-44, 1946-52,
`1953-69, 1980-91). During the period between 1969 and
`1980, he assumed the responsibility of deanship at the
`University of Illinois, where I was a graduate student. In
`1972, he offered me my first teaching job, as an instructor
`of pharmacy at the University of Illinois, while I was still
`in graduate school. I was one of the greatest beneficiaries
`of his kindness and attention. Gus has an unusual ability
`to put everyone at ease, respect everyone around him, and
`
`in the end, come out as a group leader. Whatever little 1
`have accomplished in my life is mostly due to Gus. Many
`awards, recognitions, and salutations were offered to Gus
`during his celebrated career. His research contributions
`included stability studies, suspension, emulsion stabiliza­
`tion, and later in his career, the various aspects of phar­
`maceutical education. I wish him many years of happy
`retirement and shuttling back and forth between his homes
`in Arizona and Wisconsin. Thanks, Gus.
`
`Sarfaraz K. Niazi, Ph.D.
`Pharmaceutical Scientist, Inc.
`20 Riverside Drive
`Deerfield, Illinois 60015
`
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`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 bioequiva­
`lence evaluation, and intellectual property issues (http://www.pharmsci.com).
`
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`Manufacturing Formulations
`
`99
`
`Cefpodoxime Proxetil for Oral Suspension
`
`Each 5 mL of VANTIN oral suspension contains cefpo­
`doxime proxetil equivalent to 50 mg or 100 mg of cefpo­
`doxime activity after constitution and the following inac­
`tive ingredients: artificial flavorings, butylated hydroxy
`anisole, carboxymethylcellulose sodium, microcrystalline
`cellulose, carrageenan, citric acid, colloidal silicon diox­
`ide, croscarmellose sodium, hydroxypropylcellulose, lac­
`tose, maltodextrin, natural flavorings, propylene glycol
`
`alginate, sodium citrate, sodium benzoate, starch, sucrose,
`and vegetable oil.
`CEFTIN for oral suspension, when reconstituted with
`water, provides the equivalent of 125 mg or 250 mg of
`cefuroxime (as cefuroxime axetil) per 5 mL of suspension.
`CEFTIN for oral suspension contains the inactive ingre­
`dients polyvinyl pyrrolidone K30, stearic acid, sucrose,
`and tutti-frutti flavoring.
`
`Cefuroxime Axetil Suspension
`
`Bill of Materials
`Scale (mg/ml)
`25.00
`0.40 mL
`20.00
`q.s.
`
`item Material Name
`R-cefuroxime axetil
`1
`2
`Sorbitol solution 70%
`Saccharin
`3
`Water, purified
`4
`
`Quantity/L (g)
`25.00
`0.40 L
`20.00
`q.s. to 1 L
`
`MANUFACTURING DIRECTIONS
`
`1. Charge the sorbitol solution and 20% of item 5
`in a mixing vessel.
`2. Add item 1 and mix vigorously to form a sus­
`pension.
`
`Cetrizine Hydrochloride Syrup
`
`3. Add items 3 and any flavors, if needed, and mix.
`4. Bring to volume.
`5. Fill.
`
`Bill of Materials
`Scale (mg/5 ml)
`5.00
`1750.00
`600.00
`5.00
`300.00
`4.50
`0.50
`3.75
`10.00
`q.s.
`
`Item Material Name
`Cetrizine hydrochloride
`1
`Lycosin 80/55
`2
`Sorbitol 70%
`3
`Sodium citrate
`4
`5
`Propylene glycol
`Methyl paraben
`6
`Propyl paraben
`7
`Saccharin sodium
`8
`Flavor raspberry
`9
`Water, purified
`10
`
`Quantity/L (g)
`1.03
`350.00
`120.00
`1.00
`60.00
`0.90
`0.10
`0.75
`2.00
`q.s. to 1 L
`
`MANUFACTURING DIRECTIONS
`
`1. Charge 30% of item 10 in a stainless steel-
`jacketed kettle and heat to 90° to 95°C.
`2. Add and dissolve items 6 and 7; cool to 40°C.
`3. Add to step above item 4 and item 8 and mix
`to dissolve.
`
`4. Add items 2, 3, and 5 and mix to dissolve
`5. In a separate vessel, charge 30% of item 10 and
`add to it item 1, mix to dissolve, and then add
`to step 4.
`6. Add flavor (or flavors) and bring to volume with
`item 10.
`
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`100
`
`Handbook of Pharmaceutical Formulations: Liquid Products
`
`Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu
`Syrup
`
`Bill of Materials
`Scale (mg/tablet)
`0.001 mL
`5.00
`1.32
`8.8
`0.8
`0.9
`0.1
`6.25
`2.66
`319.22
`238.33
`83.933
`40.0
`166.67
`0.8
`100.0
`q.s.
`q.s.
`
`Item Material Name
`1
`Ipecac fluid extract
`2
`Chlophedianol hydrochloride
`3
`Ephedrine hydrochloride
`4
`Ammonium chloride
`Carbinoxamine maleate
`5
`Methyl paraben
`6
`7
`Propyl paraben
`8
`Balsam, tolu (aqueous extract)
`Saccharin sodium powder dihydrate
`9
`10
`Sucrose (sugar, granulated)
`Glucose liquid (corn syrup)
`11
`12
`Sorbitol solution 70%
`13
`Alcohol (ethanol)
`14
`Dye red
`Flavor
`15
`Propylene glycol
`16
`17
`Filter aid hyflo
`18
`Water purified, approx.
`
`Quantity/L (g)
`1.00 mL
`5.00
`1.32
`8.80
`0.80
`0.90
`0.10
`6.25
`2.66
`0.32
`0.24
`0.084
`40.00
`0.16
`0.80
`100.00
`0.50
`450.0 mL
`
`MANUFACTURING DIRECTIONS
`
`1. Charge balsam tolu and 25 mL of water in a
`steam bath.
`2. Raise the temperature, stirring continuously, to
`mix water with balsam. Boil for half an hour
`and allow decanting while cooling. Discard
`extracted balsam tolu. Filter the supernatant liq­
`uid through filter paper and store apart.
`3. Charge 150 mL water in a jacketed mixing tank;
`heat to boiling.
`4. Add and dissolve parabens with mixing. Add
`and dissolve sugar with constant mixing. Heat
`to 70° to 75°C.
`5. Once sugar is dissolved, add glucose, sorbitol,
`and saccharin sodium.
`6. Mix well until dissolved.
`
`7. Dissolve ammonium chloride in 28 mL water.
`Add to mixing tank.
`8. Add extract balsam tolu with mixing.
`9. Mix well and cool to 25” to 30°C. Add and
`dissolve epehdrine, carbinoxamine in 20 mL
`water and add to mixing tank. Mix well.
`10. Add and dissolve chlophedianol in 50 g of pro­
`pylene glycol and add to mixing tank. Add bal­
`ance of propylene glycol to mixing tank.
`11. Add and dissolve Ipecac fluid extract and flavor
`raspberry in alcohol. Add to mixing tank. Dis­
`solve dye in 5 mL water; add to tank with
`continuous mixing.
`12. Rinse container with 5 mL of water and add
`rinsing.
`13. Adjust to volume with purified water.
`14. Add filter aid hyflo to syrup and mix well.
`15. Recirculate through filter press or equivalent
`until sparkling clear.
`
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`

`Manufacturing Formulations
`
`Cisapride Suspension
`
`105
`
`Bill of Materials
`Scale (mg/5 ml)
`5.00
`9.00
`1.00
`1000.00
`50.00
`12.50
`5.00
`2.50
`2.50
`—
`
`Item
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`
`Material Name
`Cisapride USE: Cisapride monohydrate
`Methyl paraben
`Propyl paraben
`Sucrose
`Microcrystalline cellulose (Avicel RC 591)
`Methylcellulose 4000
`Sodium chloride
`Polysorbate 80 (Tween 80)
`All fruit flavor
`Water, purified
`
`Quantity/L (g)
`1.04
`1.80
`0.20
`200.00
`10.00
`2.50
`1.00
`0.50
`0.50
`q.s. to 1 L
`
`MANUFACTURING DIRECTIONS
`Cisapride dispersion should be uniformity mixed or levi­
`gated. Avicel RC-591 and Methyl Cellulose dispersion
`should be uniform and smooth.
`
`1. Mix item 8 in 100.0 g of item 10 (35° to 40‘C)
`in a stainless steel vessel, using stirrer. Add item
`1 and mix to make smooth dispersion and keep
`aside. Check the smoothness of dispersion.
`2. Add 185.0 g of item 10 to a suitable mixer and
`heat to 90° to 95°C. Dissolve items 2 and 3
`while mixing. Add and dissolve item 4 while
`mixing.
`3. Cool down to about 50° to 55°C.
`4. Filter the syrup through T1500 filter pads (8 to
`10) washed with purified water. Collect the
`syrup in clean stainless steel tank. Avoid any
`loss of syrup quantity.
`5. Disperse item 6 in 150.0 g of hot item 10 (70°
`to 80°C) in mixer while mixing.
`6. Mix and homogenize at temperature 70° to
`80°C, mixer speed 18 rpm, homogenizer high
`speed and vacuum 0.4 to 0.6 bar for 5 minutes.
`
`7. Cool down to 25° to 30°C with continuous mix­
`ing. Check the smoothness of dispersion.
`8. Disperse item 5 in 250.0 g of item 10 (25° to
`30°C) in stainless steel vessel, using stirrer.
`Keep on stirring for 30 minutes to make smooth
`dispersion. Check the smoothness of disper­
`sion.
`9. Transfer syrup mixer. Transfer Avicel mucilage
`to mixer.
`10. Mix at high homogenizer speed and under vac­
`uum for 5 minutes.
`11. Dissolve item 7 in 10.0 g of item 10 and add
`to mixer while mixing. Add drug dispersion to
`mixer.
`12. Rinse the drug container with 40.0 g of item 10
`and add the rinsing to mixer.
`13. Add item 9 to mixer while mixing.
`14. Add item 10 up to final volume I L.
`15. Finally mix and homogenize for 5 minutes at
`mixer speed 18 rpm, homogenizer at high
`speed, vacuum 0.4 to 0.6 bar.
`16. Check the suspension for homogeneity. Trans­
`fer the suspension through 630-micron sieve to
`the stainless steel storage tank, previously san­
`itized.
`
`Apotex (IPR2019-00400) Ex. 1034 p. 011
`
`

`

`Manufacturing Formulations
`
`Fluorouracil Solution
`
`127
`
`Efudex solution consists of 2% or 5% fluorouracil on a
`weight/weight basis, compounded with propylene glycol,
`
`tris(hydroxymethyl)aminomethane, hydroxypropylcellu­
`lose, parabens (methyl and propyl), and disodium edetate.
`
`Fluorouracil Topical Solution
`
`Fluoroplex 1% topical solution contains fluorouracil 1%,
`propylene glycol, sodium hydroxide or hydrochloric acid
`to adjust the pH, and purified water.
`
`Fluticasone Suspension Spray
`
`MANUFACTURING DIRECTIONS
`
`1. 2 g of fluticasone propionate and 0.02 g delta-
`tocopherol are weighed into a pressure-addition
`vessel.
`2. After sealing and evacuation of the addition
`vessel, 1.5 kg of HFA 134a that has previously
`
`Furosemide Syrup
`
`been aerated with carbon dioxide and adjusted
`to a pressure of 4.5 bar (20°C) in another pres­
`sure addition vessel is added with stirring.
`3. The suspension obtained is dispensed into alu­
`minum containers sealed with metering valves
`by means of the pressure-filling technique.
`
`Bill of Materials
`Scale (mg/5 ml)
`5.00
`9.00
`1.00
`1500.00
`500.00
`500.00
`0.50
`2.50
`q.s.
`q.s.
`
`Item Material Name
`1
`Furosemide, 5% excess
`2
`Methyl paraben
`3
`Propyl paraben
`Sorbitol 70%
`4
`Glycerin
`5
`Propylene glycol
`6
`FD&C yellow no. 6
`7
`8
`Orange flavor
`9
`Sodium hydroxide
`10
`Water, purified
`
`Quantity/L (g)
`1.05
`1.80
`0.20
`300.00
`100.00
`100.00
`0.10
`0.50
`0.44
`q.s. to 1 L
`
`MANUFACTURING DIRECTIONS
`
`1. Charge 20% of item 10 to a suitable stainless
`steel-jacketed vessel.
`2. Add items 2 and 3 and heat to 90° to 95 °C to
`dissolve. Cool to 40°C after complete dissolu­
`tion.
`3. In a separate vessel, charge items 4, 5, and 6
`and mix well.
`
`4. Dissolve item 9 in a portion of item 10 in a
`separate vessel.
`5. Add item 1 to step 4 and mix well.
`6. In a separate vessel, dissolve item 7 in a portion
`of item 10.
`7. Add to step 6.
`8. Add step 2 to step 7.
`9. Add item 8 and mix well.
`10. Fill.
`
`Apotex (IPR2019-00400) Ex. 1034 p. 012
`
`

`

`Manufacturing Formulations
`
`137
`
`Iron Polystyrene and Vitamin C Syrup
`
`Bill of Materials
`Scale (mg/ml)
`125.00
`1.40
`0.16
`79.61
`3.30
`10.00
`0.20
`105.00
`50.00
`0.10 v/v
`0.10 v/v
`q.s.
`q.s.
`9.50
`10.00
`
`Item Material Name
`1
`Glycerin
`2
`Methyl paraben
`3
`Propyl paraben
`4
`Sorbitol solution
`Xanthan gum
`5
`6
`Sucrose
`7
`Saccharin
`Elemental iron USE iron polystyrene sulfonate
`8
`Acid ascorbic, 35% excess
`9
`10
`Flavor
`Flavor guarana artificial
`11
`Sodium hydroxide
`12
`Dye
`13
`14
`Water, purified
`Sorbitol solution, approximate
`15
`
`Quantity/L (g)
`125.0
`1.40
`0.16
`364.33
`3.30
`100.00
`2.00
`530.31
`61.950
`1.0 mL
`1.0 mL
`12. 1.0
`2.0
`95 mL
`10.0
`
`MANUFACTURING DIRECTIONS
`
`1. Add glycerin (item 1) to the tank. Commence
`heating with agitation.
`2. Add and disperse parabens. Continue heating
`to 70° to 80°C and mix until solution is com­
`plete.
`3. Force cool to 30°C then add and disperse xan-
`than gum (item 5).
`4. 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.
`5. Add and disperse saccharin and sugar (items 7
`and 6).
`6. Mix at 60° to 70°C until dispersion is complete.
`7. Force cool to 25° to 30°C with continuous mix­
`ing.
`8. Commence N2 gas protection and maintain for
`the remainder of the manufacturing process.
`9. Add and disperse ascorbic acid. Continue mix­
`ing for 30 minutes at 25° to 30°C. Use suitable
`stainless steel high-powered stirrer.
`10. Mix the iron polystyrene sulfonate milled
`slurry, in the original epoxy lined drums, under
`N, gas protection until uniform.
`
`11. Add the slurry to the main batch and mix for
`30 minutes at 25° to 30°C. Avoid scraping the
`epoxy lining of the steel drum while mixing and
`use a plastic or rubber scraper to assist in com­
`plete transfer of the mixed slurry.
`12. Add and disperse the flavors. Mix well.
`13. Check and record pH. Adjust pH using a 20%
`sodium hydroxide solution (1 g in 5 mL water)
`to a pH of 3 (range 2.8 to 3.2).
`14. Dissolve the dye in 5 to 7 mL of water at 40
`to 45°C by stirring for 10 minutes.
`15. Add this solution to the main batch through a
`420-micron-aperture screen with mixing.
`16. Rinse container with 2 to 3 mL water at 40° to
`45°C, and add to bulk through a 420-micron
`screen.
`17. Continue to mix under vacuum until unifonn.
`18. Pass suspension through the colloid mill at a
`gap setting of 100 to 150 micrometers.
`19. Adjust flow rate such that the temperature rise
`of the suspension does not exceed 10°C.
`20. Collect the milled suspension in a stainless
`steel-jacketed tank with vacuum. Mix at 25° to
`30°C under vacuum until a uniform suspension
`is achieved.
`21. Flush the bulk suspension with N2 and seal.
`Hold at 25° to 30°C.
`
`Apotex (IPR2019-00400) Ex. 1034 p. 013
`
`

`

`Manufacturing Formulations
`
`145
`
`Magaldrate with Simethicone Suspension
`
`Bill of Materials
`Scale (mg/5 ml)
`q.s.
`9.00
`1.00
`5.00
`3.75
`2.00 g
`1.00 g
`12.50
`q.s.
`200.00
`0.005 mL
`1.26 g
`25.00 g
`13.30
`
`Item Material Name
`1
`Water, purified
`2
`Methyl paraben
`3
`Propyl paraben
`4
`Acid benzoic
`Saccharin sodium powder dihydrate
`5
`6
`Magaldrate wet cake (18 to 20%)
`7
`Sorbitol solution
`Silicon dioxide colloidal (international)
`8
`Acid citric powder hydrous
`9
`Dimethyl polysiloxane emulsion (30%)
`10
`11
`Flavor
`12
`Glycerin
`13
`Potassium citrate monohydrate
`Xanthan gum
`14
`
`Quantity/L (g)
`q.s. to 1 L
`1.80
`0.20
`1.00
`0.75
`400.00
`260.00
`2.50
`q.s.
`40.00
`1.000 mL
`252.00
`5.00
`2.66
`
`MANUFACTURING DIRECTIONS
`This product is highly prone to microbial contamination.
`All equipment coming into contact with the product
`should be treated with a freshly prepared sodium
`hypochlorite solution (100 ppm), made with freshly boiled
`and cooled town water on the day of use. Bottles and caps
`should also be so treated. Freshly boiled and cooled puri­
`fied water should be used for rinsing.
`
`1. Charge 285 mL purified water into a suitable
`jacketed tank and heat to 90° to 95°C.
`2. Add and dissolve parabens, acid benzoic, sac­
`charin sodium, and potassium citrate.
`3. While maintaining temperature at 85° to 90°C,
`add, in small quantities, half the quantity of
`magaldrate cake or powder, if used, and dis­
`perse well. (Adjust the speed of agitator and of
`the homogenizer to ensure effective mixing and
`to maintain free mobility of the suspension.)
`4. Add sorbitol solution and mix well. Raise the
`temperature, if necessary, maintaining temper­
`ature at 85° to 90°C.
`
`5. Add, in small quan