PHARMACEUTICAL
`DOSAGE FORMS
`AND
`DRUG DELIVERY
`SYSTEMS
`
`.41
`
`fifth edition
`
`I
`
`91
`
`. _ (cid:9)
`
`.
`
`HOWARD C. ANSEL
`NICHOLAS 0. POPOVICH
`
`NOVARTIS EXHIBIT 2034
`Par v Novartis, IPR 2016-00084
`Page 1 of 45
`
`

`
`Pharmaceutical Dosage Forms
`and
`Drug Delivery Systems
`
`HOWARD C. ANSEL, Ph.D.
`Professor and Dean, College of Pharmacy
`The University of Georgia
`
`4 4
`
`NICHOLAS G. POPOVICH, Ph.D.
`Professor, School of Pharmacy and Pharmacal Sciences
`Purdue University
`
`FIFTH EDITION
`
`Lea & Febiger • Philadelphia • London
`
`1990
`
`NOVARTIS EXHIBIT 2034
`Par v Novartis, IPR 2016-00084
`Page 2 of 45
`
`

`
`Lea & Febiger
`200 Chesterfield Parkway
`Malvern, Pennsylvania 19355
`U.S.A.
`1-800-444-1785
`
`Lea & Febiger (UK) Ltd.
`145a Croydon Road
`Beckenham, Kent BR3 3RB
`U.K.
`
`Library of Congress Cataloging-in-Publication Data
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delivery systems I Howard C.
`Ansel with contribution by Nicholas G. Popovich.-5th ed.
`p. (cid:9)
`cm.
`Rev. ed of: Introduction to pharmaceutical dosage forms, 4th ed.
`1985.
`Includes bibliographies and index.
`ISBN 0-8121-1255-5
`1. Drugs—Dosage forms. 2. Drug delivery systems. I. Popovich,
`Nicholas G. II. Ansel, Howard C., 1933- (cid:9)
`Introduction to
`pharmaceutical dosage forms. III. Title.
`[DNLM: 1. Dosage Forms. 2. Drugs—administration & dosage. QV
`785 A618i]
`RS200.A57 1990
`615'.1—dc20
`DNLM/DLC
`for Library of Congress (cid:9)
`
`89-8299
`CIP
`
`of con4,.
`5 (cid:9)
`,r,p
`FE -11900
`cort
`C1P
`
`1st Edition, 1969
`Reprinted, 1972
`2nd Edition, 1976
`Reprinted, 7978
`3rd Edition, 1981
`Reprinted, 1982
`4th Edition, 1985
`Reprinted, 1987, 1988
`5th Edition, 1990
`
`Reprints of chapters may be purchased from Lea & Febiger in quantities of 100 or more.
`
`The use of portions of the text of USPXXII-NFXVII is by permission of the USP Convention. The Convention
`is not responsible for any inaccuracy of quotation or for any false or misleading implication that may arise
`from separation of excerpts from the original context or by obsolescence resulting from publication of a
`supplement.
`
`Copyright 0 1990 by Lea & Febiger. Copyright under the International Copyright Union. All Rights Reserved.
`This book is protected by copyright. No part of it may be reproduced in any manner or by any means without
`written permission of the publisher.
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Print No. 4 3 2 1
`
`NOVARTIS EXHIBIT 2034
`Par v Novartis, IPR 2016-00084
`Page 3 of 45
`
`

`
`4
`
`Dosage Form Design:
`Pharmaceutic Ingredients,
`Product Formulation, and
`Current Good Manufacturing
`Practice
`
`DRUG SUBSTANCES are seldom administered
`alone, but rather as part of a formulation in
`combination with one or more nonmedical
`agents that serve varied and specialized phar-
`maceutical functions. Through selective use of
`these nonmedicinal agents, referred to as phar-
`maceutic ingredients, dosage forms of various
`types result. The pharmaceutic ingredients sol-
`ubilize, suspend, thicken, dilute, emulsify, sta-
`bilize, preserve, color, flavor, and fashion me-
`dicinal agents into efficacious and appealing
`dosage forms. Each type of dosage form is
`unique in its physical and pharmaceutical char-
`acteristics. These varied preparations provide
`the manufacturing pharmacist with the chal-
`lenges of formulation and the physician with
`the choice of drug and drug delivery system to
`prescribe. The general area of study concerned
`with the formulation, manufacture, stability,
`and effectiveness of pharmaceutical dosage
`forms is termed pharmaceutics.
`The proper design and formulation of a dos-
`age form requires consideration of the physical,
`chemical and biological characteristics of all of
`the drug substances and pharmaceutic ingre-
`dients to be used in fabricating the product. The
`drug and pharmaceutic materials utilized must
`be compatible with one another to produce a
`drug product that is stable, efficacious, attrac-
`tive, easy to administer and safe. The product
`should be manufactured under appropriate
`measures of quality control and packaged in
`containers that contribute to product stability.
`The product should be labeled to promote cor-
`rect use and be stored under conditions that
`contribute to maximum shelf life.
`Methods for the preparation of specific types
`
`of dosage forms and drug delivery systems are
`described in subsequent chapters. This chapter
`presents some general considerations regarding
`pharmaceutic ingredients, drug product for-
`mulation, and standards for good manufactur-
`ing practice.
`
`The Need for Dosage Forms
`The potent nature and low dosage of most of
`the drugs in use today precludes any expecta-
`tion that the general public could safely obtain
`the appropriate dose of a drug from the bulk
`material. The vast majority of drug substances
`are administered in milligram quantities, much
`too small to be weighed on anything but a sen-
`sitive laboratory balance. For instance, how
`could the layman accurately obtain the 325 mg
`or 5 gr of aspirin found in the common aspirin
`tablet from a bulk supply of aspirin? He
`couldn't. Yet, compared with many other
`drugs, the dose of aspirin is formidable (Table
`4-1). For example, the dose of ethinyl estradiol,
`0.05 mg, is 1/6500 the amount of aspirin in an
`aspirin tablet. To put it another way, 6500 eth-
`inyl estradiol tablets, each containing 0.05 mg
`of drug, could be made from an amount of eth-
`inyl estradiol equal to the amount of aspirin in
`just one 5 gr aspirin tablet. When the dose of
`the drug is minute, as that for ethinyl estradiol,
`solid dosage forms such as tablets and capsules
`must be prepared with fillers or diluents so that
`the size of the resultant dosage unit is large
`enough to pick up with the fingertips.
`Besides providing the mechanism for the safe
`and convenient delivery of accurate dosage,
`dosage forms are needed for additional reasons:
`
`92
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`

`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice (cid:9)
`
`93
`
`Table 4-1. Examples of Some Drugs with
`Relatively Low Usual Doses
`Usual
`Dose,
`mg Category
`Antidepressant
`300 (cid:9)
`300 (cid:9)
`Hematinic
`Antiulcer
`300 (cid:9)
`300 (cid:9)
`Antinflammatory
`250 (cid:9)
`Antibacterial
`250 (cid:9)
`Antibacterial
`100 (cid:9)
`Antibacterial
`(urinary)
`Analgesic
`Thyroid
`Diuretic
`Analgesic
`Sedative
`Tranquilizer
`Antihistaminic
`Narcotic analgesic
`Adrenocortical
`steroid
`Antihistaminic
`
`Drug
`Lithium Carbonate
`Ferrous Sulfate
`Cimetidine
`Ibuprofen
`Amoxicillin
`Erythromycin
`Nitrofurantoin
`
`65 (cid:9)
`Propoxyphene HC1
`60 (cid:9)
`Thyroid
`Hydrochlorothiazide
`50 (cid:9)
`30 (cid:9)
`Codeine Phosphate
`Phenobarbital
`30 (cid:9)
`25 (cid:9)
`Chlorpromazine HCl
`Diphenhydramine HC1 25 (cid:9)
`Morphine Sulfate
`10 (cid:9)
`5 (cid:9)
`Prednisolone
`
`Chlorpheniramine
`maleate
`Colchicine
`Nitroglycerin
`Digoxin
`
`Levothyroxine
`Ethinyl Estradiol
`
`4 (cid:9)
`
`Gout Supressant
`0.5 (cid:9)
`Antianginal
`0.4 (cid:9)
`0.25 Cardiotonic
`(maintenance)
`Thyroid
`Estrogen
`
`0.1 (cid:9)
`0.05 (cid:9)
`
`1. For the protection of a drug substance from
`the destructive influences of atmospheric
`oxygen or humidity (e.g., coated tablets,
`sealed ampuls).
`2. For the protection of a drug substance from
`the destructive influence of gastric acid af-
`ter oral administration (e.g., enteric-coated
`tablets).
`3. To conceal the bitter, salty, or offensive
`taste or odor of a drug substance (e.g., cap-
`sules, coated tablets, flavored syrups).
`4. To provide liquid preparations of sub-
`stances that are either insoluble or unstable
`in the desired vehicle (e.g., suspensions).
`5. To provide clear liquid dosage forms of sub-
`stances (e.g., syrups, solutions).
`6. To provide time-controlled drug action
`(e.g., various controlled-release tablets,
`capsules, and suspensions).
`7. To provide optimal drug action from topical
`administration sites (e.g., ointments,
`creams, transdermal patches, ophthalmic,
`ear, and nasal preparations).
`
`8. To provide for the insertion of a drug into
`one of the body's orifices (e.g., rectal or
`vaginal suppositories).
`9. To provide for the placement of drugs di-
`rectly into the bloodstream or into body
`tissues (e.g., injections).
`10. To provide for optimal drug action through
`inhalation therapy (e.g., inhalants and in-
`halation aerosols).
`
`There are many different forms into which a
`medicinal agent may be placed for the conven-
`ient and efficacious treatment of disease (Table
`3-6). Most commonly, a pharmaceutical man-
`ufacturer prepares a drug substance in several
`dosage forms and strengths for the efficacious
`and convenient treatment of disease (Fig. 4-1).
`Before a medicinal agent is formulated into one
`or more dosage forms, among the factors con-
`sidered are such therapeutic matters as: the na-
`ture of the illness, the manner in which it is
`generally treated, locally or through systemic
`action, and the age and anticipated condition
`of the patient.
`If the medication is intended for systemic use
`and oral administration is desired, tablets and/
`or capsules are generally prepared. These dos-
`age units are easily handled by the patient and
`are most convenient in the self-administration
`of medication. If a drug substance has appli-
`cation in an emergency situation in which the
`patient may be comatose or unable to take oral
`medication, an injectable form of the medication
`may also be prepared. Many other examples of
`therapeutic situations affecting dosage form de-
`sign could be cited, including the preparation
`of agents for motion sickness, nausea, and vom-
`iting into tablets and skin patches for preven-
`tion and suppositories and injections for treat-
`ment.
`The age of the intended patient also plays a
`role in dosage form design. For infants and chil-
`dren under 5 years of age, pharmaceutical liq-
`uids rather than solid dosage forms are pre-
`ferred for oral administration. These liquids,
`which are generally flavored aqueous solutions,
`syrups or suspensions, are usually adminis-
`tered directly into the infant's or child's mouth
`by drop, spoon, or oral dispenser (Fig. 4-2) or
`incorporated into the child's food. A single liq-
`uid pediatric preparation may be used for in-
`fants and children of all ages, with the dose of
`the drug varied by the volume administered.
`When an infant is in the throes of a vomiting
`
`NOVARTIS EXHIBIT 2034
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`Page 5 of 45
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`94 (cid:9)
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`•••••••
`X•comieL
`Togiutwal•
`
`3°0 mg /S me
`laga met
`tit,C1 Liquid
`towidine
`
`4*OChlerlde
`
`le,
`
`0,,Cla met
`ha "
`
`i (cid:9)
`
`Ma QIN 5,12
`aaatr.. (cid:9)
`
`•
`
`AMAMI. .0 kW.. 4/1.1.0
`
`110ft ai k
`1,09,111,4*
`
`Hp int.ilon
`-
`a MoildIndo badrochkaida 2m1..300mg,' (cid:9)
`te.,..14 t....7 I.**
`,-n..fu rik4
`ba (cid:9)
`. E..
`g
`2 ml.vials ---"— '''''-'33•"". 1 4 (cid:9)
`11
`. (cid:9)
`• ...... L. , . (cid:9)
`•
`,.., (cid:9)
`ildn1L
`7.-717._ (cid:9)
`Tagamet 'HO Injec /km
`4:1.041.1.11.-4.
`c imetidine hkick ochloricfu
`7n11.=300 mg.
`
`Utebillu
`
`•
`
`•••••
`
`• OM_
`
`Fig. 4-1. Examples of varied dosage forms of a drug substance marketed by a pharmaceutical manufacturer to meet the
`special requirements of the patient. (Courtesy of SK&F Lab Co.)
`
`crisis, is gagging, has a productive cough, or is
`simply rebellious, there may be some question
`as how much of the medicine administered is
`actually swallowed and how much is expecto-
`rated. In such instances, injections may be re-
`quired. Infant size rectal suppositories may also
`be employed although drug absorption from the
`rectum is often erratic.
`During childhood and even in adult years, a
`person may have difficulty swallowing solid
`dosage forms, especially uncoated tablets. For
`this reason, some medications are formulated
`as chewable tablets that can be broken up in the
`mouth before swallowing. Many of these tablets
`are comparable in texture to an after-dinner
`mint and break down into a pleasant tasting,
`creamy material. Capsules have been found by
`many to be more easily swallowed than whole
`tablets. If a capsule is allowed to become moist
`in the mouth before swallowing, it becomes
`slippery and slides down the throat more read-
`ily with a glass of water. In instances in which
`a person has difficulty swallowing a capsule,
`the contents may be emptied into a spoon,
`
`mixed with jam, honey, or other similar food
`to mask the taste of the medication and swal-
`lowed. Some older persons have difficulty in
`swallowing and thus tablets and capsules are
`frequently avoided. Medications intended for
`the elderly are commonly formulated into oral
`liquids or may be extemporaneously prepared
`into an oral liquid by the pharmacist.
`Many patients, particularly the elderly, take
`multiple medications daily. The more distinctive
`the size, shape, and color of solid dosage forms,
`the easier is the proper identification of the
`medications. Frequent errors in taking medi-
`cations among the elderly occur because of their
`multiple drug therapy and reduced eyesight.
`Dosage forms that allow reduced frequency of
`administration without sacrifice of efficiency are
`particularly advantageous.
`
`Pharmaceutic Ingredients
`In order to prepare a drug substance into a
`final dosage form, pharmaceutic ingredients are
`required. For example, in the preparation of
`
`NOVARTIS EXHIBIT 2034
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`

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`P-
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice (cid:9)
`
`95
`
`Fig. 4-2. "Pee Dee Dose" brand of oral liquid dispenser used to administer measured volumes of liquid medication to
`youngsters. (Courtesy of Baxa Corporation)
`
`pharmaceutical solutions, one or more solvents
`are utilized to dissolve the drug substance, pre-
`servatives may be added to prevent microbial
`growth, stabilizers may be used to prevent drug
`decomposition, and colorants and flavorants
`added to enhance product appeal. In the prep-
`aration of tablets, diluents or fillers are commonly
`added to increase the bulk of the formulation,
`binders to cause the adhesion of the powdered
`drug and pharmaceutic substances, antiadher-
`ents or lubricants to assist the smooth tableting
`process, disintegrating agents to promote tablet
`break-up after administration, and coatings to
`improve stability, control disintegration, or to
`enhance appearance. Ointments, creams, and
`suppositories achieve their characteristic fea-
`tures due to the pharmaceutic bases which are
`
`utilized. Thus, for each dosage form, the phar-
`maceutic ingredients establish the primary fea-
`tures of the product, and contribute to the phys-
`ical form, texture, stability, taste and overall
`appearance.
`Table 4-2 presents the principal categories of
`pharmaceutic ingredients, with examples of
`some of the official agents currently used.
`
`General Considerations in Drug
`Product Formulation
`In dealing with the problem of formulating a
`drug substance into a proper dosage form, re-
`search pharmacists employ knowledge that has
`been gained through experience with other
`chemically similar drugs and through the
`
`NOVARTIS EXHIBIT 2034
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`

`
`96 (cid:9)
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`Table 4-2. Examples of Pharmaceutic Ingredients
`Definition
`Used in liquid preparations to provide
`acidic medium for product stability.
`
`Acidifying Agent
`
`Ingredient Type
`
`Alkalinizing Agent
`
`Used in liquid preparations to provide
`alkaline medium for product stability.
`
`Adsorbent
`
`Aerosol Propellant
`
`Air Displacement
`
`Antifungal Preservative
`
`An agent capable of holding other mol-
`ecules onto its surface by physical or
`chemical (chemisorption) means.
`An agent responsible for developing the
`pressure within an aerosol container
`and expelling the product when the
`valve is opened.
`An agent which is employed to displace
`air in a hermetically sealed container to
`enhance product stability.
`Used in liquid and semi-solid prepara-
`lions to prevent the growth of fungi.
`
`Antimicrobial Preservative
`
`Used in liquid and semi-solid prepara-
`tions to prevent the growth of micro-
`organisms.
`
`Antioxidant
`
`An agent which inhibits oxidation and
`thus is used to prevent the deterioration
`of preparations by the oxidative process.
`
`Buffering Agent
`
`Used to resist change in pH upon di-
`lution or addition of acid or alkali,
`
`Examples
`acetic acid
`hydrochloric acid
`nitric acid
`ammonia solution
`ammonium carbonate
`potassium hydroxide
`sodium borate
`sodium carbonate
`sodium hydroxide
`trolamine
`powdered cellulose
`activated charcoal
`
`dichlorodifluoromethane
`dichlorotetrafluoroethane
`trichloromonofluoromethane
`
`nitrogen
`
`benzoic acid
`butylparaben
`ethylparaben
`methylparaben
`propylparaben
`sodium benzoate
`sodium propionate
`benzalkonium chloride
`benzethonium chloride
`benzyl alcohol
`cetylpyridinium chloride
`chlorobutanol
`phenol
`phenylethyl alcohol
`phenylmercuric nitrate
`thimerosal
`ascorbyl palmitate
`butylated hydroxyanisole
`butylated hydroxytoluene
`hypophophorous acid
`monothioglycerol
`propyl gallate
`sodium bisulfite
`sodium formaldehyde
`sulfoxylate
`sodium metabisulfite
`potassium metaphosphatc
`potassium phosphate,
`monobasic
`sodium acetate
`edetate disodium
`edetic acid
`
`Chelating Agent
`
`A substance that forms stable complexes
`with metals. Chelating agents are used
`in some liquid pharmaceuticals as sta-
`bilizers to complex heavy metals which
`might promote instability. In such use
`they are also called sequestering agents.
`
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`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice (cid:9)
`
`97
`
`Table 4-2. Continued
`Ingredient Type
`
`-
`
`Colorant
`
`Emulsifying Agent
`
`Encapsulating Agent
`
`Flavorant
`
`Humectant
`
`Levigating Agent
`
`Ointment Base
`
`Definition
`Used to impart color to pharmaceutical
`preparations.
`
`Used to promote and maintain the dis-
`persion of finely subdivided particles of
`a liquid in a vehicle in which it is im-
`miscible.
`Used to form thin shells for the purpose
`of enclosing a drug substance or drug
`formulation for ease of administration.
`Used to impart a pleasant flavor and of-
`ten odor to a pharmaceutical prepara-
`tion.
`
`Used to prevent the drying out of prep-
`arations—particulalry ointments and
`due to the agent's ability to re-
`creams (cid:9)
`tain moisture.
`
`A liquid used as an intervening agent to
`reduce the particle size of a drug powder
`by grinding together, usually in a mor-
`tar.
`
`The semisolid vehicle into which drug
`substances may be incorpoated in pre-
`paring medicated ointments.
`
`Solvent
`
`An agent used to dissolve another phar-
`maceutic substance or a drug in the
`preparation of a solution.
`
`Examples
`FD&C Red No. 3
`FD&C Red No. 20
`FD&C Yellow No. 6
`FD&C Blue No. 2
`D&C Green No. 5
`D&C Orange No. 5
`D&C Red No. 8
`caramel
`ferric oxide, red
`acacia
`sorbitan monooleate
`polyoxyethylene 50 stearate
`
`gelatin
`cellulose acetate phthalate
`
`anise oil
`cinnamon oil
`cocoa
`menthol
`orange oil
`peppermint oil
`vanillin
`glycerin
`propylene glycol
`sorbitol
`
`mineral oil
`glycerin
`
`lanolin
`hydrophilic ointment
`polyethylene glycol ointment
`petrolatum
`hydrophilic petrolatum
`white ointment
`yellow ointment
`rose water ointment
`
`alcohol
`isopropyl alcohol
`mineral oil
`oleic acid
`peanut oil
`purified water
`water for injection
`sterile water for injection
`sterile water for irrigation
`
`Stiffening Agent
`
`Used to increase the thickness or hard-
`ness of a pharmaceutical preparation,
`usually an ointment.
`
`cetyl alcohol
`paraffin
`white wax
`yellow wax
`
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`
`98 (cid:9)
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`Table 4-2. Continued
`Ingredient Type
`
`Suppository Base
`
`Surfactant
`(surface active agent)
`
`Definition
`Used as a vehicle into which drug sub-
`stances are incorporated in the prepa-
`ration of suppositories.
`Substances which adsorb to surfaces or
`interfaces to reduce surface or interfacial
`tension. May be used as wetting agents,
`detergents or emulsifying agents.
`
`Suspending Agent
`
`A viscosity increasing agent used to re-
`duce the rate of sedimentation of dis-
`persed particles.
`
`Sweetening Agent
`
`Tablet Antiadherents
`
`Tablet Binders
`
`Tablet and Capsule Diluent
`
`Tablet Coating Agent
`
`Tablet Disintegrant
`
`Tablet Glidant
`
`Tablet Lubricant
`
`Tablet Polishing Agent
`
`Used to impart sweetness to a prepa-
`ration.
`
`Agents which prevent the sticking of
`tablet (cid:9)
`formulation (cid:9)
`ingredients (cid:9)
`to
`punches and dies in a tableting machine
`during production.
`Substances used to cause adhesion of
`powder particles in tablet granulations.
`
`Inert substances used as fillers to create
`the desired bulk, flow properties, and
`compression characteristics in the prep-
`aration of tablets and capsules.
`Used to coat a formed tablet for the pur-
`pose of protecting against drug decom-
`position by atmospheric oxygen or hu-
`midity, to provide a desired release
`pattern for the drug substance after ad-
`ministration, to mask the taste or odor
`of the drug substance, or for aesthetic
`purposes.
`Used in solid dosage forms to promote
`the disruption of the solid mass into
`smaller particles which are more readily
`dispersed or dissolved.
`Agents used in tablet and capsule for-
`mulations to improve the flow proper-
`ties of the powder mixture.
`Substances used in tablet formulations
`to reduce friction during tablet corn-
`pression.
`Used to impart an attractive sheen to
`coated tablets.
`
`Examples
`cocoa butter
`polyethylene glycols
`(mixtures)
`benzalkonium chloride
`nonoxynol 10
`octoxynol 9
`polysorbate 80
`sodium lauryl sulfate
`sorbitan monopalmitate
`agar
`bentonite
`carboxymethylcellulose
`sodium
`hydroxypropyl methyl-
`cellulose
`methylcellulose
`tragacanth
`veegum
`aspartame
`saccharin sodium
`sucrose
`magnesium stearate
`talc
`
`acacia
`ethylcellulose
`gelatin
`methylcellulose
`microcrystalline cellulose
`lactose
`
`cellulose acetate phthalate
`sucrose
`pharmaceutical glaze
`(shellac in alcohol)
`
`cornstarch
`sodium alginate
`
`colloidal silica
`cornstarch
`talc
`calcium stearate
`magnesium stearate
`stearic acid
`carnauba wax
`white wax
`
`NOVARTIS EXHIBIT 2034
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`Page 10 of 45
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`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice (cid:9)
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`99
`
`Table 4-2. Continued
`Ingredient Type
`
`Tonicity Agent
`
`Vehicle
`
`Definition
`
`Examples
`
`Used to render a solution similar in os- dextrose
`sodium chloride
`motic characteristics to physiologic
`fluids. (cid:9)
`.
`A carrying agent for a drug substance. Flavored/Sweetened
`Acacia Syrup
`Aromatic Elixir
`Cherry Syrup
`Cocoa Syrup
`Orange Syrup
`Syrup
`Oleaginous
`Corn Oil
`Mineral Oil
`Peanut Oil
`Sesame Oil
`Sterile
`Bacteriostatic Sodium
`Chloride Injection
`Bacteriostatic Water
`for Injection
`
`proper utilization of the disciplines of the phys-
`ical, chemical, and biologic and pharmaceutical
`sciences. The early stages of any new formu-
`lation involves studies to collect basic infor-
`mation on the physical and chemical character-
`istics of the drug substance to be prepared into
`pharmaceutical dosage forms. These basic stud-
`ies comprise the preformulation work needed be-
`fore actual product formulation begins.
`
`Preformulation Studies1
`
`Physical Description
`
`It is important to have an understanding of
`the physical description of a drug substance
`prior to dosage form development. The majority
`of drug substances in use today occur as solid
`materials. Most of them are pure chemical com-
`pounds of either crystalline or amorphous con-
`stitution. Liquid drugs are used to a much lesser
`extent; gases, even less frequently.
`Among the few liquid medicinal agents in use
`today are the following:
`
`Amyl nitrite, vasodilator by inhalation
`Castor oil, cathartic
`Clofibrate, antihyperlipidemic
`Dimercaprol, antidote for arsenic, gold, and
`mercury poisoning
`
`Dimethylsulfoxide, analgesic in interstitial
`cystitis
`Ethchlorvynol, hypnotic
`Glycerin, cathartic in suppository form
`Mineral oil, cathartic
`Nitroglycerin (as tablets), anti-anginal
`Paraldehyde, sedative-hypnotic
`Paramethadione, anticonvulsant
`Prochlorperazine, tranquilizer and antiemetic
`Propylhexedrine, vasoconstrictor by nasal
`inhalation
`Undecylenic acid, fungistatic agent
`
`Liquid drugs pose an interesting problem in
`the design of dosage forms or drug delivery
`systems. Many of the liquids are volatile sub-
`stances and as such must be physically sealed
`from the atmosphere to insure their continued
`presence. Amyl nitrite, for example, is a clear
`yellowish liquid that is volatile even at low tem-
`peratures and is also highly flammable. It is
`maintained for medicinal purposes in small
`sealed glass cylinders wrapped with gauze or
`another suitable material. When amyl nitrite is
`administered, the glass is broken between the
`fingertips and the liquid wets the gauze cov-
`ering, producing vapors that are inhaled by the
`patient requiring vasodilation. Propylhexedrine
`provides another example of a volatile liquid
`drug that must be contained in a closed system
`to maintain its presence. This drug is used as a
`
`NOVARTIS EXHIBIT 2034
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`Page 11 of 45
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`ir
`
`100 (cid:9)
`
`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice
`
`nasal inhalant for its vasoconstrictor action. A
`cylindrical roll of fibrous material is impreg-
`nated with propylhexedrine, and the saturated
`cylinder is placed in a suitable, generally plastic,
`sealed nasal inhaler. The inhaler's cap must be
`securely tightened each time it is used. Even
`then, the inhaler maintains its effectiveness for
`only a limited period of time due to the vola-
`tilization of the drug.
`Another problem associated with liquid
`drugs is that those intended for oral adminis-
`tration cannot generally be formulated into tab-
`let form, the most popular form of oral medi-
`cation, without undertaking major chemical
`modification of the drug. An exception to this
`is the liquid drug nitroglycerin which is for-
`mulated into tablet triturates which disintegrate
`within seconds after placement under the
`tongue. However, because the drug is volatile,
`it has a tendency to escape from the tablets dur-
`ing storage and it is critical that the tablets be
`stored in tightly sealed glass containers. For the
`most part, when a liquid drug is to be admin-
`istered orally and a solid dosage form is desired,
`two approaches are used. First, the liquid sub-
`stance may be sealed in a soft gelatin capsule.
`Paramethadione and ethchlorvynol are exam-
`ples of liquid drugs commercially available in
`capsule form.2 Secondly, the liquid drug may
`be developed into a solid ester or salt form that
`will be suitable for tableting or drug encapsu-
`lating. For instance, scopolamine hydrobrom-
`ide is a solid salt of the liquid drug scopolamine
`and is easily produced into tablets.
`For certain liquid drugs, especially those em-
`ployed orally in large doses or applied topically,
`their liquid nature may be of some advantage
`in therapy. For example, 15-mL doses of mineral
`oil may be administered conveniently as such.
`Also, the liquid nature of undecylenic acid cer-
`tainly does not hinder but rather enhances its
`use topically in the treatment of fungus infec-
`tions of the skin. However, for the most part,
`solid materials are preferred by pharmacists in
`formulation work because of their ease of prep-
`aration into tablets and capsules.
`Formulation and stability difficulties arise less
`frequently with solid dosage forms than with
`liquid pharmaceutical preparations, and for this
`reason many new drugs first reach the market
`as tablets or dry-filled capsules. Later, when the
`pharmaceutical problems are resolved, a liquid
`form of the same drug may be marketed. This
`procedure, when practiced, is doubly advan-
`
`tageous, because for the most part physicians
`and patients alike prefer small, generally taste-
`less, accurately dosed tablets or capsules to the
`analogous liquid forms that may have an un-
`pleasant taste and are likely to be measured by
`the patient with highly variable household
`spoons. Therefore, marketing a drug in solid
`form first is more practical for the manufacturer
`and also suits the majority of patients. It is es-
`timated that tablets and capsules comprise the
`dosage form dispensed 70% of the time by com-
`munity pharmacists, with tablets dispensed
`twice as frequently as capsules.
`
`Microscopic Examination
`Microscopic examination of the raw drug sub-
`stance is an important step in preformulation
`work. It gives an indication of particle size and
`particle size range of the raw material as well
`as the crystal structure. Photomicrographs of
`the initial and subsequent batch lots of the drug
`substance can provide important information
`should problems arise in formulation process-
`ing attributable to changes in particle or crystal
`characteristics of the drug.
`
`Particle Size
`Certain physical and chemical properties of
`drug substances are affected by the particle size
`distribution, including drug dissolution rate, bi-
`oavailability, content uniformity, taste, texture,
`color, and stability. In addition, properties such
`as flow characteristics and sedimentation rates,
`among others, are also important factors related
`to particle size. It.s essential to establish as early
`as possible how the particle size of the drug
`substance may affect formulation and product
`efficacy. Of special interest is the effect of par-
`ticle size on the drug's absorption. Particle size
`has been shown to significantly influence the
`oral absorption profiles of certain drugs as gri-
`seofulvin, nitrofurantoin, spironolactone, and
`procaine penicillin.
`Satisfactory content uniformity in solid dos-
`age forms depends to a large degree on particle
`size and the equal distribution of the active in-
`gredient throughout the formulation.
`There are several methods available to eval-
`uate particle size and distribution including
`sieving or screening, microscopy, sedimenta-
`tion, and stream scanning. For powders in the
`range of approximately 44 microns and greater,
`sieving or screening is the most widely used
`method of size analysis. The difficulty with us-
`
`NOVARTIS EXHIBIT 2034
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`Page 12 of 45
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`Dosage Form Design: Ingredients, Product Formulation, Manufacturing Practice (cid:9)
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`101
`
`ing this method early in the preforrnulation pro-
`gram is the requirement of a relatively large
`sample size. The main advantage of the sieve
`method is simplicity, both in technique and
`equipment requirements. Optical microscopy is
`frequently the first step in the determination of
`particle size and shape for the new drug sub-
`stance. This is usually a qualitative assessment
`since quantitation by the microscope technique
`is tedious and time consuming. A key element
`in utilizing the microscope for particle size de-
`termination is preparation of the slide. It must
`be representative of the bulk of the material and
`be properly suspended and thoroughly dis-
`persed in a suitable liquid phase. In order to do
`a quantitative particle size evaluation a mini-
`mum of 1000 of the particles should be counted.
`Sedimentation techniques utilize the relation-
`ship between rate of fall of particles and their
`size. Techniques utilizing devices that contin-
`uously collect a settling suspension are used.
`These methods share the disadvantage of the
`microscope technique in that it is tedious to ob-
`tain the data. Also, proper dispersion, consis-
`tent sampling, temperature control, and other
`experimental variables must be carefully con-
`trolled in order,to obtain consistent and reliable
`results.
`Stream scanning is a valuable method for de-
`termining particle size distribution of powdered
`drug substances. This technique utilizes a fluid
`suspension of particles which pass the sensing
`zone where individual particles are sized,
`counted, and tabulated. Sensing units may be
`based on light scattering or transmission, as
`well as conductance. Two popular units in the
`pharmaceutical industry for this purpose are the
`Coulter Counter and Hiac Counter. Both units
`electronically size, count, and tabulat