SEVENTH EDITION
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 001
`
`

`

`Pharmaceutical
`Dosage Forms
`and Drug
`
`Delivery Systems
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 002
`
`

`

`Hong Kong - Sydney - Tokyo
`
`- New York - London
`
`$5 LIPPINCOTT WILLIAMS & WILKINS
`' A Wolters Kluwer Company
`Philadelphia - Baltimore
`Buenos Aires -
`
`Howard C. Ansel, Ph.D.
`Professor and Dean Emeritus
`College of Pharmacy
`The University of Georgia
`
`Loyd V. Allen, Jr., Ph.D.
`Professor Emeritus
`College of Pharmacy
`University of Oklahoma, and
`Editor—in—Chief
`InternationalJournal ofPharmaceutical Compounding
`Nicholas G. Popovich, Ph.D.
`Professor and Associate Head
`Department of Pharmacy Practice
`School of Pharmacy and Pharmacal Sciences
`Purdue University
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 003
`
`

`

`Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott VViIliams & VVllkins
`
`351 West Camden Street
`Baltimore, Maryland 21201—2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor-
`mation storage and retrieval system without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in—
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack-
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, Lode. Allen, Jr., Nicholas G. I’opovich. — 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`
`2. Drug delivery systems.
`1. Drugs—Dosage forms.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms.
`2. Drug Delivery Systems. QV 785 A6181 1999]
`RSZOO.A57
`1999
`615’.1—dc21
`DNLM/‘DLC
`
`I. Allen, Lode.
`
`for Library of Congress
`
`99—17498
`CIP
`The publishers have made every effort to trace the copyright holdersfor borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`thefirst opportunity.
`
`The use of portions of the text of USP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc. 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.
`
`To purchase additional copies of this book call our customer service department at (800)
`638—3030 or fax orders to (301) 824—7390. International customers should call (301)
`714—2324.
`
`99000102
`12345678910
`
`
`
`The purpc
`technologies
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`and biophar.
`the various c
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`written at a 1
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`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 004
`
`

`

`In addition to, or instead of, raising the tempera-
`ture of the solvent to increase the rate of solution, a
`
`pharmacist may choose to decrease the particle size
`of the solute. This may be accomplished by the com-
`
`Oral Solutions and Preparations
`for Oral Solution
`
`Solutions intended for oral administration usu—
`
`Solutions
`
`305
`
`minution (grinding a solid to a fine state of subdivi—
`sion) of the solute with a mortar and pestle on a
`small scale or industrial microniZer on a large scale.
`The reduced particle size causes an increase in the
`surface area of the substance exposed to the solvent.
`If the powder is placed in a suitable vessel (as a
`beaker, graduate cylinder, or bottle) with a portion of
`the solvent and is stirred or shaken, as suited to the
`container, the rate of solution may be increased due
`to the continued circulation of fresh solvent to the
`
`drug’s surface and the constant removal of newly
`formed solution from the drug’5 surface.
`Most solutions are prepared by simple solution of
`the solutes in the solvent or solvent mixture. On an
`
`industrial scale, solutions are prepared in large mix—
`ing vessels with ports for mechanical stirrers to effect
`solution (Fig. 12.1). When heat is desired, thermo—
`statically controlled mixing tanks may be used.
`
`perature, for many medicinal agents are destroyed
`at elevated temperatures, and the advantage of
`rapid solution maybe completely offset by drug de-
`terioration. If volatile solutes are to be dissolved or
`if the solvent is volatile (as alcohol), the heat would
`encourage the loss of these agents to the atmos—
`phere and must therefore be avoided. Pharmacists
`are aware that certain chemical agents, particularly
`calcium salts, undergo exothermic reactions as they
`dissolve and give off heat. For such materials the use
`of heat would actually discourage the formation of a
`solution. The best pharmaceutical example of this
`type of chemical is calcium hydroxide, which is used
`in the preparation of Calcium Hydroxide Topical So-
`lution, USP. This solute is soluble in water to the ex-
`tent of 140 mg per 100 mL of solution at 25°C (about
`77°F) and 170 mg per 100 mL of solution at 15°C
`(about 59°F). Obviously the temperature at which
`the solution is prepared or stored can affect the con—
`centration of the resultant solution.
`
`ally contain flavorants and colorants to make the
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 005
`
`

`

`
`
`306
`
`Solutions
`
`medication more attractive and palatable for the
`patient. When needed, they may also contain sta-
`bilizers to maintain the chemical and physical sta—
`bility of the medicinal agents and preservatives to
`prevent the growth of microorganisms in the solu-
`tion. The formulation pharmacist must be wary of
`chemical interactions which may occur between
`the various components of a solution which may
`result in an alteration in the preparation’s stability
`and/or potency. For instance, it has been demon—
`strated that esters of p—hydroxybenzoic acid
`(methyl—, ethyl—, propyl-, and butylparabens), fre—
`quently used preservatives in oral preparations,
`have a tendency to partition into certain flavoring
`oils (4). This partitioning effect could reduce the ef—
`fective concentration of the preservatives in the
`aqueous medium of a pharmaceutical product be-
`low the level needed for preservative action.
`Liquid pharmaceuticals for oral administration
`are usually formulated such that the patient re—
`ceives the usual dose of the medication in a conve—
`niently administered volume, as 5 mL (one tea—
`spoonful), 10 mL, or 15 mL (one tablespoonful). A
`few solutions have unusually large doses, as Mag-
`nesium Citrate Oral Solution, USP with a usual
`adult dose of 200 mL. On the other hand many so-
`lutions used in pediatric patients are given by drop,
`utilizing a calibrated dropper usually furnished by
`the manufacturer in the product package.
`
`Dry Mixtures for Solution
`
`A number of medicinal agents, particularly certain
`antibiotics, have insufficient stability in aqueous so-
`lution to meet extended shelf—life periods. Thus,
`commercial manufacturers of these products pro—
`vide them to the pharmacist in dry powder or gran—
`ule form for reconstitution with a prescribed amount
`of purified water immediately before dispensing to
`the patient. The dry powder mixture contains all of
`the forrnulative components including drug, flavo-
`rant, colorant, buffers, and others, except for the sol—
`vent. Once reconstituted by the pharmacist the re-
`sultant solutions remain stable when stored in the
`refrigerator for the labeled periods, usually from 7 to
`14 days depending upon the preparation. This is a
`sufficient period of time for the patient to complete
`the volume of medication usually prescribed. How-
`ever, if medication remains after the patient com—
`pletes the course of therapy, instructions should be
`explained to discard the remaining portion which
`would be unfit for use at a later date.
`Examples of dry powder mixtures intended for
`reconstitution to oral solutions are the following:
`
`Cloxacillin Sodium for Oral Solution, USP
`(Teva); an antiinfective antibiotic
`Oxacillin Sodium for Oral Solution, USP
`[Prostaphlin (Teva)]; an antiinfective an—
`tibiotic
`
`Penicillin V Potassium for Oral Solution, USP
`[Pen—Vee K (Wyeth-Ayerst)]; an antiinfec—
`tive antibiotic
`
`Potassium Chloride for Oral Solution, USP [1(—
`LOR (Abbott)]; a potassium supplement
`
`Orul Solutions
`
`In the practice of pharmacy, the pharmacist may
`be called on to dispense a commercially prepared
`oral solution; dilute the concentration of a solution,
`as in the preparation of a pediatric form of an adult
`product; prepare a solution through the reconstitu—
`tion of a dry powder mixture; or extemporaneously
`compound an oral solution from bulk components.
`In each instance, the pharmacist should be suffi-
`ciently knowledgeable of the dispensed product to
`expertly advise the patient of the proper use,
`dosage, method of administration, and storage of
`the product. Knowledge of the solubility and sta-
`bility characteristics of the medicinal agents and
`the solvents employed in the commercial products
`is useful to the pharmacist in informing the patient
`of the advisability of mixing the solution with juice,
`milk, or other beverages upon administration. In—
`formation regarding the solvents used in each
`commercial product appears on the product label
`and in the accompanying package insert. Table 12.5
`presents examples of some oral solutions. Some so—
`lutions of special pharmaceutical interest are de-
`scribed later in this chapter.
`
`Orul Rehydrution Solutions
`
`Rapid fluid loss associated with diarrhea can lead
`to dehydration and ultimately death in some pa—
`tients, particularly infants. More than five million
`children younger than 4 years of age die due to di—
`arrheal illnesses each year worldwide (5). Diarrhea
`is characterized by an increased frequency of loose,
`watery stools, and because there is an intensive
`fluid loss, dehydration can be an outcome. During
`diarrhea, the small intestine secretes far above the
`normal amount of fluid and electrolytes, and this
`simply exceeds the ability of the large intestine to
`reabsorb it. This fluid loss occurs mostly from the
`body’s extracellular fluid compartment and can
`lead to a progressive loss of blood volume culmi-
`nating in hypovolemic shock.
`
`Table 12.5. Exam;
`
`Oral Solution
`
`Antidepressants
`.‘Qthriptyline HCl 01
`Solution
`Fiuoxetine HCl
`
`Antiperistaltic
`lDiphenoxylate HCl
`and Atropine Sulfa
`Oral Solution
`
`Loperamide HCl
`Oral Solution
`
`Antipsychotics
`Haloperidol Oral
`Solution
`
`Perphenazine
`Oral Solution
`Thiothixene HCl
`Oral Solution
`
`Bronchodilator
`
`Theophylline Oral
`Solution
`
`Cathartics
`
`Magnesium Citrate
`Oral Solution, USP
`
`Sodium Phosphate 0]
`Solution
`
`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 006
`
`

`

`Solutions
`
`307
`
`
`
`
`Table 12.5. Examples of Oral Solutions by Category
`Concentration of
`Some Representative
`Commercial Product
`Commercial Products
`
`Oral Solution
`
`Antidepressants
`Nortriptyline HCl Oral
`Solution
`Fluoxetine HCl
`
`Antiperistaltic
`Diphenoxylate HCl
`and Atropine Sulfate
`Oral Solution
`
`Pamelor Oral
`Solution (Novartis)
`Prozac Liquid (Dista)
`
`10 mg nortriptyline/S
`mL
`
`20 mg fluoxetine/S mL
`
`Lomotil Liquid (Searle)
`
`2.5 mg of
`diphenoxylate HCl
`and 0.025 mg of
`atropine sulfate/5 mL
`
`Loperamide HCl
`Oral Solution
`
`lmodium A—D Liquid
`(McNeil Consumer
`Products)
`
`1 mg of loperamide
`HCl per 5 mL
`
`Antipsychotics
`Haloperidol Oral
`Solution
`
`Perphenazine
`Oral Solution
`Thiothixene HCl
`Oral Solution
`
`Haldol Concentrate
`(Ortho—McNeil)
`Trilafon Concentrate
`
`(Schering)
`Navane concentrate
`
`(Pfizer)
`
`2 mg haloperidol/mL
`
`16 mg perphenazine/S
`mL
`
`equivalent of 5 mg
`thiothixene/mL
`
`Theophylline Oral
`Solution (Roxane)
`
`80 mg of theophylline
`per 15 mL
`
`Bronchodilator
`
`Theophylline Oral
`Solution
`
`Cathartics
`
`Magnesium Citrate
`Oral Solution, USP
`
`Sodium Phosphate Oral
`Solution
`
`Phospho—Soda (Fleet)
`
`amount of magnesium
`citrate equivalent to
`between 1.55 g and
`1.9 g/100 mL of
`magnesium oxide
`2.4 g monobasic
`sodium phosphate
`and 0.9 g dibasic
`sodium phosphate
`per 5 mL.
`
`Comments
`
`Tricyclic antidepressant
`
`Used in the treatment of depression and
`for obsessive—compulsive disorder.
`
`This preparation is indicated in the
`management of diarrhea.
`Diphenoxylate is related structurally
`and pharmacologically to the narcotic
`meperidine. Atropine sulfate is added
`to the solution in subtherapeutic
`amounts to discourage (by virtue of
`side effects) deliberate overdosage.
`This preparation is indicated for the
`treatment of diarrhea for both adults
`
`and children 6 years of age and older.
`Loperamide is structurally related to
`haloperidol.
`
`These solutions are used primarily in
`severe neuropsychiatric conditions
`when oral medication is preferred and
`other oral dosage forms (as tablets
`and capsules) are considered
`impractical. The concentrated
`solutions are employed by adding the
`desired amount of the concentrate by
`calibrated dropper to soup or a
`beverage as tomato or fruit juices,
`milk, coffee, tea or carbonated
`beverages.
`
`This alcohol—free solution is used for the
`treatment of bronchial asthma and
`
`reversible bronchospasm associated
`with chronic bronchitis and
`
`emphysema.
`
`Discussed in text
`
`Works as laxative within 1 hour when
`taken before meals or overnight
`when taken at bedtime. Usual dose is
`10 to 20 mL of solution, best taken
`diluted with one—half glass of water
`and followed with a full glass of
`water.
`
`continued
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 007
`
`

`

`308
`
`Solutions
`
`
`
`Table 12.5. Examples of Oral Solutions by CategoryR
`
`Concentration of
`Some Representative
`Comments
`
`Commercial ProductsOral Solution Commercial ProductH—
`
`Corticosteroid
`
`Prednisolone Sodium
`Phosphate Oral Liquid
`
`Pediapred Oral
`Solution (Medeva)
`
`5 mg prednisolone (as
`sodium phosphate)
`per 5 mL
`
`Dental Caries Protectant
`
`Sodium Fluoride Oral
`Solution
`
`Pediaflor Drops (Boss)
`
`0.5 mg/mL
`
`Electrolyte Replenisher
`Potassium Chloride
`Oral Solution
`
`KaoChlor 10% Liquid
`(Savage)
`
`20 mEq of KC1/15 mL,
`in a flavored
`aqueous vehicle
`
`Fecal Softener
`
`Docusate Sodium
`Solution
`
`Colace Syrup (Roberts)
`
`10 mg docusate
`sodium/mL
`
`Hematinic
`
`Ferrous Sulfate Oral
`Solution
`
`Fer—ln-Sol Drops
`(Mead Johnson
`Nutritional)
`
`15 mg ferrous sulfate/
`0.6 mL
`
`Histamine H2 Antagonist
`Cimetidine HCl Liquid
`Tagamet HCl Liquid
`(SmithKline
`Beecham)
`
`300 mg of cimetidine
`HCl per 5 mL
`
`Narcotic Agonist Analgesic
`Methadone HCl Oral
`Methadone HCL
`Solution
`(Roxane)
`
`1 or 2 mg/mL
`
`Synthetic adrenocortical steroid with
`predominantly glucocorticoid
`properties indicated in the treatment
`of endocrine, rheumatic, collagen,
`allergic, and other disorders.
`
`Prophylaxis of dental caries; intended for
`use when community water supplies
`are inadequately fluoridated.
`
`Used in conditions of hypopotassemia
`(low level of potassium in the blood).
`Condition may be prompted by severe
`or chronic diarrhea, a low level of
`potassium intake in the diet, increased
`renal excretion of potassium, and
`other causes.The solution is diluted
`
`with water or fruit juice before taking.
`
`Usually 50 to 200 mg of the drug is
`measured by calibrated dropper and
`mixed with milk, fruit juice, or other
`liquid (to mask the taste) before
`administration.The drug softens the
`fecal mass by lowering the surface
`tension, thus permitting normal bowel
`habits, particularly in geriatric, pediatric
`cardiac, obstetric, and surgical patients.
`Dosage is taken for several days or
`until bowel movements are normal.
`
`Used for prevention and treatment of
`iron deficiency anemias. Usual
`prophylactic dose of 0.3 or 0.6 mL
`measured by calibrated dropper and
`mixed with water, fruit juice, or
`vegetable juice before administration.
`Dosage form intended primarily for
`infants and children.
`
`This preparation is indicated to treat
`peptic ulcer disease and pathological
`hypersecretory conditions, e.g.,
`Zollinger—Ellison syndrome.
`
`For relief of severe pain; detoxification
`and maintenance treatment of
`narcotic addiction.
`
`Vitamin D Source
`
`Ergocalciferol Solution
`
`Calciferol Drops
`(Schwarz)
`
`
`
`8,000 units/mL
`
`A solution of water-insoluble
`
`ergocalciferol (vitamin D2) in
`propylene glycol. The usual
`prophylactic dose of ergocalciferol is
`about 400 units and the therapeutic
`dose may be as high as 200,000 to
`500,000 units daily in treating rickets.
`
`Diarrhea is a norm
`to rid itself of a noxior
`tavirus, Escherichia cr
`proach is to allow the
`to terminate it too qui
`fluid and electrolytes
`dration. The loss of fit
`
`panied by a depletion
`carbonate ions, whi
`mentioned, in hypow
`sis, hyperpnea and v
`of vomiting and diarr
`well. Consequently, t
`water with an oral re:
`nutritional foods su
`bran.
`
`Oral rehydration sc
`treatment of patients
`5 to 10% of body we
`the—counter, are relati
`has diminished the in
`
`ciated with parente
`solutions. Therapy wi
`the observation that
`from the small intesti
`rhea. This active trai
`
`geous because it is co
`Almost like in domir
`
`promotes anion abso
`water absorption to
`produce maximal ab:
`studies have demons-
`
`trations of glucose a1
`tion are 110 mM (2
`sodium ion, respectix
`ions are also includec
`
`rect the subsequent
`caused by diarrhea a1
`A typical oral reh
`mEq Na+, 20 mEq K
`and 25 g of dextrose I
`available in liquid or
`stitution. It is import
`cific amount of water
`forms. Further, these
`with or given with 0
`uids, such as milk or
`no method to calcu
`
`patient actually recs
`ready-to—use oral el
`dehydration or achi
`alyte Solution (R0
`(Ross).These produr
`cose. Ricelyte Oral f
`tains electrolytes in
`
`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 008
`
`

`

`Diarrhea is a normal physiologic body response
`to rid itself of a noxious or toxic substance, e. g., Ro-
`taoirus, Escherichia coli. Thus, the treatment ap—
`proach is to allow the diarrhea to proceed and not
`to terminate it too quickly, but promptly replace the
`fluid and electrolytes that are lost to prevent dehy—
`dration. The loss of fluid during diarrhea is accom—
`panied by a depletion of sodium, potassium and bi—
`carbonate ions, which if severe can result, as
`mentioned, in hypovolemic shock, as well as acido—
`sis, hyperpnea and vomiting. If continuous, bouts
`of vomiting and diarrhea can cause malnutrition as
`well. Consequently, the goal is to replace lost fecal
`water with an oral rehydration solution and utilize
`nutritional foods such as soybean formula and
`bran.
`
`Oral rehydration solutions are usually effective in
`treatment of patients with mild volume depletion of
`5 to 10% of body weight. These are available over—
`the-counter, are relatively inexpensive and their use
`has diminished the incidence of complications asso—
`ciated with parenterally—administered electrolyte
`solutions. Therapy with these solutions is based on
`the observation that glucose is actively absorbed
`from the small intestine, even during bouts of diar—
`rhea. This active transport of glucose is advanta—
`geous because it is coupled with sodium absorption.
`Almost like in domino fashion, sodium absorption
`promotes anion absorption which in turn promotes
`water absorption to short circuit dehydration. To
`produce maximal absorption of sodium and water,
`studies have demonstrated that the optimal concen—
`trations of glucose and sodium in an isotonic solu—
`tion are 110 mM (2%) glucose and 60 mEq/L of
`sodium ion, respectively. Bicarbonate and/or citrate
`ions are also included in these solutions to help cor»
`rect the subsequent metabolic acidosis which is
`caused by diarrhea and dehydration.
`A typical oral rehydration solution contains 45
`mEq Na+, 20 mEq Ki 35 mEq Cl‘, 30 mEq citrate,
`and 25 g of dextrose per liter. These formulations are
`available in liquid or powder/packet form for recon-
`stitution. It is important that the user add the spe-
`cific amount of water needed to prepare the powder
`forms. Further, these products should not be mixed
`with or given with other electrolyte—containing liq—
`uids, such as milk or fruit juices. Otherwise, there is
`no method to calculate how much electrolyte the
`patient actually received. Commercially available,
`ready-to-use oral electrolyte solutions to prevent
`dehydration or achieve rehydration include Pedi-
`alyte Solution (Ross), and Rehydrate Solution
`(Ross).These products also contain dextrose or glu—
`cose. Ricelyte Oral Solution (Mead Johnson) con—
`tains electrolytes in a syrup of rice solids. The rice—
`
`Solutions
`
`309
`
`based formula produces a lower osmotic effect than
`the dextrose- or glucose—based formulas and is
`thought to be more effective in reducing stool out-
`put and shortening the duration of diarrhea. The
`pharmacist must discourage the production of
`homemade versions of electrolyte solutions. The
`success of the commercial solutions is based on the
`
`accuracy of the formulation. If prepared incorrectly,
`homemade preparations could cause hyperna—
`tremia or cause the diarrhea to worsen.
`
`In 4800 mL disposable container.
`
`Oral Colonic Lavage Solution
`
`Traditionally, the preparation of the bowel for
`procedures such as a colonoscopy have consisted of
`the administration of clear liquid diets for 24 to 48
`hours preceding the procedure, the administration
`of oral
`laxatives,
`e.g., magnesium citrate or
`bisacodyl, the night before, and cleansing enemas
`administered 2 to 4 hours prior to procedure com—
`mencement. Typically, to circumvent the cost of
`having to hospitalize the patient the night before
`the procedure, patients were allowed to perform
`this regimen at home. However, while the results
`have been satisfactory, that is, the bowel is cleared
`for the procedure, poor patient compliance with
`and acceptance of this regimen can cause problems
`during the procedure. Further, additive effects of
`malnutrition and poor oral intake prior to the pro-
`cedure can cause more patient problems.
`Consequently, an alternative method to prepare
`the gastrointestinal tract has been devised. This
`procedure requires less time and dietary restriction
`and obviates the need for cleansing enemas. This
`method involves the oral administration of a bal—
`
`anced solution of electrolytes with polyethylene
`glycol (PEG-3350). Prior to its dispensing to the pa—
`tient,
`the pharmacist reconstitutes this powder
`with water creating an iso—osmotic solution having
`a mildly salty taste. The polyethylene glycol acts as
`an osmotic agent within the gastrointestinal tract
`and the balanced electrolyte concentration results
`in virtually no net absorption or secretion of ions.
`Thus, a large volume of this solution can be ad—
`ministered without a significant change in water or
`electrolyte balance.
`The formulation of this oral colonic lavage solu—
`tion is as follows:
`
`Polyethylene Glycol 3350 ..................... 236.00 g
`Sodium Sulfate. .....................................
`22.74 g
`Sodium Bicarbonate ..............................
`6.74 g
`Sodium Chloride ...................................
`5.86 g
`Potassium Chloride ...............................
`2.97 g
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 009
`
`

`

`310
`
`Solutions
`
`The recommended adult dosage of this product is
`4 L of solution before the gastrointestinal proce-
`dure. The patient is instructed to drink 240 mL of
`solution every 10 minutes until about 4 L are con—
`sumed.The patient is advised to drink each portion
`quickly rather than sipping it continuously. Usually,
`the first bowel movement will occur within 1 hour.
`Several regimens are utilized, and one method is to
`schedule patients for a midmorning procedure, al—
`lowing the patient 3 hours for drinking and a 1-
`hour waiting period to complete bowel evacuation.
`To date, this approach to bowel evacuation has
`been associated with a low incidence of side effects,
`primarily nausea,
`transient abdominal fullness,
`bloating, and occasionally, cramps and vomiting.
`Ideally, the patient should not have taken any food
`3 to 4 hours before beginning the administration of
`the solution. In no case should solid foods be taken
`by the patient for at least 2 hours before the solu-
`tion is administered. No foods, except clear liquids,
`are permitted after this product is administered and
`prior to the examination. The product must be
`stored in the refrigerator after reconstitution, and
`this aids somewhat in decreasing the salty taste of
`the product.
`
`Magnesium Citrate Oral Solution
`
`Magnesium citrate oral solution is a colorless to
`slightly yellow, clear, effervescent liquid having a
`sweet, acidulous taste and a lemon flavor. It is com—
`monly referred to as” Citrate” or as” Citrate of Mag-
`nesia.” It is required to contain an amount of mag—
`nesium citrate equivalent to between 1.55 and 1.9
`g of magnesium oxide in each 100 mL.
`The solution is prepared by reacting official mag-
`nesium carbonate with an excess of citric acid
`(equation 1), flavoring and sweetening the solution
`with lemon oil and syrup, filtering with talc, and
`then carbonating it by the addition of either potas—
`sium or sodium bicarbonate (equation 2).The solu—
`tion may be further carbonated by the use of car—
`bon dioxide under pressure.
`
`(1) (MgCO3)4 ’ M8(OH)2 + 5H3C 6H 507 —>
`5MgHC6HSO7 + 4.co2 + 6H 20
`
`(2) 31<Hco3 + H3C 6111507 —>K3C 61-1507
`+ 3co2 + 3HZO
`
`The solution provides an excellent medium for
`the growth of molds, and any mold spores present
`during the manufacture of the solution must be
`killed if the preparation is to remain stable. For this
`
`reason, during the preparation of the solution the
`liquid is heated to boiling (prior to carbonation),
`boiled water is employed to bring the solution to its
`proper volume, and boiling water is used to rinse
`the final container. The final solution may be steril-
`ized.
`
`Magnesium citrate solution has always been
`troublesome because it has a tendency to deposit a
`crystalline solid upon standing. Apparently this is
`due to the formation of some almost insoluble,
`normal magnesium citrate (rather than the exclu—
`sively dibasic form as in equation 1). The cause of
`the problem has largely been attributed to the in-
`definite composition of the official magnesium car:
`bonate, which by definition is ”a basic hydrated
`magnesium carbonate or a normal hydrated mag-
`nesium carbonate” (see equation 1). It contains the
`equivalent of 40 to 43.5% of magnesium oxide. Ap—
`parently, solutions prepared from magnesium car-
`bonates with differing equivalents of magnesium
`oxide vary in stability, with the most stable ones be—
`ing prepared from samples of magnesium carbon—
`ate having the lower equivalent of magnesium ox—
`ide. The formula for the preparation of 350 mL of
`magnesium citrate solution calls for the use of 15 g
`of official magnesium carbonate, which corre—
`sponds to approximately 6.0 to 6.47 g of magne-
`sium oxide.
`
`In carbonating the solution, the bicarbonate may
`be added in tablet form rather than as a powder in
`order to delay the effervescence resulting from its
`contact with the citric acid. If the powder were
`used, the reaction would be immediate and Violent,
`and it would be virtually impossible to close the
`bottle in time to prevent the loss of carbon dioxide
`or solution.The solution may be further carbonated
`by the use of CO2 under pressure. Most of the mag—
`nesium citrate solutions prepared commercially to-
`day are packaged in the same type of bottles as”soft
`drink” carbonated beverages. The solution is pack—
`aged in bottles of 300 mL. Since the solution is car-
`bonated, it loses some of its character if allowed to
`stand for a period of time after the container has
`been opened. Magnesium citrate solution is stored
`in a cold place, preferably in a refrigerator, keeping
`the bottle on its side so the cork or rubber liners of
`the caps are kept moist and swollen, thereby main—
`taining the airtight seal between the cap and the
`bottle.
`
`The solution is employed as a saline cathartic,
`with the citric acid, lemon oil, syrup, carbonation,
`and the low temperature of the refrigerated solu—
`tion all contributing to the patient’s acceptance of
`the large volume of medication. For many patients
`
`it represents a plea:
`bitter saline cathar1
`
`Sodium
`Acid
`
`This official solu
`
`citrate and 67 mg c
`ous solution. The 5
`doses of 10 to 30
`
`daily as a systemic
`tion is useful in pat
`long term mainter
`sirable, such as pal
`calculi of the urin.
`
`useful adjuvant wt
`agents in gout thei
`lize out of an acid '
`
`Syrups are conc
`of a sugar or su
`added flavoring ag
`Syrups containing
`inal substances arr
`
`vehicles (syrups). f
`and examples of c
`icated syrups are
`syrups are intende
`hicles for medicin;
`
`extemporaneous c
`in the preparation
`
`Table 12.6. Exam]
`
`Nonmedicated 5],
`
`Cherry Syrup
`
`Cocoa Syrup
`
`Orange Syrup
`
`Ora—Sweet and Ora
`(Paddock Laborat
`
`Raspberry Syrup
`
`Symp
`
`
`
`Apotex, Inc. (IPR2019-00400), Ex. 1021, p. 010
`
`

`

`Solutions
`
`311
`
`it represents a pleasant way of taking an otherwise
`bitter saline cathartic.
`
`Sodium Citrate and Citric
`Acid Oral Solution
`
`This official solution contains 100 mg of sodium
`citrate and 67 mg of citric acid in each mL of aque—
`ous solution. The solution is administered orally in
`doses of 10 to 30 mL as frequently as four times
`daily as a systemic alkalinizer. Systemic alkaliniza—
`tion is useful in patients having conditions in which
`long term maintenance of an alkaline urine is de—
`sirable, such as patients with uric acid and cystine
`calculi of the urinary tract. The solution is also a
`useful adjuvant when administered with iiricosuric
`agents in gout therapy since urates tend to crystal—
`lize out of an acid urine.
`
`Syrups
`
`Syrups are concentrated, aqueous preparations
`of a sugar or sugar—substitute with or without
`added flavoring agents and medicinal substances.
`Syrups containing flavoring agents but not medic—
`inal substances are called nonmedicuted or flavored
`vehicles (syrups). Some official, previously official
`and examples of commercially available nonmed-
`icated syrups are presented in Table 12.6. These
`syrups are intended to serve as pleasant-tasting ve—
`hicles for medicinal substances to be added in the
`extemporaneous compounding of prescriptions or
`in the preparation of a standard formula for a med~
`
`icated syrup, which is a syrup containing a thera—
`peutic agent. Due to the inability of some children
`and elderly people to swallow solid dosage forms,
`it is not unusual today for a pharmacist to be asked
`to prepare an oral liquid dosage form of a medica—
`tion available in the pharmacy only as tablets or
`capsules. In doing so, considerations of drug solu-
`bility, stability, and bioavailability must be consid-
`ered case by case (6,7). The liquid dosage form se—
`lected for compounding may be a solution or a
`suspension, depending upon the chemical and
`physical characteristics of the particular drug and
`its solid dosage form. Vehicles are commercially
`available for this purpose (7).
`Medicated syrups are commercially prepared
`from the starting materials; that is, by combining
`each of the individual components of the syrup, as
`sucrose, purified water, flavoring agents, coloring
`agents, the therapeutic agent, and other necessary
`and desirable ingredients. Naturally, medicated
`syrups are employed in therapeutics for the value of
`the medicinal agent present in the syrup.
`Syrups provide a pleasant means of administer—
`ing a liquid form of a disagreeable tasting drug.
`They are particularly effective in the administration
`of drugs to youngsters, since their pleasant taste
`usually dissipates any reluctance on the part of the
`child to take the medicine. The fact that syrups con-
`tain little or no alcohol adds to their favor among
`parents.
`Any water—soluble drug that is stable in aqueous
`solution may be added to a flavored syrup. How-
`ever care must be exercised to ensure the compati—
`
`\
`
`Table 12.6. Examples of Nonmedicated Syrups (Vehicles)
`Nonmedicuted Syrup
`Cherry Syrup
`
`Cocoa Syrup
`
`Orange Syrup
`
`Ora—Sweet and Ora—Sweet SF
`(Paddock Laboratories)
`
`Raspberry Syrup
`
`Syrup
`
`Comments
`A sucrose—based syrup containing about 47% by volume of cherry juice. The
`syrup’s tart and fruit flavor is attractive to most patients and the acidic pH of
`the syrup makes it useful as a vehicle for drugs requiring an acid medium.
`This syrup is a suspension of cocoa powder in an aqueous vehicle sweetened
`and thickened with sucrose, liquid glucose, and glycerin, and flavored with
`vanilla and sodium chloride. The syrup is particularly effective in
`administering bitter tasting drugs to children.
`This sucrose—based syrup utilizes sweet orange peel tincture, and citric acid as
`the source of flavor and tar