The Theory
`and Practice of Industrial
`Pharmacy
`
`LEON LACHMAN, Ph.D.
`Lachman Consultant Services, Inc.
`Garden City, New York
`HERBERT A. LIEBERMAN, Ph.D.
`H. H. Lieberman Associates, Inc.
`Consultant Services
`Livingston, New Jersey
`JOSEPH L. KANIG, Ph.D.
`Kanig Consulting and Research Associates, Inc.
`Ridgefield, Connecticut
`
`THIRD EDITION
`
`LEA & FEBIGER • 1986 • PHILADELPHIA
`
`LUYE1021
`IPR of Patent No. 6,667,061
`
`

`
`Lea & Febiger
`600 Washington Square
`Philadelphia, PA 19106-4198
`U.S.A.
`(215) 922-1330
`
`/02.--
`
`Library of Congress Cataloging in Publication Data
`Main entry under title:
`
`The Theory and practice of industrial pharmacy.
`
`Includes bibliographies and index.
`I. Lachman, Leon,
`1. Pharmacy.
`2. Drug trade.
`1929-
`II. Lieberman, Herbert A., 1920-
`III. Kanig, Joseph L., 1921-
`[DNLM: 1. Drug
`Industry.
`QV 704 T396]
`RS192.L33 1985
`ISBN 0-8121-0977-5
`
`84-27806
`
`615' .19
`
`First Edition, 1970
`Second Edition, 1976
`
`Copyright © 1986 by Lea & Febiger. Copyright under the
`International Copyright Union. All Rights Reserved. This
`book is protected by copyright. No part of it may be repro-
`duced in any manner or by any means without written per-
`mission from the publisher.
`
`PRINTED IN THE UNITED STATES OF AMEJUCA
`Print No. 4 3 2 1 ·
`
`LUYE1021
`IPR of Patent No. 6,667,061
`
`

`
`Solutes
`throughout the useful life of the product. There-
`fore, these agents must be selected with great
`care, and they must be evaluated as to their ef-
`The physical and chemical purity of solutes
`used for sterile preparations must also be excep-
`fect upon the entire formulation. An extensive
`tional. Obviously, contaminants entering a prod-
`review of excipients used in parenteral products
`uct with a solute have the same effect as if they
`and tlie means for adjusting pH of these prod-
`ucts has recently been published and should be
`entered via the vehicle. Even small traces of
`referred to for more detailed information. 14
`contaminants may be detrimental to products,
`necessitating purification of the solute. For a
`Table 22-1 provides a list, adapted from that re-
`few substances (for example, ascorbic acid and
`view, of excipients commonly used in commer-
`calcium gluconate ), special parenteral grades
`cial parenteral products.
`Antibacterial Agents. Antibacterial agents
`are commercially available.
`in bacteriostatic concentration must be included
`In addition, solutes should be free from micro-
`in the formulation of products packaged in mul-
`bial and pyrogenic contamination. This entails
`tiple dose vials, and are ofJ:en included in formu-
`not only proper quality of the chemical as pro-
`lations to be sterilized by marginal processes or
`cured but storage conditions designed to prevent
`made by aseptic manipulation. The require-
`contamination, particularly after a container has
`ments of activity, stability, and effectiveness of
`been opened. Preferably, production lots should
`antibacterial agents in parenterals have been
`be designed to use the entire contents of pack-
`reviewed in published ·papers.15- 17
`ages of chemicals whenever possible.
`Antioxidants. Antioxidants,
`included in
`Added Substances. Substances added to a
`many formulations
`to protect a therapeutic
`product to enhance its stability are essential for
`agent susceptible
`to oxidation, particularly
`almost every product. 13 Such substances in-
`under the accelerated conditions of thermal ster-
`clude
`solubilizers,
`antioxidants,
`chelating
`ilization, may function in at least two ways., i.e.,
`agents, buffers, tonicity contributors, antibacte-
`(1) by being preferentially oxidized (reducing
`rial agents, antifungal agents, hydrolysis inhibi-
`agents) and thereby gradually used up, or (2) by
`tors, antifoaming agents, and numerous other
`blocking an oxidative chain reaction in which
`substances for specialized purposes. At the same
`they are not usually consumed. In addition, cer-
`time, these agents must be prevented from ad-
`tain compounds have been found to act as syner-
`versely affecting the product. In general, added
`gists, increasing the effectiveness of antioxi-
`substances must be nontoxic in the quantity
`dants, particularly those blocking oxidative
`administered to the patient. They should not in-
`reactions. A fourth group of compounds are use-
`terfere with the therapeutic efficacy nor with the
`ful in this connection in that they complex with
`assay of the active therapeutic compound. They
`catalysts that otherwise would accelerate the
`must also be present and active when needed
`TABLE 22-1. Excipients Used for Commercial Parenteral Products
`Concentration Range (%)
`Excipients
`Antimicrobial Preseroatives
`Benzyl alcohol
`Benzethonium chloride
`Butylparaben
`Chlorobutanol
`Metacresol
`Methylparaben
`Myristylgamma picolinium chloride
`Phenol
`Phenylmercuric nitrate
`Propylparaben
`Thimerosal
`Solubilizers, Wetting Agents, or Emulsifiers
`Dimethylacetamide
`Dioctyl sodium sulfosuccinate
`Egg yolk phospholipid
`Ethyl alcohol
`Ethyl lactate
`Glycerin
`
`0.5-10.0
`0.01
`0.015
`0.25-0.5
`0.1-0.25
`0.01-0.18
`0.17
`0.065-0.5
`0.001
`0.005-0.035
`0.001-0.02
`
`0.01
`O.Dl5
`1.2
`. 0.61-49.0
`0.1
`14.6-25.0
`
`642 • The Theory and Practice of Industrial Pharmacy
`
`LUYE1021
`IPR of Patent No. 6,667,061
`
`

`
`Concentration Range (%)
`
`0.5-2.3
`7.0-11.5
`0.01-50.0
`0.01
`0.05
`0.04-4.0
`0.2-1.0
`0.2-50.0
`0.21
`0.05
`5.0
`
`0.22
`1.0
`5.0
`0.5
`0.1
`1.6
`0.1
`1.7
`0.71
`0.8
`0.005
`0.06
`4.0
`1.2
`0.65
`
`Excipients
`Solubilizers, Wetting Agents, or Emulsifiers-continued
`Lecithin
`PEG-40 castor oil
`Polyethylene glycol 300
`Polysorbate 20
`Polysorbate 40
`Polysorbate 80
`Povidone
`Propylene glycol
`Sodium desoxycholate
`Sorbitan monopalmitate
`Theophylline
`Buffers
`Acetic acid
`Adipic acid
`Benzoic acid and sodium benzoate
`Citric acid
`Lactic acid
`Maleic acid
`Potassium phosphate
`Sodium phosphate monobasic
`Sodium phosphate dibasic
`Sodium acetate
`Sodium bicarbonate
`Sodium carbonate
`Sodium citrate
`Sodium tartrate
`Tartaric acid
`Bulking Substances or Tonicity Modifiers
`Glycerin
`Lactose
`Mannitol
`Dextrose
`Sodium chloride
`Sodium sulfate
`Sorbitol
`Suspending Agents
`Gelatin
`Methylcellulose
`Pectin
`·
`Polyethylene glycol 4000
`Sodium carboxymethylcellulose
`Sorbitol solution
`Chelating Agents
`Edetate disodium
`Edetate calcium disodium
`Edetate tetrasodium
`Local Anesthetics
`Procaine HCl
`Benzyl alcohol
`Stabilizers
`0.5-0.8
`Creatinine
`1.5-2.25
`Glycine
`1.25-2.5
`Niacinamide
`0.53
`Sodium acetyltryptophanate
`0.4
`Sodium caprylate
`0.03
`Sodium saccharin
`Adapted from Wang, Y.J .• and Kowal, R.R.: J. Parent. Drug Assoc., 34:452, 1980.
`
`1.6-2.25
`0.14-5.0
`0.4-2.5
`3.75-5.0
`varies
`1.1
`2.0
`
`2.0
`0.03-1.05
`0.2
`2.7-3.0
`0.05-0.75
`50.0
`
`0.00368-0.05
`0.04
`0.01
`
`1.0
`5
`
`STERILE PRODUCTS • 643
`
`LUYE1021
`IPR of Patent No. 6,667,061
`
`

`
`oxidative reaction. Because of the differences in
`action, combinations of these agents are some-
`times used. In Table 22-2, the more commonly
`employed antioxidants are listed according to
`the above four groupings. The reader is referred
`to the literature for more details concerning an-
`tioxidants and their activities. 18- 20
`It should also be mentioned that for those
`products in which oxygen enters into a degrada-
`tive reaction, an antioxidant effect can be
`achieved by displacing oxygen (air) from contact
`with the product. Usually, this is accomplished
`by saturating the liquid with either nitrogen or
`carbon dioxide and sealing the final container
`after displacing the air above the product with
`the gas.
`Higuchi and Schroeter have warned of the
`reactivity of bisulfi.tes with drug molecules, 21
`and Halaby and Mattocks have warned of the
`potential toxicity of sodium bisulfi.te absorbed
`from peritoneal dialysis solutions. 22
`Buffers. Buffers are added to maintain a re-
`quired pH for many products; a change in pH
`may cause significant alterations in the rate of
`degradative reactions. Changes in pH may occur
`during storage as a result of the dissolving of
`glass constituents in the product, release of con-
`stituents from rubber closures or plastic compo-
`nents in contact with the.product, dissolving of
`gases and vapors from the airspace in the con-
`tainer and diffusion through the rubber or plas-
`
`TABLE 22-2. Antioxidants Used in Sterile Prod-
`ucts
`
`Compound
`Antioxidants· (reducing agents)
`Ascorbic acid
`Sodium bisulfite
`Sodium metabisulfite
`Sodium formaldehyde sulfoxylate
`Thiourea
`Antioxidants (blocking agents)
`Ascorbic acid esters
`Butyl hydroxytoluene (BHT)
`Tocopherols
`Synergists
`Ascorbic acid
`Citric acid
`Citraconic acid
`Phosphoric acid
`Tartaric acid
`Chelating agents
`Ethylenediaminetetraacetic acid salts
`
`Usual
`Cancentratian
`(%)
`
`0.02-0.1
`0.1-0.15
`0.1-0.15
`0.1-0.15
`0.005
`
`0.01-0.015
`0.005-0.02
`0.05-0.075
`
`0.01-0.05
`0.005-0.01
`0.03-0.45
`0.005-0.01
`0.01-0.02
`
`0.01-0.075
`
`tic component, or reactions within the product.
`Buffers must have the capacity to maintain the
`pH of the product against these influences, but
`not enough to prevent the body fluids from over-
`whelming the buffer following administration.
`In most cases, the biologic effectiveness of the
`drug is maximum at or near the biologic fluid pH
`rather than at the stabilizing pH of the·injected
`product.
`Acetates, citrates, and phosphates are the
`principal buffer systems used, but buffer sys-
`tems making use of other ingredients in the for-
`mulation are often used to reduce the total num-
`ber of ingredients in the product. Buffer systems
`must be selected with consideration of their ef-
`fective range, concentration, and chemical ef-
`fect on the total product. These factors have
`been reviewed by Windheuser.23
`Tonicity Contributors. Compounds con-
`tributing to the isotonicity of a product reduce
`the pain of injection in areas with nerve end-
`ings. Buffers may serve as tonicity contributors
`as well as stabilizers for the pH. Other added
`substances also contribute to the colligative
`properties of the preparation. Whenever possible
`such dual activity is desirable.
`Although the freezing point depression of the
`solution is most frequently used to determine
`whether a solution is isotonic, isotonicity actu-
`ally depends on the permeability of a living sem-
`ipermeable membrane that separates the solu-
`tion from a biologic cell system. Most frequently,
`for sterile pharmaceutical preparations, the
`membrane concerned is the one enclosing the
`red blood cells. Therefore, a preparation cannot
`be considered to be isotonic until it has been
`tested in a biologic system. A hemolytic method,
`using red blood cells, has been described. 24•25
`Isotonicity values for various drugs have been
`recorded. 26-29 Testing by such a method be-
`comes even more important when all or part of
`the water is replaced with another solvent, since
`dissociation is different when water is displaced
`by another solvent.
`
`Containers
`Containers are in intimate contact with the
`product. No container presently available is
`totally nonreactive, particularly with aqueous
`solutions. Both the chemical and physical char-
`acteristics affect the stability of the product, but
`the physical characteristics are given primary
`consideration in the selection of a protective
`container.
`Glass cont:ainers traditionally have been used
`for sterile products, many of which are closed
`with rubber stoppers. Interest in plastic con-
`
`644 • The Theory and Practice of Industrial Pharmacy
`
`LUYE1021
`IPR of Patent No. 6,667,061
`
`

`
`The stability of pharmaceutical compounds
`undergoing oxidative degradation can be in-
`creased by several approaches.
`Oxygen Content. Since, Jn many cases, oxi-
`dative degradation of a drug takes place in aque-
`ous solution, it is helpful to keep the oxygen con-
`tent of these solutions at a minimum. In a study
`to determine the oxygen content of water pre-
`pared and treated by different techniques, it was
`found that water in equilibrium with atmos-
`pheric oxygen contains 5. 75 ml per liter of oxy-
`gen at 25°C and 9.14 ml per liter of oxygen at
`4°C, and that all free oxygen is expelled from
`water at 100°C.56 Freshly distilled water col-
`lected directly from the distillation apparatus
`and stored at 4°C in closed containers contains
`% to 1/a the oxygen content of water saturated
`with oxygen from the atmosphere. Boiling and
`cooling this freshly distilled water to 20°C re-
`sults in almost a twofold increase in the oxygen
`content of the water; however, if the water is
`cooled in an atmosphere essentially free from
`atmospheric oxygen, there is no increase in oxy-
`gen content. To obtain water that contains a
`minimum amount of free oxygen, water after it
`is first boiled is purged with carbon dioxide or
`nitrogen gas. The oxygen content of water
`treated with carbon dioxide is reduced
`to
`0.45 ml per liter at 20°C.
`Since most oxidative degradations of pharma-
`ceutical compounds are probably autoxidative in
`nature and involve chain reactions that require
`only a small amount of oxygen for initiating the
`reaction, reduction of oxygen concentration
`alone is not sufficient in many cases to prevent
`degradation from occurring. The traces of oxy-
`gen left may be sufficient to start a chain reac-
`tion. Consequently, it is necessary to add agents
`such as antioxidants and chelating agents to ob-
`tain acceptable protection against oxidative deg-
`radation.
`Antioxidants. Antioxidants are added to
`pharmaceutical formulations as redox systems
`possessing higher oxidative potential than the
`drug that they are designed to protect, or as
`chain inhibitors of radical induced decomposi-
`tion. In general, the effect of antioxidants is to
`break up the chains formed during the propaga-
`tion process by providing a hydrogen atom or an
`electron to the free radical and receiving the
`excess energy possessed by the activated mole-
`cule.
`Although the selection of an antioxidant can
`be made on sound theoretic grounds based on
`the difference in redox potential between the
`drug and antioxidant, electrometric measure-
`ments only rarely predict the efficiency of anti-
`
`TABLE 26-6. Antioxidants Cammonly Used for
`Aqueous Systems
`Sodium sulfite
`Sodium metabisulfite
`Sodium bisulfite
`Sodium thiosulfate
`Sodium formaldehyde
`sulfoxylate
`Sulfur dioxide
`
`Ascorbic acid
`Isoascorbic acid
`Thioglycerol
`Thioglycolic acid
`Cysteine hydrochloride
`Acetylcysteine
`
`oxidants in complex pharmaceutical systems.
`The effectiveness of an antioxidant or the com-
`parative value of various antioxidants for a par-
`ticular pharmaceutical preparation is best ac-
`complished by subjecting the pharmaceutical
`system with the antioxidant to standard oxida-
`tive conditions and periodically assaying the for-
`mulation for both drug and antioxidant. Al-
`though this method may require maximum
`effort, it yields the most useful information.
`It should be remembered that because of the
`complexity of free radical oxidative processes
`and their sensitivity to trace amounts of impuri-
`ties, attempts to compare the effectiveness of
`antioxidants among different pharmaceutical
`systems are of limited validity.
`Antioxidant materials used in pharmaceutical
`systems are listed in Tables 26-6 and 26-7.
`Water-soluble antioxidants act by preferen-
`tially undergoing oxidation in place of the drug.
`Oil-soluble antioxidants serve as free radical
`acceptors and inhibit the free radical chain proc-
`ess. Sulfurous acid salts consume molecular
`oxygen present in solution. Structurally, other
`antioxidants have the property of losing a hydro-
`gen free radical and/or an electron.
`The effectiveness of these antioxidants can
`depend on the concentration used, whether they
`are used singularly or in combination, the solu-
`tion pH, and the package integrity and nonreac-
`tivity.
`Although sodium metabisulfite has been used
`extensively in the past and is still used to a con-
`siderable extent as an effective antioxidant, re-
`cent reports have indicated that the antioxidant
`
`TABLE 26-7. Antioxidants Commonly Used for
`Oil Systems
`Ascorbyl palmitate
`Hydroquinone
`Propyl gallate
`N ordihydroguaiaretic
`acid
`
`Butylated hydroxy
`toluene
`Butylated hydroxy anisole
`a-tocopherol
`Lecithin
`
`KINETIC PRINCIPLES AND STABILITY TESTING • 783
`
`LUYE1021
`IPR of Patent No. 6,667,061
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`

`
`activity of this substance is inhibited by a num-
`ber of compounds, that it actually undergoes
`degradation itse1f, and that iiJ>otentiates the
`degradation of epinephrine.57-
`The effectiveness of bisulfite as an antioxi-
`dant ·in typical phannaceutical systems depends
`on the ease with which this compound is oxi-
`dized in comparison with the drug it is to pro-
`tect. Substances that inhibit bisulfite oxidation
`may exert important effects on the overall stabil-
`ity of the product by decreasing the antioxidant
`effect of bisulfite. It has been postulated that the
`mechanism by which these substances inhibit
`sulfite activity is through the formation of coor-
`dination compounds between inhibitor and bi-
`sulfite. Typical substances that can inhibit the
`oxidation of bisulfite are mannitol, phenols, in-
`organic anions, aldehydes, ketones, and alka-
`loids.
`It has been shown that bisulfite reacts with
`epinephrine to form a colorless, inactive epi-
`nephrine sulfonate, which thus indicates the
`need for caution in using bisulfite in formula-
`tions without performing adequate studies to
`determine its effect on active ingredients. 59
`These investigators showed that a substantial
`breakdown of epinephrine takes place in the
`presence of bisulfite as depicted in Figure 26-24.
`Higuchi and Schroeter reported that the degra-
`dation of chloramphenicol induced by bisulfite
`appears to be considerably more complex than
`that found with epinephrine. 58 Loss of optical
`activity was found to occur at a much faster rate
`in the presence of bisulfite.
`Riegelmen and Fisher, in their study to stabi-
`lize epinephrine against sulfite-catalyzed degra-
`
`80
`
`UJ z
`a: 60
`:I: c..
`UJ z40
`a: UJ
`
`~ 20
`
`pH4, O.IM BUFFERS
`0.1% EPINEPHRINE
`•-CITRATE &0.1% NaHSOa
`•-ACETATE
`,.. ao-BLANKS
`
`HOURS
`FIG. 26-24. Percentage of epinephrine remaining in 0.1%
`(0.0055 molar) solutions containing 0.1% sodium bisulfite
`(0. 0096 molar) buffered at pH 4.0 with 0.1 molar acetate or
`citrate. The solutions were stored in sealed, evacuated
`ampuls at so•. (From Schroeter, L. C., Higuchi, T., and
`Schuler, E. E.: ]. Am. Pharm. Assoc., Sci. Ed., 47:724,
`1958.)
`
`784 • The Theory and Practice of Industrial Pharmacy
`
`dation, found that when boric acid was added to
`the solution, a marked stabilization of epineph-
`rine took place. 60 They postulated that this stabi-
`lizing effect of boric acid was due to chelate for-
`mation between boric acid and the catechol
`grouping of epinephrine.
`The epinephrine is able to form a one-to-one
`chelate through its dihydroxy structure, as fol-
`lows:
`
`In the presence of boric acid, the rate of sulfite
`attack is reduced as the hydrogen ion concentra-
`tion decreases. The ha1f-life for epinephrine
`under the reaction conditions at pH 6.0 in the
`absence of boric acid was found to be 195 hours,
`whereas in the presence of boric acid, the ha1f-
`life was found to be 267 hours. At pH 7.5, how-
`ever, the ha1f-life of epinephrine was found to be
`74 hours in the absence of boric acid and 1,270
`hours in its presence. It was postulated that epi-
`nephrine is increasingly chelated by the boric
`acid molecules as the pH is made more alkaline,
`and that the chelated epinephrine is far less sus-
`ceptible to sulfite attack than free epinephrine.
`The effectiveness of antioxidants can be en-
`hanced through the use of synergists such as
`chelating agents.
`Chelating Agents. Chelating agents. tend to
`form complexes with the trace amounts of heavy
`metal ions inactivating their catalytic activity in
`the oxidation of medicaments. Examples of
`some chelating agents are ethylenediamine tet-
`raacetic acid derivatives and salts, dihydroxy-
`ethyl glycine, citric acid, and tartaric acid.
`pH. It is also desirable to buffer solutions
`containing ingredients that are readily oxidiza-
`ble to a pH in the acid range. This causes an
`increase of the oxidation potential of the system
`with a concurrent increase in stability when oxi-
`dations are catalyzed by hydrogen or hydroxyl
`ions. The pH of optimum stability in the acid
`range, however, must be determined experi-
`·
`mentally for each drug.
`Solvents. Solvents other than water may
`have a catalyzing effect on oxidation reactions
`when used in combination with water or alone.
`
`LUYE1021
`IPR of Patent No. 6,667,061