`and Practice of Industrial
`Pharmacy
`
`LEON LACHMAN, Ph .D.
`Lachman Consultant Services, Inc.
`Gru:den 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.& FEB I GER· 1986 ·PHILADELPHIA
`
`DRL - EXHIBIT 1013
`DRL001
`
`
`
`Lea & Febiger
`600 Washington Square
`Philadelphia, PA 19106-4198
`u:s.A.
`(215) 922-1330
`
`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. Pha1macy.
`2. Drug trad~.
`1929-
`II. Liebe1man, Herbert A., 1920-
`I!I. Kanig, Joseph L., 1921-
`[DNLM: 1. Drug
`Industry.
`QV 704 T396)
`615'.19
`RS192.L33 1985
`ISBN 0-8121-0977-5
`
`84-27806
`
`First Edition, 1970
`Second Edition, 1976
`
`Copy1ight © 1986 by Lea & Febiger. Copyright under the
`Intemalional Copyright Union. AIJ Rights Reserved. This
`book is protected by copyiight. No part of it may be repro(cid:173)
`duced in any manner or by any means without written per(cid:173)
`mission from the publisher.
`
`PRINTED IN THE UNITED STATES OF AMEl\ICA
`
`P1int No. 4 3 2 1
`
`DRL - EXHIBIT 1013
`DRL002
`
`
`
`Contents
`
`Section I. Principles of Pharmaceutical Processing
`1. Mixing
`3
`EDWARD G. RIPPIE
`2. Milling
`21
`EUGENE L. PARROT
`3. Drying
`47
`ALBERT S. RANKELL, HERBERT A. LIEBERMAN, ROBERT F. SCHIFFMANN
`4. Compression and Consolidation of Powdered Solids
`66
`KEITH MARSHALL
`5. Basic Chemical Principles Related to Emulsion and Suspension
`Dosage Forms
`100
`STANLEY L. HEM, JOSEPii R. FELDKAMP, .JOEL. WHITE
`6. Pharmaceutical Rheology
`123
`JOHN H. WOOD
`7. Clartfication and Filtration
`S. CHRAI
`
`146
`
`Section II. Pharmaceutical Dosage Form Design
`8. Preformulation
`1 71
`EUGENE F. FIESE, TIMOTHY A. HAGEN
`9. Biopharmaceutics
`197
`K.C. KWAN, M.R. DOBRINSKA, J.D. ROGERS, A.E. TILL, K.C. YEH
`10. Statistical Applications in the Pharmaceutical Sciences
`SANFORD BOLTON
`
`243
`
`Section III. Pharmaceutical Dosage Forms
`11. Tablets
`293
`GILBERT S. BANKER, NEIL R. ANDERSON
`12. Tablet Coating
`346
`JAMES A. SEITZ, SHASHI P. MEHTA, JAMES L. YEAGER
`
`xi
`
`DRL - EXHIBIT 1013
`DRL003
`
`
`
`374
`
`398
`
`412
`
`374
`13. Capsules
`Part One Hard Capsules
`VAN B. HOSTETLER
`Part Two Soft Gelatin Capsules
`J.P. STANLEY
`Part Three Microencapsulation
`J.A. DAKAN
`"14. Sustained Release Dosage Forms
`NICHOLAS G. LORDI
`15. Liquids
`457
`J.C. BOYLAN
`479
`16. Pharmaceutical Suspensions
`NAGIN K. PATEL, LLOYD KENNON*, ll. SAUL LEVINSON
`17. Emulsions
`502
`MARTIN M. RIEGER
`18. Semisolids
`534
`BERNARD IDSON, JACK LAZARUS*
`19. Suppositories
`564
`LARRY J. COBEN, HERBERT A. LIEBERMAN
`20. Pharmaceutical Aerosols
`589
`JOHN J. SCIARRA, ANTHONY J. CUTIE
`21. Sterilization
`619
`KENNETH E. AVIS, MICHAELJ. AKERS
`22. Sterile Products
`639
`KENNETH E. AVIS
`
`430
`
`,-
`681
`
`Section IV. Product Processing, Packaging, Evaluation , and
`Regulations
`23. Pilot Plant Scale-Up Techniques
`SAMUEL HARDER, GLENN VAN BUSKIRK
`24. Packaging Materials Science
`711
`CARLO P. CROCE, ARTHUR FISCHER, RALPH H. TI-IOMAS
`25. Production Management
`733
`J.V. BATTISTA
`760
`26. Kinetic Principles and Stability Testing
`LEON LACHMAN, PATRICK DELUCA, MICHAEL J. AKERS
`27. Quality Control and Assurance
`804
`LEON LACHMAN, SAMIR A. HANNA, KARL LIN
`28. Drug Regulatory Affairs
`856
`·
`WILLIAM R. PENDERGAST, RAYMOND D. MCMURRAY*
`
`INDEX
`
`883
`
`•oeceased.
`
`x:l1 • Contents
`
`DRL - EXHIBIT 1013
`DRL004
`
`
`
`3 ·
`
`Drying
`
`ALBERT S. RAN KELL, HERBERT A. LIEBERMAN,
`and ROBERT F. SCHIFFMANN
`
`There is hardly a pharmaceutical plant engaged
`in the manufacture of tablets or capsules that
`does not contain dryers. Unfortunately, the op(cid:173)
`eration of drying is so taken for granted that ef(cid:173)
`forts for achieving increased efficiency in the
`production of tablets do not include a stuqy of
`drying. This chapter introduces the industrial
`pharmacist to the theory and fundamental con(cid:173)
`cepts of drying.
`Definition. For the purpose of this discus(cid:173)
`sion, drying is defined as the removal of a liquid
`from a material by the application of heat, and is
`accomplished by the transfer of a liquid from a
`surface into an unsaturated vapor phase. This
`definition applies to the removal of a small
`amount of water from moisture-bearing table
`salt as well as to the recovery of salt from the sea
`by evaporation. Drying and evaporation are dis(cid:173)
`tinguishable merely by the relative quantities of
`liquid removed from the solid.
`There are, however, many nontherrnal meth(cid:173)
`ods of drying, for example, the expression of a
`solid to remove liquid (the squeezing of a wetted
`sponge), the extraction of liquid from a solid by
`use of a solvent, the adsorption of water from a
`solvent by the use of desiccants (such as anhy(cid:173)
`drous calcium chloride), the absorption of mois(cid:173)
`ture from gases by passage through a sulfmic
`acid column, and the desiccation of moisture
`from a solid by placing it in a sealed container
`with a moisture-removing material (silica gel in
`a bottle).
`Purpose. Drying is most commonly used in
`pharmaceutical manufacturing as a unit process
`in the preparation of granules, which can be dis(cid:173)
`pensed in bulk or converted into tablets or cap(cid:173)
`sules. Another application is found in the proc(cid:173)
`essing of materials, e.g., the preparation of dried
`aluminum hydroxide, the spray drying of lac(cid:173)
`tose, and the preparation of powdered extracts.
`Drying also can be used to reduce bulk and
`
`weight, thereby lowering the cost of transporta(cid:173)
`tion and storage. Other uses include aiding in
`the preservation of animal and vegetable drugs
`by minimizing mold and bacterial growth in
`moisture-laden material and facilitating commi(cid:173)
`nution by making the dried substance far mor~
`friable than the original, water-containing drug.
`Dried products often are more stable than
`moist ones, as is the case in such diverse sub(cid:173)
`stances as effervescent salts, aspirin, hygro(cid:173)
`scopic powders, ascorbic acid, and penicillin.
`The drying reduces the chemical reactivity of
`the remaining water, which is expressed as a ·
`reduction in the water activity of the product.
`Various processes for the removal of moisture
`are used in the production of these materials.
`After the moisture is removed, the product is
`maintained at low water levels by the use of
`desiccants and/or low moisture transmission
`packaging materials. The proper application of
`drying
`techniques and moisture-protective
`packaging requires a lqiowledge of the theory of
`drying, with particular reference to the concept
`of equilibrium moisture content.
`
`Psychrometry
`A critical factor in drying operations is the
`vapor-carrying capacity of the air, nitrogen, or
`other gas stream passing over the drying mate(cid:173)
`rial. This carrying capacity detf'.rmines not only
`the rate of drying but also the extent of drying,
`i.e., the lowest moisture content to which a
`given material can be dried. The determination
`of the vapor concentration and carrying capacity
`of the gas is termed psychrometry. The air(cid:173)
`water vapor system is the system most com(cid:173)
`monly employed in pharmaceutical drying oper(cid:173)
`ations and
`is
`therefore
`included
`in
`this
`discussion.
`The concentration of water vapor in a gas is
`
`47
`
`DRL - EXHIBIT 1013
`DRL005
`
`
`
`called the humidity of the gas. Humidity may be
`expressed in various ways, depending on the
`information required. A knowledge of humidity
`is necessary, therefore, to understand the basic
`principles of drying.
`PsychrometJ.ic Chart. The humidity char(cid:173)
`acteristics of air are best shown graphically in a
`1Jsychrometric or humidity chart. Such charts
`can be found in vaiious handbooks. 1
`2 The psy(cid:173)
`·
`chrometric chart has a formidable look because
`
`of Lhe wealth of information presented in a small
`area. If the different curves in the chart are sep(cid:173)
`arated and analyzed individually, however, their
`utility and ease of use becomes apparent.
`The basic curves of the psychrometlic chart
`are shown in a simplified version in Figµre 3-1.
`These curves are graphic representations of the
`relationship between the temperature and hu-
`. midity of the air-water vapor system at constant
`pressure. The temperature is shown in the hori-
`
`---------- 185 -... ...
`
`- - - - --
`
`~
`h ...
`161 ~
`"1::9
`r:
`::s
`~
`~
`.........
`...
`~ ...
`~
`&:
`4IO r: ... c:.i ...
`
`~ ....._
`;;..c
`e.-.
`.....
`~ .....
`~
`i:;)
`=::
`~ e.-.
`- -- 62
`i:;)
`..,;i
`-- -- - - -- 53 c
`I
`I
`
`99
`
`78
`
`fl)
`CCl
`~
`
`- -
`
`81 85
`50 54 60 67
`150
`DRY-BULB TEMPERATURE (°F)
`FIG. 3-1. Diagram of psychrametric chart showing the relationship of air temperature to /tumidity.
`
`48 • The Theory and Practice of Industrial Pharmacy
`
`DRL - EXHIBIT 1013
`DRL006
`
`
`
`dW/d8 = k' A(Hs - Hg)
`
`(2)
`
`where dW/d8 is the rate of diffusion expressed
`as pounds of water per hour; k' is the coefficient
`of mass transfer [pounds of water/(hour) (square
`foot) (absolute humidity difference)]; A is the
`area of the evaporating surface in square feet; H5
`is the absolute humidity at the evaporating sur(cid:173)
`face (pounds of water per pound of d.ry air); and
`Hg is the absolute humidity in the passing air
`stream (pounds of water per pound of dry air).
`The coefficient of mass transfer, k', is not a
`coristant, but varies with the velocity of the air
`stream passing over the evaporating surface.
`The relationship is in the form:
`
`(3)
`
`where c is a proportionality constant, G is the
`rate of flow of air [pounds of dry air/(hour)
`(square foot)], and n is a fractional exponent,
`usually about 0.8.2
`After an initial period of adjustmep.t, the rate
`of evaporation is equal to the rate of diffusion of
`vapor, and the rate of heat transfer [equation
`(1)) can be equated with the rate of mass trans(cid:173)
`fer [equation (2)], or:
`
`dW/d8 = q/A = k'A(Ha - Hg).
`
`(4)
`
`If the overall rate of heat transfer, q, is ex(cid:173)
`pressed as the sum of the rates of heat transfer
`by convection, radiation, anti conduction, equa(cid:173)
`tion (4) is expanded ~o the form:
`
`dW/d8 = (qc +qr+ qJ/A
`= k' A(Hs - Hg)
`
`(5)
`
`where qc, g,, and qk are the rates of heat transfer
`by convection, radiation, and conduction, re(cid:173)
`spectively.
`The rate of drying may be accelerated by in(cid:173)
`creasing any of the individual terms in equation
`(5). The rate of convection heat transfer, gc, can
`be increased by increasing the air flow rate and
`by raising the inlet air temperature. The rate of
`radiation heat transfer, q .. can be speeded up by
`introducing a high-temperature radiating heat
`source into the drying chamber. The rate of con(cid:173)
`duction heat transfer, qk> can be stepped up by
`reducing the thickness of the material being
`dried and by allowing it to come in contact with
`raised-temperature surfaces. Increasing the air
`velocity also speeds up the rate of drying by in(cid:173)
`creasing the coefficient of mass transfer, k', as
`
`shown in equation (3). Dehumidifying the inlet
`air, thus increasing the humidity differential,
`(Hs - Hg), is still another means of speeding up
`the rate of drying.
`Rapid drying may also be accomplished
`through the application of a microwave or die(cid:173)
`lectric field. In this case, heat is generated inter(cid:173)
`nally by the interaction of the applied electro(cid:173)
`magnetic field with the solvent. Mass transfer
`results from an internal pressure gradient estab(cid:173)
`lished by the internal heat generation, while the
`mass concentration remains relatively uniform.
`The drying rate, then, prima1ily depends on the
`strength of the field applied to the material.
`The utility of equation (5) in actual practice
`can be demonstrated by the following analysis:
`What is the effect of heating the air in a dryer to
`150°F if the outside air is 81°F with 50% relative
`humidity? From the psychrometric chart (Fig.
`3-1 ), it can be seen that for ambient air at this
`condition (point A), the absolute humidity is 78
`grains water/pound dry air. Following the wet(cid:173)
`bulb temperature line from this point to the sat(cid:173)
`uration curve (point D) yields an absolute hu(cid:173)
`midity of 99 grains water/pound dry air.
`For the ambient air, the humidity differential
`(H, - HJ is (99 - 78), which is equal to 21
`grains (0.003 pounds) water/pound dry air.
`When this air is heated to 150°F, the absolute
`humidity remains the same, but the relative ·
`humidity is now reduced to 7%, and following
`the new wet-bulb temperature line (85°F) to the
`saturation curve yields a saturation humidity of
`185 grains water/pound dry air. The humidity
`gradient is now 185 - 78, which is equal to 107
`grains (0.0153 pounds) water/pound dry air, an
`increase of fivefold, indicating an increase in
`drying rate of 500% produced by a 69°F rise in
`temperature. In actual practice, the increase in
`drying rate would be even higher because in(cid:173)
`creasing the inlet air temperature would in(cid:173)
`crease k' as well as the humidity gradient. It
`should be noted that this increase in the drying
`rate does not produce a serious increase in the
`temperature of the maierial being dried, because
`the wet-bulb temperature of the l 50°F air is only
`85°F.
`The foregoing discussion holds true as long as
`there is a film of moisture on the smface of the
`material being d1ied. When the smface becomes
`partially or completely dry, the heat and mass
`transfer equations become more complex. In
`this case, the rate of drying is controlled by the
`rate of diffusion of moisture from the interior of
`the material. This diffusion is greatly influenced
`by the molecular and capillary structure of the
`solid. The process becomes further complicated
`when the drying surface caus~s a sh1inkage of
`
`onYING . 51
`
`DRL - EXHIBIT 1013
`DRL007
`
`
`
`FIG. 3-6. Tray dryer. (Courtesy of the Proctor and
`Schwartz Company.)
`
`formed in a moving belt dryer. Batch drying is
`used extensively in the manufacture of pharma(cid:173)
`ceuticals for several reasons: (1) Each batch of
`material can be handled as a separate entity. (2)
`The batch sizes of the pharmaceutical industry
`are relatively small (500 or less pounds per
`batch) compared with the chemical industry
`(2000 or more pounds per hour). (3) The same
`equipment is readily adjusted for use in drying a
`wide variety of materials.
`Tray dryers may be classified as direct or indi(cid:173)
`rect. Most tray dryers used in the pharmaceuti(cid:173)
`cal industry are of the direct type, in which heat(cid:173)
`ing is accomplished by the forced circulation of
`large volumes of heated air. Indirect tray dryers
`utilize heated shelves or radiant heat sources
`inside the drying chamber to evaporate the
`moisture, which is then removed by either a vac(cid:173)
`uum pump or a small amount of circulated gas.
`Further discussion in this section is confined lo
`the direct (convection-type) dryer. Vacuum dry(cid:173)
`ers are described separately later in the chapter.
`The trays used have solid, pe1forated, or wire
`mesh bottoms. The circulation of drying air in
`trays with a solid base is limited to the top and
`bottom of the pan, whereas in trays with a perfo(cid:173)
`rated screen, the circulation can be controlled to
`pass through each tray and the solids on it. The
`screen trays used in most pharmaceutical drying
`operations are lined with paper, and the air thus
`circulates across rather than through the drying
`material. The paper is used as a disposable tray
`liner to reduce cleaning time and prevent prod(cid:173)
`uct contamination.
`To achieve ,uniform drying, there must be a
`constant temperature and a unifo1m airflow over
`the material being dried. This is accomplished
`in modem dryers by the use of a well-insulated
`cabinet with strategically placed fans and heat(cid:173)
`ing coils as integral parts of the unit. The air
`circulates through the dryer at 200 to 2000 feet
`per minute. The use of adjustable louvers helps
`to eliminate nonuniform airflow and stagnant
`pockets.
`The preferred energy sources for heating the
`
`drying air used on pharmaceutical products are
`steam or electricity. Units fired with coal, oil,
`and gas produce higher temperatures at lower
`cost, but are avoided because of possible product
`contamination with fuel combustion products,
`and explosion hazards when flammable solvents
`are being evaporated. Steam is preferred over
`electricity, because steam energy is usually
`cheaper. If steam is not readily available, and
`drying loads are small, eleclric heat is used.
`Tunnel and Con veyor Dryers. Tunnel dry(cid:173)
`ers are adaptations of the truck dryer for contin(cid:173)
`uous drying. The trucks are moved progressively
`through the drying tunnel by a moving chain.
`These trucks are loaded on one side of the dryer,
`allowed to reside in the heaµng chamber for a
`time sufficiently long to effect the desired dry(cid:173)
`ing, and then discharged at the exit. The op(cid:173)
`eration may be more accurately described as
`sem1cantinuous, because each truck requires
`individual loading and unloading before and
`after the drying cycle. Heat is usually supplied
`by direct convection, but radiant energy also
`may be used.
`Conveyor dryers are an improvement over
`tunnel dryers because they are truly continuous.
`The individual trucks of the tunnel are replaced
`with an endless belt or screen that carries the
`wet material through the drying tunnel. Con(cid:173)
`veyor dryers provide for unintem1pted loading
`and unloading and are thus more suitable for
`handling large volumes of materials.
`The drying curve characteristic of the mate(cid:173)
`rial in batch drying is altered considerably when
`contmuous type c:!Tyers are used. As the mass is
`moved along its drying path in a continuous op(cid:173)
`eration, this mass is subjected to drying air, the
`temperature and humidity of which are con tinu(cid:173)
`ally changing. As a consequence, the "constant
`rate" period is not constant, but decreases as the
`air temperature decreases, although the surface
`temperature of the wetted mass remains con(cid:173)
`stant. Thus, drying rate curves for batch drying
`are not equally applicable to continuous drying
`procedures.
`
`Movin g-Bed Systems
`Turbo-Tray Dryer s. The turbo-tray dryer,
`illustrated in Figure 3-7, is a continuous shelf,
`moving-bed dryer. It consists of a series of rotat(cid:173)
`ing annular trays arranged in a vertical stack, all
`of which rotate slowly at 0.1 to 1.0 rpm. Heated
`air is circulated over the trays by turbo-type fans
`mounted in the center of the stack. Wet mass
`fed through the roof of the dryer is leveled by a
`stationary wiper. After about seven-eighths of a
`revolution, the matelial being dried is pushed
`
`I
`DRYING • 57
`
`DRL - EXHIBIT 1013
`DRL008
`
`
`
`,
`ployed: condensers, desiccants, and pumps. The
`water vapor is removed from the drying chamber
`and condensed in the form of a thin layer of ice
`on a heat-transfer surface in the condenser. The
`ice is removed intermittently by melting it with a
`heated fluid that is circulated through the con(cid:173)
`denser, or in the case of a continuous operation,
`by means of scraper blades. Liquid or solid
`desiccants are often employed in the initial
`vapor removal to enhance the efficiency of the
`pumps removing the water vapor. In general,
`scraper blades and desiccants are used for freeze
`drying large-volume biologicals (e.g., serum,
`penicillin), and usually are not used for prepar(cid:173)
`ing pharmaceutical dosage forms.
`Mic1·owave Drying. The application of mi(cid:173)
`crowave energy to the drying of solids represents
`a radical departure from conventional means of
`drying. Instead of applying heat externally to a
`material, energy in the form of microwaves is
`converted into internal heat by interaction with
`the mate1ial itself. This pe1mits extremely rapid
`heat transfer throughout the material, which in
`tum can lead to rapid drying.
`The heating effect is produced by the interac(cid:173)
`tion of a rapidly oscillating electric field (915 or
`2450 megahertz) with the polarized molecules
`and ions in the mate1ial. The field imposes order
`on otherwise randomly oriented molecules. As
`the field reverses polaiity, it relaxes and allows
`the molecules to retum to their random orienta(cid:173)
`tion, giving up stored potential energy as ran(cid:173)
`dom kinetic energy, or heat. The interaction of
`the alternating field with ions causes billiai·d(cid:173)
`ball-like collisions with un-ionized molecules,
`and the impact energy is converted into heat.
`A given material's moleculai· and
`ionic
`makeup intimately affects its ability to be dried,
`as is shown in the power conversion equation for
`microwave heating:9
`
`(9)
`
`where: P = the power developed,
`(watts/unit volume)
`k = a constant
`f = the frequency
`E = the electric field strength,
`(volts/unit distance)
`e' = the relative dielectric constant
`of the material being heated
`tan 8 = the loss tangent, or dissipation
`factor of the material
`€' = the loss factor of the material,
`equal to the product e' tan 8
`
`64 • The Theo1y and Practice of Industrial Pharmacy
`
`In microwave drying, the mass transfer is pri(cid:173)
`maiily the result of a pressure gradient due to
`rapid vapor generation inside the material, that
`is, most of the internal moisture is vap01ized be(cid:173)
`fore leaving the sample. Thus, the moisture is
`mobilized as a vapor rather than a liquid, and its
`movement to the1suiface can be exu·emely rapid
`because it does not depend on mass concentra(cid:173)
`tion gradients or on slow liquid diffusion rates.
`Industrial microwave dryers are usually of the
`static bed continuous type. Materials to be dried
`are placed on conveyor belts and conveyed
`through the microwave applicator. Generally, a
`stream of hot air is used simultaneously with the
`microwaves to sweep away the moisture evolv(cid:173)
`ing from the surface of the mate1ial being dried.
`Often, the microwave treatment is used in the
`last stages of hot air drying (the second falling
`rate period of Fig. 3-3) to remove the last re(cid:173)
`maining portion of the solvent, reducing total
`drying time by 50% or more.
`Microwave drying can be used for the drying
`of pharmaceutical materials at low ambient tem(cid:173)
`peratures, avoiding high surface temperatures,
`case hardening, and solute migration. Micro(cid:173)
`wave vacuum drying at low pressure (1 to
`20 mm Hg) and moderate temperature (30 to
`40'C) can be used for drying the1molabile mate(cid:173)
`rials such as vitamins, enzymes, proteins. and
`flavors.
`The iising cost of energy has generated a great
`deal of interest in microwave drying. The micro(cid:173)
`waves couple directly into the solvent, and no
`energy is used to heat the air, the walls of the
`dryer, the conveyor, or the trays. This results in
`extremely efficient energy utilization, and en(cid:173)
`ergy savings of as much as 70% have been real(cid:173)
`ized in industrial installations.
`
`References
`1. Zimmerman, 0. T., and Lavine, I.: Psychrometric
`Charts and Tables. Industrial Research Service, Dover,
`NH, 1945.
`2. Perry, R.H., and Green, D. W. : Perry's Chemical Engi(cid:173)
`neers' Handbook. 6th Ed. McGraw-Hill, New York,
`1984.
`3. Bone, D. P.: Food Prod. Devel., 3:81, 1969.
`4. Callahan, J.C., et al.: Drug Devel. and Industrial Phar(cid:173)
`macy, 8:355, 1982.
`5. Rockland, L. B., and Nishi, S. K.: Food Technol.,
`34:42, 1980.
`6. Scott, M. W., et al.: J. Phann Sci., 52:284, 1963.
`7. Kuelling, W., and Simon, E. J.: Pharm. Technol. Int.,
`3:29, 1980.
`8. Nuernberg, E.: Acta Phann. Technol., 26:39, 1980.
`9. Lyons, D. W., and Hatcher, J. D.: J. Heat Mass n·ans·
`fer, 15:897, 1972.
`
`DRL - EXHIBIT 1013
`DRL009
`
`
`
`Pharmaceutical Rheology
`
`JOHN H. WOOD
`
`6
`
`Pharmaceutical fluid preparations are recog(cid:173)
`nized as materials that pour and flow, having no
`ability to retain their original shape when not
`confined. The semisolids are a more nebulous
`gxouping. They essentially xetain their shape
`when unconfined but flow or deform when an
`external force is app'fi.ed. Those materials that
`readily pour from bottles and form a puddle are
`clearly fluids. Ointments or pastes that clearly
`retain their shape after extrusion from a tube
`characteristically arn associated with pharma(cid:173)
`ceutical semisolids. Obviously a continuum of
`properties exists between these limits.
`Rheology (from the Greek rheos meaning flow
`and logos meaning science) is the study of the
`flow or deformation under stress. In pharmaceu(cid:173)
`tical and allied re~earch aml lechnology, rheo(cid:173)
`logic measurements are utilized to characterize
`the ease of pouring from a bottle, squeezing from
`a tube or other defonnable container, maintain(cid:173)
`ing product shape in ajar or after extrusion, rub(cid:173)
`bing the product onto and into the skin, and
`even pumping the product from mixing and
`storage to filling equipment. Of extreme impor(cid:173)
`tance in both product development and quality
`assurance is the determination that the desired
`attributes of body and flow are retained for the
`required shelf-life of the product.
`
`Definitions and Fundamental
`Concepts
`The tangential application of a force to a body
`and the resultant deformation of that body are
`the essential components for a rheologic obser(cid:173)
`vation. If this force is applied for only a short
`time and then withdrawn, the deformation is
`defined as elastic if the shape is restored, but as
`fl.ow if the defo1mation remains. A fluid or liquid
`then becomes a body that flows under the action
`
`of an infinitesimal force. In practice, gravity is
`generally regarded as the criterion of such a
`minimal force.
`To best understand the fundamental compo(cid:173)
`nents of viscous flow, consider Figure 6-1. Two
`parallel planes are a distance x apart; between
`the planes, the viscous body is confined. The
`top, plane A, moves horizontally with velocity v
`because of the action of force F. The lower
`plane B is motionless. As a consequence, there
`exists a velocity gradient v/x between the planes.
`This gradient is given the definition of rate of
`shear, D. The shear stress, S, is the force per unit
`area creating the deformation.
`Example 1. If some oil is rubbed into the skin
`with a relative rate of motion between the two
`surfaces of 15 cm/sec, and the film thickness is
`0.01 cm, then the shear rate is as follows:
`
`0 = 15 cm/sec
`cm
`0.01
`= 1500 seC-1
`
`This shear stress may be applied either mo(cid:173)
`mentarily or continuously. Elastic deformation
`occurs if, as the force is applied, the upper plate
`moves in the direction of the force only momen(cid:173)
`tarily and then stops but returns to its original
`position when the deforming force is removed.
`On the other hand, pure viscous flow occurs if
`there is continuous movement dming the ap(cid:173)
`plied force, and no restoxative motion follows
`removal of the deforming force.
`Between the limits of elastic deformation and
`pure viscous flow, there exists a continuum of
`combinations of these limits. Such behavior is
`called viscoelastic flow. The elastic component
`of viscosity is considered in a later section.
`Newtonian (7.uid is a fluid in which a -direct
`
`123
`
`DRL - EXHIBIT 1013
`DRL010
`
`
`
`A (Mobile}
`
`
`
`__ _ __ _ __ _ , , , ___ _
`
`F (Force)
`, ,
`/'
`l ~- -t'---
`i·- Ov/dx _____ _
`. ---------
`1'1. !- --------
`. -------(cid:173)
`' --------
`" Velocity= o
`
`FIG. 6-1. Model to demonstrate components of classic vis·
`COll.S flaw.
`
`proportionality exists, for all values of shear, be(cid:173)
`tween shear stress and shear rate.
`Viscosity or coefficient of viscosity is the pro(cid:173)
`portionality constant between shear rate and
`sheai- stress. Conventionally, viscosity is repre(cid:173)
`sented by 'Tl· Then:
`
`'Tl= SID
`
`(1)
`
`The centimeter-gram-second (C.G.S.) sys(cid:173)
`tem uses grams per centimeter per second
`(g cm- 1 sec- 1) as the dimensional units of vis(cid:173)
`cosity. In these units, viscosity is expressed in
`poises, a term used in recognition of the pioneer(cid:173)
`ing work in the 1840s of the French scientist
`J. L. M. Polseuille. For dUul~ ayueous solutions
`2
`the common unit becomes the centipoise (lo(cid:173)
`poise), cp. The viscosity of water is about 1 cp.
`In the newly adopted International System of
`Units (SI), the unit conesponding to the centi(cid:173)
`poise is the millipascal-second (mPas).
`A perspective of these units may be obtained
`by considering the case of Figure 6-1 when a
`force of 1 dyne acts to produce a velocity of
`1 cm/sec for plate A when the distance between
`plates is 1 cm, and both plates are 1 cm2 in
`cross-sectional area. Under these terms, viscos(cid:173)
`ity is calculated as:
`s
`'T/ = -D
`force/area
`= - -----,..-----------
`velocity difference/distance
`dyne/cm2
`(cm/sec)/cm
`= dyne sec cm - 2
`
`124 · The Theon1 and Practice of Industrial Pharmacy
`
`However, the dyne is the force acting for 1 sec to
`produce a velocity in a 1-g mass of 1 cm/sec.
`Hence, this dimensional analysis for viscosity
`reduces to:
`
`'Tl = g · cm- 1 sec- 1
`= poise
`
`In the International System of Units, which is
`not yet used routinely in viscosity references,
`the pascal (Pa) is the unit of stress and has the
`dimensions of newton/meter2 , where the new(cid:173)
`ton is a kilogram meter/second2
`. Hence, equiva(cid:173)
`lence occurs for the centipoise with millipascal(cid:173)
`seconds.
`Example 2. If in example 1, the oil had the
`same viscosity as water, then the force used to
`create the shear can be determined as follows:
`s
`'T]=-D
`
`1 x 10- 2 poise= _S_ sec-1
`1500
`
`Then S = (1500)(1 x 10- 2)(seC 1~(poise)
`= 15 (sec1)(dyne sec cm- )
`= 15 dyne cm- 2
`
`Example 3. In SJ. units, the above terms
`would become :
`
`'Tl = 1 mPas
`D = 1500 sec- 1
`S = 1.5 Pa
`
`Fluidity is the reciprocal of the viscosity, usu(cid:173)
`ally designated by the symbol <f>. This is an occa(cid:173)
`sional unit of convenience but not an essential
`one.
`Kinematic viscosity ( v) is the Newtonian vis(cid:173)
`cosity divided by density (TJ/d). The unit is now
`the stoke, in honor of the English scientist who
`studied problems of gravitational settlement in
`fluids. As discussed later in this chapter, certain
`fluid flow viscometers give values in this kine!!)
`matic scale.
`Example 4. If the oil from examples 1 and 2
`had a density of 0.82, then the kinematic viscos(cid:173)
`ity would be:
`1J = .!L
`d
`1 x 10- 2
`= -- - -
`0.82
`= 1.22 x 10- 2 stokes
`= 1.22 centistokes
`
`DRL - EXHIBIT 1013
`DRL011
`
`
`
`Non-newtonian fluids are those in whiCh there
`is no direct linear relationship between shear
`stress and shear rate. Most systems of pharma(cid:173)
`ceutical interest fall into this category. The
`shear stress necessary to achieve a given shear
`rate may increase more rapidly or less rapidly
`than is required by the linear direct proportion(cid:173)
`ality (Fig. 6-2).
`A pseudoplastic material is one in which the
`stress increases at less than a linear rate with
`increasing shear rate, while a dilatant material
`is one in which the increase is more rapid. Thus,
`if viscosity is calculated at each of a series of
`sh ear rate points by use of equation (1), then the
`resultant values decrease with increasing shear
`rate for pseudoplastic materials and increase for
`dilatant ones. Measurements at such single
`points are frequently referred to as apparent vis(cid:173)
`cosit;y to recognize clearly tl1at the number
`quoted refers only to the condition of measure-
`
`yield
`value
`
`A
`
`8
`
`c
`
`VII
`
`"' ... -...
`VII -c ... ::z:
`
`VII
`
`SHEA R RATE
`FIG. 6-2. &;_amples of basic types ofrheograms. A, Pseu(cid:173)
`doplastic or power law; B, Newtonian; C, dilatant; D, pseu(cid:173)
`doplastic with yield value; E, Bingham or Newtonian with
`yield value; F, dilatant with yield value.
`
`ment. Aliliough frequently, reference is cru:e(cid:173)
`lessly made to a lotion having a Viscosity of
`300 cp or to a paste or ointment having a viscos(cid:173)
`ity of 1200 poises, these are meaningless terms
`unless the shear rate at which the measurement
`was made becomes a clear part of the statement.
`The fact that one number cannot characterize
`ilie viscous behavior, however, requires the use
`of some equation of state. One such empiric one
`is the Power Law Equation:
`
`(2)
`
`where S and D are the shear stress and shear
`rate respectively, A is an appropriate proportion(cid:173)
`ality constant, and n is the Power Index. In this
`form,