theory of
`pharmaceutical
`systems
`
`J. THUR0~STENSEN
`UniversUy of Wisconsin
`Madison, Wisconsin
`
`VOLUME II
`Heterogeneous Systems
`
`ACADEMIC PRESS New York and London 1973
`
`1831.03
`
`DRL - EXHIBIT 1014
`DRL001
`
`

`
`COPYRIGHT© 1973, BY ACADEMIC PRESS, JNC.
`ALL RIGHTS RESERVED.
`NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
`TRANSMITIED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
`OR MECHANICAL, lNCLUDTNG PHOTOCOPY, RECORDING, OR ANY
`INFORMATION STORAGE AND RETRI EVAL SYSTEM, WITHOUT
`PERMISSION IN WRITING FROM THE PUBLISHER.
`
`ACADEMIC PRESS, INC.
`111 Fifth Avenue, New York, New York 10003
`
`United Kingdom Edition published by
`ACADEMIC PRESS, INC. (LONDON) LTD.
`24/28 Oval Road, London NWl
`
`LIBRARY OF CONGRESS CATALOG CARD NUMBER: 72-82630
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`DRL - EXHIBIT 1014
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`
`

`
`contents
`
`Preface
`Co11tents of Volume I
`
`1 DISPERSE SYSTEMS
`
`List of Symbols
`1-1 Suspensions
`1-2 Preparation of a Batch of Suspension
`1-3 Stokes's Law
`1-4 Application of Stokes's Law
`1-5 Particle Size Distribution
`1-6 Determination of Particle Size D istributions
`1-7 Density Matching
`1-8 Sedimentation
`1-9 Flocculated Suspensions
`1-10 Rheology of Suspensions
`1-11 Yield Diameter
`1-12 Absolute Yield Values
`1-13 Zeta Potential and Influence of Solutes on Suspensions
`1-14 Rate of Aggregation
`1-15 Comminution and Deaggregation
`1-16 Adsorption
`1-17 Chemical and Physical Stability of Suspensions
`1-18 Parenteral Suspensions
`
`xi
`xiii
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`2
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`vii
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`viii
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`CONTENTS
`
`1-19 Emulsions and Partial Miscibility
`1-20 Distribution Coefficient
`1-21 Surface Tension
`1-22 Ingredients
`1-23 Preparation of an Emulsion
`1-24 Classification of Emulsions
`1-25 Emulsifiers: The HLB System
`1-26 Appearance of Emulsions
`1-27 "Breaking and Creaming
`1-28 Homogenization
`1-29 Phase Volume Ratio
`1-30 Flocculation and Coalescence
`1-31 Rheology
`1-32 Newtonian Flow
`1-33 Electroviscous Effects
`1-34 Pseudoplasticity
`1-35 Particle Size Determination
`1-36 Effect of Particle Size on Viscosity
`1-37 Release of Active Ingredients
`1-38 Globule Shape
`References
`
`2 FUNDAMENTAL PROPERTIES OF THE SOLlD STATE
`
`List of Symbols
`2-1 Chemical Bonding in Solids
`2-2 Ionic Crystals
`2-3 Van der Waals Bonding
`2-4 Covalent Crystals
`2-5 Hydrogen Bonding
`2-6 Polarization Bonding
`2-7 The. Crystal Systems
`2-8 Phase Diagrams
`2-9 Transformations and Order- Disorder Concepts
`2-10 Polymorphism
`2-11 Availability and Polymorphism
`2-J 2 Pseudopolymorphism and Solvates
`2-13 Physical Formulation Considerations and Polymorphism
`2-14 Hydrates
`2-15 Dislocations
`2-16 Lattice Defects
`2-17 Crystalliza lion
`2-J 8 Nucleation
`2-19 Heterogeneous Nucleation
`2-20 Rate of Crystal Growth
`2-21 The Dissolution Process
`2-22 Effect of Agitation on Crystal Growth
`2-23 Effect of Additives on Crystal Growth
`2-24 Crystal Habit
`
`59
`62
`63
`66
`67
`68
`68
`71
`72
`73
`74
`74
`76
`76
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`84
`
`90
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`93
`98
`99
`101
`103
`103
`105
`111
`113
`120
`122
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`124
`128
`130
`132
`133
`135
`135
`136
`142
`144
`147
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`CONTENTS
`
`2-25 Surface Areas of Solids
`2-26 Adsorption of G~ses on 8oli<ls
`2-27 Thermal Methods
`References
`
`3 POWDERS
`
`Lisl of Symbols
`3-1 Degree of Mixing
`3-2 Multicomponent Systems
`3-3 Powders
`3-4 The Mixing Process
`3-5 Mixing Parameters
`3-6 Segregation
`3-7 Number of Particles in Dosage Forms
`3-8 Angle of Rep_ose
`3-9 Flow Rates
`3-10 Glidants
`3-11 Flowability and Aging
`3-12 Friction and Interparticular Forces
`3-13 Packing Parameters
`3-14 Compactability
`3-J 5 Fluidized Powders
`3-16 Shape Factor
`3-17 Parenteral Powders
`References
`
`4 SOLID DOSAGE FORMS
`
`List of Symbols
`4-1 Tablets
`4-2 Granulations
`4-3 Drying from Beds
`4-4 Flu id Bed Drying
`4-5 Psychrometric Charts
`4-6 Milling of Granulations
`4-7 Strength of Granulations
`4-8 Direct Compression
`4-9 Flow and Compression
`4-10 Instrumented Tablet Machines
`4-11 Solids Behavior under Compression
`4-12 Die Wall Pressure
`4-13 Bonding during Compression
`4-14 Hardness of Tablets
`4-15 Tablet Defects
`4-16 Friability
`4-17 Optimization
`
`ix
`
`147
`149
`154
`158
`
`164
`165
`168
`169
`170
`172
`173
`176
`180
`186
`192
`194
`194
`207
`210
`211
`211
`213
`215
`
`220
`221
`223
`224
`230
`233
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`238
`240
`241
`244
`247
`249
`250
`251
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`254
`255
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`x
`
`CONTENTS
`
`4-18 Uniformity of Tablets
`4-19 Heat of Compression
`4-20 Disintegration of Tablets
`4-21 Dissolutiqn Rates
`4-22 Effect of Porosity
`4-23 Tablet Coating
`4-24 Wurster Coating
`4-25 Enteric Coats
`4-26 Compression-Coated Tablets
`4-27 Hard-Shell Gelatin Capsules
`4-28 Soft-Shell Capsules
`4-29 Sustained-Release Pellets
`Bibliography
`References
`
`5 STABILITY IN THE SOLID STATE
`
`List of Symbols
`5-1 Chemical Stability of Solids and Solid Dosage Forms
`5-2 Drugs per se
`'
`5-3 Decomposition Producing Nonreactive Degradation Products
`5-4 The Liquid Layer Theory
`5-5 Equilibria in Crystalline Compounds
`5-6 Decompositions Involving Gaseous Reaction Products
`5-7 Contracting Cube Equation
`5-8 Systems with Decompositions in Condensed Form
`5-9 Decompositions Involving Water Vapor
`5-10 Decompositions Involving Oxygen
`5-11 Reactivity Involving Gases in General
`5-12 Photolysis of Pure Compounds
`5-13 Solid-~olid Interactions
`5-14 Solid Dosage Forms
`5-15 Reaction Order
`5-16 Equilibria
`5-17 Equilibria Involving Adsorption
`5-1 8 Decompositions Involving Moisture
`5-19 Impurity Equilibria
`5-20 Scavenging
`5-21 Solid-Solid Interactions in Dosage Forms
`5-22 Reactions via the Gas Phase
`5-23 pH Effect in Tablets
`5-24 Effects of Pressure
`.5-25 Light Sensitivity of Solid Dosage Forms
`5-26 Compatibility Tests
`5-27 Stability of Appearance
`References
`
`Author Index
`Subject Index
`
`255
`255
`258
`262
`267
`270
`273
`275
`276
`277
`282
`285
`288
`289
`
`294
`295
`296
`297
`300
`303
`304
`3]]
`312
`313
`320
`321
`322
`325
`328
`329
`333
`336
`337
`339
`340
`341
`342
`344
`345
`346
`347
`349
`352
`
`357
`367
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`

`
`1-1 SUSPENSIONS
`Suspensions are by their very nature less elegant dosage forms than solutions
`and as an introduction it may be worthwhile to examine the reason for having
`certain pharmaceutical products in suspension form at all.
`Two main reasons come to mind immediately: solubility and stability.
`In the former case, we are dealing with a drug which is not sufficiently soluble
`in conventially and regulatorily acceptable vehicles (water, sucrose solution,
`alcohol-water, solutions, etc.) to provide the desired dose per one or two
`teaspoons (i.e., per 5 or 10 cc) or per tablespoon (15 cc). In the latter case,
`we are dealing with a substance which is not sufficiently stable in aqueous
`(or other) solution to permit marketing of a solution. By producing a rela(cid:173)
`tively insoluble derivative (salt, ester, etc.) of the compound, only the small
`amount of drug in solution will be subject to deterioration, and overall
`stabilization is therefol'e effected in suspension form. The principle, of course,
`can also be applicable for pharmacokinetic manipulation, prolonging the
`length of time of action. Procaine penicillin G is an example where both
`stability and length of action are achieved by making a poorly soluble
`derivative of an active compound and utilizing suspensions rather than
`solutions as the dosage form.
`·
`Finally, a series of elegant patents by Zentner (1967) has added a new
`aspect to suspension formulation: Many drugs are bitter-tasting, but may
`
`4
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`

`
`1-1 SUSPENSIONS
`
`5
`
`be rendered quite tasteless if adsorbed on montmorillonite clays of various
`natures.
`Details of all types of systems will be dealt with in the following, but it is
`clear at the outset that different storage problems may result in the various
`cases. In a case of a suspension of a poorly soluble derivative of an unstable
`compound, the vehicle will change chemically because the amount of drug
`which is iJJ solution will degrade fairly rapidly, be replenished, further degrade
`and so on, so that this type of system presents further complications.
`We have made the statement that a suspension is less elegant from a
`pharmaceutical point of view than is a solution. The reason for this is that
`suspensions, of course, have a tendency to settle, a point which shall require
`a fair amount of our attention in the following. For this reason, or more
`generally because they are heterogeneous, they carry a "shake well" state(cid:173)
`ment on the label. Even so, failure to shake the bottle on the part of the
`consmner presents the possibility of improper-dosage, and we include this as
`another reason for considering pharmaceutical suspensions as less elegant.
`Here, the pharmacist at the retail level must play the role of educator to
`ensure that the suspension be well shaken by the patient before being taken.
`Aside from the points of view voiced so far, there are at times other con(cid:173)
`siderations that warrant formulating a product as a susp~nsion. A type of
`product may over the years have acquired an image as being of the suspen(cid:173)
`sion type-antacid liquid preparations, for example- and in such circum(cid:173)
`stances there might be marketing reasons for introducing a new product
`as a suspension even though it could also be formulated as a solution.
`From what has been said so far, it would appear that the product develop(cid:173)
`ment chemist or pharmacist musl be well versed in the theory and practice
`of suspension preparations. The role of the industrial pharmacist, be he en(cid:173)
`gaged in productiou or product development, is one of ensuring that the
`final suspension preparation at the time of its use (i.e., at the time of dispens(cid:173)
`ing and subsequent times of pa9ent use) can readily be brought into a state
`where the correct dose is delivered and where (as in the case of other dosage
`forms) other parameters of pharmaceutical elegance are maintained. There(cid:173)
`fore, he must be aware of the principles underlying tht many changes that
`may occur, know how changes can be detected at"an early stage of storage
`or of development, and know how these manifestations can be extrapolated
`and interpreted. This presents one very challenging aspect of product develop.
`ment. The sections to follow will deal with this problem. They will not
`constitute a manual of remedies for possible problems with suspensions,
`but they will help pinpoint problems long before they become severe, and
`hence the text is diagnostic in character rather than curative o.r inventive.
`The topic of suspensions is of interest not only in pharmacy, but in many
`other branches of science, as witnessed by the fact that fundamental theory
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`
`6
`
`1 DISPERSE SYSTEMS
`
`and basic research are treated in a multitude of journals, e.g., J. Pharm. Sci.,
`J. Pharm. Pharmacol., J. Colloid Interface Sci., Ind. Eng. Chem., J. Phys.
`Chem., J. Chem. Phys., and Trans. Soc. Rheol., to mention a few. For practical
`pharmaceutical systems, the former two journals will be our principal litera(cid:173)
`ture source, but frequent reference will be made to the others.
`The term suspension shall be used here for systems containing particles
`larger than 0.1 µm . For systems containing particles exclusively smaller than
`0.1 µm in diameter, the term dispersion shall be used (Hiestand, 1964).
`The question then is: What parameters must the pharmaceutical develop(cid:173)
`ment chemist or pharmacist worry about in the development of a product
`(a) in terms of producing the best formula for a given product, and (b) in
`terms of producing the best formula from a large-scale production point
`of view? It is not intuitively obvious that the two might differ, but an example
`will tend to substantiate this.
`If as criterion we note that a suspension should contain the solid phase in
`a particle size distribution with a number-ave~age particle size of, say, 10 µm,
`then in development of the product we might have arrived at two formulas
`A and B, with A appearing to be the best formula by a certain set of require(cid:173)
`ments. But suppose that the viscosity of the vehicle is high and that suspend(cid:173)
`ing the powder is best accomplished at 50°C, where higher fluidity prevails.
`If, in smaller-scale trials, the powder has simply been suspended at 50°C,
`milled (homogenized), and been incorporated into a premix, and then into
`the remainder over a relatively short span of time, then a representative
`comparison has not been made between formulas A and B since in produc(cid:173)
`tion equipment it may take t hr, not 5 min, to make the premix, it may
`take 1 hr to mill and 1 hr to cool the final blend. If the solubility- temperature
`gradient and the change of the dissolution rate with increased temperature are
`greater in formula A. than in formula B, then the number-average particle
`size might have increased significantly in formula A because the longer
`exposure caused more of the solid to be dissolved (and later to be reprecipi(cid:173)
`tated, increasing particle size) in formula A than in formula B. On a larger
`scale, vehicle B might be more suitable than vehicle A.
`A product development chemist or pharmacist must therefore always have
`intimate knowledge of production cycles, heat transfer data, and production
`habits (scheduling,
`time requirement in multiproduct operation, etc.).
`Knowledge of available large-scale equipment is necessary for good formula-
`1 tion of disperse systems.
`It is obvious that particle size distribution, as mentioned before, is of
`importance, both from the point of view of physical stability and, even more
`importantly, from the clinical point of view. Therefore the industrial pharma(cid:173)
`cists should know the effect of temperature and subsequent cooling times as they
`occur in production before he makes his first preparation in the laboratory.
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`
`1-2 PREPARATION OF A BATCH OF SUSPENSION
`
`7
`
`This is but one example. The task, furthermore, goes beyond the question
`of whether a product may be produced properly; it is also necessary to esti(cid:173)
`mate to as large an extent as possible what may go wrong. To establish a
`product to one manufacturing procedure with set times, temperatures, settings,
`etc. is unrealistic. Every variable should have ranges, and the industrial
`pharmacist should know how his product behaves at the extremes of these
`ranges.
`We have thus seen that there is indeed a need for exhaustive knowledge
`in the field of suspension formulation, and that the task is one of the more
`difficult tasks of pharmaceutical development, requiring not only knowledge
`of physical and chemical principles, but also knowledge to some extent of
`large-scale production. As everything else, it requires, above all, common
`sense.
`In view of the importance of the production aspects of this subject, a short
`description will be devoted to a hypothetical manufacturing procedure for
`I 000 liters of a suspension of a solid drug in a sucrose syrup. The purpose
`here is merely to have a reference in further discussion and to prevent
`ambiguities regarding nomenclature.
`
`1..:2 PREPARATION OF A BATCH OF SUSPENSION
`
`The ingredients in a typical suspension formula are as follows: (a) drug,
`(b) thickener (which retards crystal growth and imparts yield value and
`body), (c) sweetener (noting that sugar in high concentrations is also a
`preservative, thickener, and, occasionally, a chemical stabilizer), ( d) surfac(cid:173)
`tant (e.g., for the purpose of wetting the powder), (e) highly charged ion,
`(f) humectant (for prevention of fap-lock), (g) flavor, (h) buffer, preservative,
`and water.
`The function of some of these ingredients will come under discussion
`
`Table 1-1
`
`Amount
`per 5 cc
`
`Amount
`per 1000 liters
`
`Drug
`Sucrose
`Humectants, gums,
`preservatives,
`flavors, surfactants
`Water q.s. ad
`
`)
`
`50mg
`3000 mg
`
`10 kg
`600 kg
`
`As required
`
`As required
`
`5 cc
`
`1000 liters
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`
`8
`
`1 DISPERSE SYSTEMS
`
`elsewhere, but it should be noted here that the problems which arc to be
`overcome are those involving (a) included air, (b) crystal growth, (c) settling,
`and (d) caking.
`Of these, air inclusion is overcome by te1.;hnical means as shown shortly; ·
`the subject of crystal growth is covered in Chapter 2; the discussion to follow
`will concentrate on settling and caking.
`Table 1-1 gives a rough flow chart of the events leading from raw materials
`to final packaged suspension product. For convenience, a highly simplified
`formula is selected.
`
`COM MINUTE
`
`DRUG
`
`MILLED DRUG
`
`600 kg SUCROSE ""'
`/ HEAT, DISSOLVE
`
`j
`
`300 LITERS WATER
`
`HUME CT ANTS, GUMS
`
`FILTER
`
`LITER
`
`DYES, PRESER(cid:173)
`VATIVES
`
`-+ 300
`
`COOL
`~MILL:
`FLAVORS-i
`DEAERATE
`f
`STRAIN
`
`WATER q.s, ---i
`
`FILL
`t
`
`Fig. 1-1. Flow chart of suspension manufacture.
`
`The flow sheet would have the appearance shown in Fig. 1- l. In this
`simplified scheme, it is noted that the drug itself is first given a suitable
`particle size distribution (comminution step). The suga~· is dissolved in water
`at about 100°C, filtered (e.g., through a filter press using a filter aid), and
`300 liters of it are transferred to a smaller premix kettle and cooled to 50°C.
`The humectants and gums are added to the remainder, which is then cooled
`to 50°C. In the premix kettle, the insoluble drug and (if appropriate) the dyes,
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`
`1-3 STOKES'S LAW
`
`9
`
`preservatives, and surfactants are added, and the premix is milled and then
`returned to the kettle containing the remainder of the vehicle; it is then
`cooled while being agitated. The flavors are worked in at a lower tempera(cid:173)
`ture, the entire suspension is deaerated in vacuo (e.g., through a Versator),
`gross-filtered through a stainless steel plate filter (e.g., Cuno), brought to
`volume under mild but sufficient agitation, and filled under agitation.
`Of course, many modifications can be made to such a scheme, but the
`simple arrangement used here will serve as a point of reference.
`It should be emphasized again that preparing the premix, milling it, and
`transferring it into the main kettle each are operations that .require time.
`It is convenient whenever overviewing a suspension process to make a flow
`chart such as shown in Fig. 1-1. It is a small time investment, but aids in the
`write-up of a procedure, in the analysis of trouble spots, In attempting to
`simplify the flow, and finally in discussions with third ·parties.
`
`1-3 STOKES'S LAW
`
`It is evident that in the case of suspensions, the rate and degree of settling
`would be a subject of investigation for the pharmaceutical development
`chemist. It would be instructive, prior to studying more complex systems,
`to examine the most simple suspension one might conceive of, namely one
`sphere in a bulk solution.
`Taking p as the density of the sphere, p0 the density of the liquid, r the
`radius of the sphere, rt the viscosity of the liquid, v (or v00) the terminal
`constant velocity, and g the gravitational acceleration, then Stokes's law
`(Stokes, 1856) states
`
`2r2(p - Po)g
`Voo =
`917
`
`(1-1)
`
`Stokes's law implies that the larger the diameter of the sphere and the lower
`the Newtonian viscosity of the liquid, the more rapidly the sphere will ultima(cid:173)
`tely fall. We should note, of course~ that there is a restriction on the time t
`in the sense that t must be less than the time required for the sphere to reach
`bottom. Later, we shaU examine the situation after the sphere has reached
`bottom, i.e., the problem of the height of a sediment, involving the so-called
`sedimentation ratio; for this simple system, the sedimentation ratio would
`be given by
`
`H H 0 - vt
`-=
`Bu
`2r
`where H 0 is the height of the cylinder, H u the ultimate height of the sediment
`
`(1-2)
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