`pharmaceutical
`systems
`
`I
`J. THURQI CARSTENSEN
`University of Wisconsin
`
`Madison, Wisconsin
`
`V 0 L U ME I I
`
`Heterogeneous Systems
`
`ACADEMIC PRESS New York and London
`
`1973
`
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`COPYRIGHT © 1973, BY ACADEMIC PRESS, INC.
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`
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`ACADEMIC PRESS, INC. (LONDON) LTD.
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`
`contents
`
`Preface
`Contents of Volume I
`
`1 DISPERSE SYSTEMS
`
`List of Symbols
`1 Suspensions
`-2 Preparation of a Batch of Suspension
`-3 Stokes’s Law
`
`—4 Application of Stokes’s Law
`45 Particle Size Distribution
`-6 Determination of Particle Size Distributions
`-7 Density Matching
`-8 Sedimentation
`-9 Flocculated Suspensions
`10 Rheology of Suspensions
`-11 Yield Diameter
`-12 Absolute Yield Values
`-13 Zeta Potential and Influence of Solutes on Suspensions
`~14 Rate of Aggregation
`-15 Comininution and Deaggregation
`-16 Adsorption
`-1
`7 Chemical and Physical Stability of Suspensions
`-1
`8 Parenteral Suspensions
`
`1 1 1 1 1 1 1 1 1 1 1 1 1 l 1 1 1 1
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`1-19 Emulsions and Partial Miscibility
`1-20 Distribution Coeflicient
`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
`1-311 Rheology
`1-32 Newtonian Flow
`1-33 Electroviscous Effects
`W
`1-34 Pseudoplasticity
`A
`1-35 Particle Size Determination
`1-36 Effect of Particle Size on Viscosity
`1-37 Release of Active Ingredients
`1-38 Globule Shape
`References
`
`CONTENTS
`
`-
`
`I
`
`"
`
`1
`
`'
`
`__
`
`59
`62
`63-
`66
`67
`68
`68
`71
`72
`73
`74
`74
`76
`76
`77
`77
`78
`80
`80
`84
`84
`
`2 FUNDAMENTAL PROPERTIES OF THE SOLID 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
`2-12 Pseudopolymorphism and Solvates
`2-13 Physical Formulation Considerations and Polymorphism
`2-14 Hydrates
`'
`2-15 Dislocations
`2-16 Lattice Defects
`
`2-17 Crystallization
`2-18 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
`
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`CON TEN TS
`
`2-25 Surface Areas of Solids
`2-26 Adsorption of Gases on Solids
`2-27 Thermal Methods
`References
`'
`
`3 POWDERS
`
`List of Symbols
`3-1 Degree of Mixing
`3-2 Multicomponent Systems
`3-3 Powders“
`3-4 The Mixing Process
`3-5 Mixing Parameters
`3-V6 Segregation
`3-7 Number of Particles in Dosage Forms
`Angle of Repose
`Flow Rates
`Glidants
`
`1‘
`
`--»—~\cd<>:--O
`‘(noun
`
`3 3 3
`
`Flowability and Aging
`Friction and Interparticular Forces
`Packing Parameters
`Compactability
`Fluidized Powders
`
`Shape Factor
`Parenteral Powders
`References
`
`12
`313
`3-14
`315
`I
`316
`317
`
`4 SOLID DOSAGE FORMS
`
`List of Symbols
`.4-1' Tablets
`4-2 Granulations
`
`4-3 Drying from Beds
`4-4 Fluid Bed Drying
`4-5 Psyclirometric 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
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`CONTENTS
`
`255
`255
`258
`262
`267
`270
`273
`275
`276
`277
`282
`285
`288
`289
`
`4-18 Uniformity of Tablets
`4-19 Heat of Compression
`4-20 Disintegration of Tablets
`4-21 Dissolution 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
`S-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-Solid Interactions
`5-14 Solid Dosage Forms
`5-15 Reaction Order
`
`5-16 Equilibria
`5-17 Equilibria Involving Adsorption
`S-18 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 EiTects of Pressure
`
`.5-25 Light Sensitivity of Solid Dosage Forms
`5-26 Compatibility Tests
`5-27 Stability of Appearance
`References
`
`Author Index
`
`Subject Index
`
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`
`1-1 SUSPENSIONS
`
`vv.
`
`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 sufliciently 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 Co) or per tablespoon (15 Co). 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-
`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 therefore effected in suspension form. The principle, of course,
`can also be applicable for pharrnacokinetio 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.
`I
`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
`
`be rendered quite tasteless if adsorbed on montrnorillonite 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 in 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-
`ment on the label. Even so, failure to shake the bottle on the part of the
`consumer 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-
`siderations that warrant formulating a product as a suspension. A type of
`product may over the years have acquired an image as being of the suspen-
`sion type—~—antacid liquid preparations, for example-wand in such circum-
`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-
`ment chemist or pharmacist must be well versed in the theory and practice
`of suspension preparations. The role of the industrial pharmacist, be he en~
`gaged in production 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-
`ing and subsequent times of patient 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-
`fore, he must be aware of the principles underlying the many changes that
`may occur, know how changes can be detected atan 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 or 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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`l DISPERSE SYSTEMS
`
`and basic research are treated in a multitude of journals, e. g., J. Pharm. Sczl,
`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-
`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 am. For systems containing particles exclusively smaller than
`0.1 pm in diameter, the term dispersion shall be used (Hiestand, 1964).
`The question then is: What parameters must the pharmaceutical develop-
`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 difl"er, 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-average particle size of, say, 10 ,um,
`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-
`ments. But suppose that the viscosity of the vehicle is high and that suspend-
`ing the powder is best accomplished at 50°C, where higher fluidity prevails.
`If, in smaller—scalc 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-
`tion equipment it may take 3%,’ 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~
`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-
`,tion of disperse systems.
`is of
`It is obvious that particle size distribution, as mentioned before,
`importance, both from the point of View of physical stability a11d, even more
`importantly, from the clinical point of view. Therefore the industrial pharma~
`cists should know the elfect 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
`
`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-
`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
`1000 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-
`tant (e.g., for the purpose of wetting the powder), (e) highly charged ion,
`(f) humectant (for prevention of éap-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
`
`I
`
`50 mg
`3000 mg
`
`10 kg
`600 kg
`
`Drug
`Sucrose
`Humectants, gums,
`preservatives,
`flavors, surfactants
`
`5 ccWater q.s. ad 1000 liters
`
`As required
`
`As required
`
`
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`1 DISPERSE SYSTEMS
`
`elsewhere, but it should be noted here that the problems which are to be
`overcome are those involving (a) included air, (b) crystal growth, (c) settling,
`
`and (d) caking.
`Of these, air inclusion is overcome by technical 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 l—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.
`
`«
`
`DRUG
`
`COMMINUTE
`
`MILLED DRUG
`
`600 kg sucRosE\
`/HEAT, DISSOLVE
`
`1F
`
`ILTER
`
`soo LITERS WATER
`
`HUMECTANTS,GUMS
`
`300 __
`_,_
`LITER
`DYES_ PRESER-.
`VATIVES
`
`COOL
`
`JMILL
`
`FLAVORS
`
`DEAERATE
`I
`‘STRAIN
`
`WATER qsj-flFILL
`
`I
`
`Fig.1-1. Flow chart of suspension manufacture.
`
`The flow sheet would have the appearance shown in Fig. 1-1. In this
`simplified scheme, it is noted that the drug itself is first given a suitable
`particle size distribution (comminution step). The sugar is dissolved in water
`at about 100°C, filtered (eg, 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
`
`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-
`ture, the entire suspension is deaerated in vacuo (e.g., through a Versator),
`gross~filte'red 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 _mair'i 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 isra 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 thirdparties.
`
`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,
`11 the viscosity of the liquid, v (or 1200) the terminal
`constant velocity, and g the gravitational acceleration, then Stokes’s law
`(Stokes, 1856) states
`_
`
`Doc
`
`2 20> ~ )9
`= .’"_,3_!3.9._
`71
`
`~
`
`.
`
`p
`
`(1-1)
`
`Stol<es’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-
`tely fall. We should note, of course, that there is a restriction on the time t
`in the sense that 1 must be less than the time required for the sphere to reach
`bottom. Later, we shall 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
`
`)
`(
`2r
`Hu
`where H0 is the height of the cylinder, HU the ultimate height of the sediment
`
`l~2
`
`HO “" DI
`If
`- =2 ~~
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