Pharmaceutical dosage forms : tablets

1558 Pages·2008·26.132 MB·English

by  Augsburger, Larry L., Hoag, Stephen W

Pharmaceutical Science
V TP
o h PHARMACEUTICAL
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about the book…
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The ultimate goal of drug product development is to design a system that maximizes the 1 dM DOSAGE FORMS: TABLETS
therapeutic potential of the drug substance and facilitates its access to patients. Pharmaceutical : U itA
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Dosage Forms: Tablets, Third Edition is a comprehensive treatment of the design, formulation, n o
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manufacture, and evaluation of the tablet dosage form. With over 700 illustrations, it guides it n
E Third Edition
pharmaceutical scientists and engineers through difficult and technical procedures in a simple O
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easy-to-follow format.
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New to the Third Edition: a I
• developments in formulation science and technology ti C Volume 1:
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• changes in product regulation n A
s
• streamlined manufacturing processes for greater efficiency and productivity L Unit Operations and
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Pharmaceutical Dosage Forms: Tablets, Volume One examines: n D
d
• modern process analyzers and process and chemical process tools M O Mechanical Properties
• formulation and process performance impact factors
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• cutting-edge advances and technologies for tablet manufacturing and product regulation c
A
h
about the editors... a G
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LARRY L. AUGSBURGER is Professor Emeritus, University of Maryland School of Pharmacy, Baltimore, ic E
a
and a member of the Scientific Advisory Committee, International Pharmaceutical Excipients l F

Council of the Americas (IPEC). Dr. Augsburger received his Ph.D. in Pharmaceutical Science from P O
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the University of Maryland, Baltimore. The focus of his research covers the design and optimization o R
p
of immediate release and extended release oral solid dosage forms, the instrumentation of automatic
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capsule filling machines, tablet presses and other pharmaceutical processing equipment, and the r
product quality and performance of nutraceuticals (dietary supplements). Dr. Augsburger has also tie S
published over 115 papers and three books, including Pharmaceutical Excipients Towards the 21st s :

Century published by Informa Healthcare. T
A
STEPHEN W. HOAG is Associate Professor, School of Pharmacy, University of Maryland, Baltimore.
B
Dr. Hoag received his Ph.D. in Pharmaceutical Science from the University of Minnesota, Minneapolis.
L
The focus of his research covers Tablet Formulation and Material, Characterization, Process Analytical
E
Technology (PAT), Near Infrared (NIR) Analysis of Solid Oral Dosage Forms, Controlled Release
T
Polymer Characterization, Powder Flow, Thermal Analysis of Polymers, Mass Transfer and Controlled
S
Release Gels. Dr. Hoag has also published over 40 papers, has licensed four patents, and has written

more than five books, including Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third
Edition and Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems, both
published by Informa Healthcare.
Augsburger
Printed in the United States of America
■
Hoag
(cid:36)(cid:43)(cid:25)(cid:16)(cid:17)(cid:20)
Edited by
Larry L. Augsburger
Stephen W. Hoag
LACITUECAMRAHP
D EGASO :SMRO F AT B SETL
To my loving wife Jeanni e,
the light and laugh ter in my life.
—Larry L. Augsburger
To my dear wife Cathy and my children Elena
and Nina and those who helped me
so much with my educat ion:
My parents Jo Hoag and my late father
Jim Hoag, Don Hoag , and Edwa rd G. Rippie.
—Stephen W. Hoag
20 Hoag andLim
particles,lamellarisastackofplates,conglomeratesareamixtureoftwoormoretypes
of particles, and spherulites are radial clusters (7). In many references, the term primary
particleisused,forthistextthe termissynonymous withtheUSPdefinitionofparticle.
Oneofthekeyelementsformeaningfulparticlesizedeterminationsisdefiningthe
type of particle (primary particle or group of particles) that can best represent the
application andproperties ofinterest. Forexample,when studying a granulationprocess
the particle size of the agglomerate is the critical size needed for characterizing the
granulation.Ontheotherhand,ifthedissolutionprofileofthedrugisbeingcharacterized
then the particle size of the primary particle is the critical size. Knowing the type of
particle to be measured is critical because certain sample preparation techniques and
analysis conditions can influence the degree of particle aggregation.
DEFINITION OF PARTICLE SIZE
Thefirststepinthestatisticalanalysisofparticlesizeistodefine theradiusordiameter
of the particle in question. For spherical particles the diameter or radius is easy to
measure and can be defined by a unique number that is characteristic of a sphere. If the
diameter of a sphere is known then the surface area, volume, mass (using true density),
and sieve diameter of that particle can be determined, which is useful for assessing
propertiessuchasdissolutionrate.However,mostparticlesusedintabletmanufacturing
arenotperfectsphereswithaneasilydefineddiameter.Forexample,theirregularshaped
particle in Figure 4A has an infinite number of different diameters which could be
drawn;inaddition,noneofthesediametersgivesanyinformationaboutthesurfacearea
orvolumeoftheparticle,whichdecreasestheusefulnessofthedeterminedparticlesize.
Ideally the diameter should uniquely define the particle and give information about its
surfaceareaandorvolume.Currently,thetwomostpopularmethodsfordefiningparticle
size are the equivalent diameters and the statistical diameters; these two methods are
discussed in the following two sections.
FIGURE 4 (A) An irregularly shaped particle with an infinite number of diameters. (B) The
equivalent volume,surface, andprojected area diameter of(A).
28 Hoag andLim
Thedensityfunctionf(x)inFigure9wasgeneratedusingEquation(13).Thecumulative
distribution function F(x) is obtained by integrating the density function:
Z
x
(cid:7)¼FðxÞ¼ fðxÞdx ð15Þ
(cid:1)1
There are some general properties of all distribution functions irrespective of the
type of distribution. For example, F(x) ‡0 is a practical constraint because negative
probabilities have no meaning. Typically, the probability distribution functions are
normalized, i.e., the density function integrated over the entire domain of the density
function has a total area under the curve of one:
Z
1
fðxÞdx¼1 ð16Þ
(cid:1)1
where f(x) >0. In addition, the probability of a random variable x occurring between x
i
and x can be calculated by integrating the density function:
iþ1
Z
xþ1
i
P½x <x<x (cid:3)¼ fðxÞdx ð17Þ
i iþ1
x
i
This is a very useful property for determining the probabilities of certain events
occurring. For the discrete case:
Z
ni ðx;x Þ¼P½x <x<x (cid:3)¼ xiþ1fðxÞdx ð18Þ
N i iþ1 i iþ1
x
i
where n is the number of particles in the ith interval and N is the total number of
i
particles in all intervals. Note, the notation n divided by N is equivalent to the integral
i
1
0.9
0.8 Cumulative distribution →
0.7
0.6
y
bilit
a 0.5
b
o
Pr
0.4
0.3
0.2
0.1
← µ ← σ
0
71 72 73 74 75 76 77 78 79
Particle size (µm)
FIGURE 9 Normal frequency or density distribution and the cumulative distribution function
used toillustrate adistributionand transformationsof thecumulativedistributionfunction.
Particle andPowder BedProperties 37
0.08 1
0.9
0.07
0.8
0.06
0.7
y y
sit 0.05 sit 0.6
n n
e e
d d
y 0.04 y 0.5
bilit bilit
a a
b b 0.4
o 0.03 o
Pr rP
0.3
0.02
0.2
0.01
0.1
0 0
0 20 40 60 80 0 1 2 3 4 5
d z = ln(d)
FIGURE 10 Lognormaldistribution.
The fact that d or z can be used as the independent variable for the log normal
distribution creates confusion among students because the log normal density function
cantakeondifferentformsdependingonwhichvariableisused.Thus,ifweletxbethe
actual particle size and z be the ln transformation then we have the following
relationships:
z¼lnðxÞ; z¼lnx and (cid:5) ¼ln(cid:5) ð54Þ
g z g
where x is thegeometric meanands is thegeometric standarddeviation, asdiscussed
g g
in Equations (28)(cid:150)(30). The probability distribution function of the log normal dis-
tribution expressed in terms of the transformed variable z is given by:
d’ðzÞ 1 (cid:1)1ðz(cid:1)zÞ2
dZ ¼fðzÞ¼(cid:5) pffi2ffiffi(cid:1)ffiffiffi e 2(cid:5)2z ð55Þ
z
Log d
1 d FIGURE 11 Log d versus
d. As d approaches zero the
log d asymptotically approa-
ches minus infinity. This ex-
pands the lower end of the
distributionwhilelogdtends
towards infinity at a slower
rate asd increases.
Particle andPowder BedProperties 45
Quantitative Shape Factors
Characterizing the shape of an irregular particle can be complicated; to address this
problem a lot of research by many different groups has been done to find a numerical
valuethatcan quantitatively characterize the shape ofanirregular particle.Collectively,
thesenumericalvaluesareoftenreferredtoastheshapefactor;thegoalofashapefactor
is to define the shape of an irregular particle. For instance, how spherical or square a
particle is or how different is the irregular particle from acommonly seen shape using a
mathematical model.
Thissectionwilldiscusssomeofthecommonlyusedandcitedshapefactorsinthe
pharmaceutical industry; the shape factors discussed in this section are: Wadell(cid:146)s true
sphericity and circularity, rugosity coefficient, correction factor, Dallavalle(cid:146)s shape
factor,Heywood(cid:146)sshapefactor,Schneiderho¤hn(cid:146)saspectratio,oneplanecriticalstability
(OPCS), and Podczeck(cid:146)s two- and three-dimensional factor. There are also many other
shape factors but they are beyond the scope of this chapter (11,14,26(cid:150)31).
Wadell’s True Sphericity and Circularity
One of the earliest particle shape factors used in the pharmaceutical industry was
Wadell(cid:146)s true spheritcity, c . The true sphericity defines the proximity of the irregular
w
particle measuredtoaperfectsphereand therelationship between the irregular particles
to the perfect sphere is given by:
(cid:8) (cid:9)
S0 d 2
¼ ¼ v ð74Þ
w S d
s
where S’ is the surface area of a sphere having the same volume as the particle and S is
theactualsurfaceareaoftheparticle.c is1.0whentheparticleisaperfectsphereand
w
islessthan1.0forallothershapes;thesmallerthevaluethelesssphericaltheparticlesis.
This true sphericity is not the roundness of a particle as roundness is only a sense of
smoothnessorthesharpnessofthecorners.Whileroundnessisanintrinsicpropertyofa
sphere, many other circular forms (e.g., an ellipse) can show some degree of roundness
but yet they are not considered as a sphere (14,32). Hence, roundness and the true
sphericity are two independent variables.
The inverse of Wadell(cid:146)s true sphericity is known as the rugosity coefficient by
some researchers to express any lack of smoothness in a particle(cid:146)s perimeter (27,33,34).
Hence,therugositycoefficient,g,canbeusetodescribetheroughnessofaparticleandis
defined as:
S A
(cid:8) ¼ ¼ BET ð75Þ
S0 A
g
whereA isthemeasuredspecificsurfaceareausuallyobtainedbynitrogenadsorption
BET
while A is the surface area of a sphere having the same volume as the particle and it is
g
usually obtained by microscopy or sieve analysis.
Wadell also defined the degree of circularity, ¢, to determine the proximity of a
particle outline to a circle. This relationship can be described by:
C0 P2
¢ ¼ ¼ ð76Þ
C 4(cid:1)A
where C(cid:146) is the circumference of a circle having the same cross-sectional area as the
particle, C is the actual perimeter of the cross section, P is the perimeter of the particle
62 Hoag andLim
TABLE 11 SieveStandards Specified byUSPand Tyler
ISOnominalaperture
Principal
sizes Supplementarysizes U.S. Recommended Japan Tyler
sieve USP European sieve mesh
R20/3 R20 R40/3 no. sieves(mesh) sieve no. no. no.
11.20mm 11.20mm 11.20mm
10.00mm
9.50mm
9.00mm
8.00mm 8.00mm 8.00mm
7.10mm
6.70mm
7.10mm
6.70mm
6.30mm
5.60mm 5.60mm 5.60mm 5600 3.5
5.00mm
4.75mm 4 4 4
4.50mm
4.00mm 4.00mm 4.00mm 5 4000 4000 4.7 5
3.55mm
3.35mm 6 5.5 6
3.15mm
2.80mm 2.80mm 2.80mm 7 2800 2800 6.5 7
2.50mm
2.36mm 8 7.5 8
2.24mm
2.00mm 2.00mm 2.00mm 10 2000 2000 8.6 9
1.80mm
1.70mm 12 10 10
1.60mm
1.40mm 1.40mm 1.40mm 14 1400 1400 12 12
1.25mm
1.18mm 16 14 14
1.12mm
1.00mm 1.00mm 1.00mm 18 1000 1000 16 16
900mm
850mm 20 18 20
800mm
710mm 710mm 710mm 25 710 710 22 24
630mm
600mm 30 26 28
560mm
500mm 500mm 500mm 35 500 500 30 32
450mm
425mm 40 36 35
(Continued)
88 Baxter etal.
P
Flow function
F
P
Consolidation Fracture F
FIGURE 9 Schematic of (cid:147)idealized(cid:148) strengthtest.
times to develop a (cid:147)flow function,(cid:148) which is a curve illustrating the relationship
between the unconfinedyield strength(F)and the major consolidation pressure (P).
Since this idealized strength test is not possible for the broad range of bulk solids
that might be tested, several different cohesive strength test methods have been devel-
oped, and their respective strengths and weaknesses have been assessed (3,4). Although
many different test methods can be used to measure cohesive strength, this section
focuses specifically upon the Jenike direct shear test method since it is the most uni-
versally accepted method. The Jenike direct shear test method is described in ASTM
standard D 6128 (5). It is important that these tests be conducted at representative
handling conditions such as temperature, relative humidity, and storage at rest, since all
these factors can affect the cohesive strength. An arrangement of a cell used for the
JenikedirectsheartestisshowninFigure10.Thedetailsofthismethodareprovidedin
Ref. 1, including the generation of a Mohr(cid:146)s circle to plot the shear stress (t) versus the
consolidationpressure(s),thegenerationoftheeffectiveyieldlocus,andthegeneration
of a flow function.
Consolidating and
shear test weight
Bracket
Loading pin
Cover
Ring
Shear
load Plane of
shear
Stem
Base
Disc
Frame
FIGURE 10 Jenike direstshear test, cohesive strengthtestset-up.
104 Baxter etal.
FIGURE21 Internalagitator(Matcon(cid:1)
dischargevalve).
Thewallfrictiontestsanddesignchartsusedtodetermineifabinwilldischargein
mass flow or funnel flow were discussed previously.
Regardlessofwhethertheequipmentbeingdesignedformassflowisabin,transfer
chute or press hopper, the same design criteria apply for obtaining mass flow discharge.
Therefore, although this section focus on design techniques for mass flow bins, these
techniques may be extended to obtain mass flow in a transfer chute and press hopper as
well.Thesetechniquesmaybeappliedindesigningnewequipmentormodifyingexisting
equipment to provide mass flow.
Whendesigningthebintoprovidemassflow,thefollowinggeneralstepsshouldbe
taken:
1. Size the outlet to prevent a cohesive arch from forming by making the outlet dia-
meter equal to or larger than the minimum required outlet diameter (B , Fig. 22).
c
Ifaslottedoutletisused(maintaininga3:1length:widthratiofortheoutlet),theout-
let width should be sized to be equal to or larger than the minimum required outlet
width (B , Fig. 22). The outlet may also need to be sized based upon feed rate and
p
two-phaseflowconsiderationsasdiscussedinthefollowingsection.Iftheoutletcan
not be sized to prevent an arch (e.g., press hopper outlet that must mate with a feed
frameinlet),aninternalmechanicalagitatororexternalvibratorcouldbeconsidered,
as discussed in the proceeding section
2. Oncetheoutletissized,thehopperwallslopedshouldbedesignedtobeequaltoor
steeper than the recommended hopper angle for the given outlet size and selected
wall surface. For a conical hopper, the walls should be equal to or steeper than
the recommended mass flow angle for a conical hopper (u , Fig. 22). If the bin
c
has a rectangular-to-round hopper, the valley angles should be sloped to be equal