Download - Solid Dosage Processing
-
8/9/2019 Solid Dosage Processing
1/60
Introduction to Solid Dosage
Processing
-
8/9/2019 Solid Dosage Processing
2/60
Stages of pharmaceutical manufacturing
API
Excipients
PrimaryPackaging
SecondaryPackaging
API FinishedProduct
Starting Materials
(Chemicals)
-
8/9/2019 Solid Dosage Processing
3/60
Drug product manufacture
Dosage Form
Wet
granulation
milling
blending
Fluid Bed Dryer
lubrication
tableting
coating
imprintingProcess combines the drug andexcipients into the dosage form
ExcipientsAPI
crystallization
filtration
oven drying
Dry granulation
/ milling
Directcompression
-
8/9/2019 Solid Dosage Processing
4/60
Solid dosage processing
Dosage forms Quality factors
xcipients
Particle properties
Processing routes !nit operations
Size reduction "milling#
$lending
Dry granulation "roll compaction#
Wet granulation Drying
%ablet compaction
&oating
-
8/9/2019 Solid Dosage Processing
5/60
Solid dosage forms
'ral %ablets
(ozenges
&he)able tablets ffervescent tablets
*ulti+layer tablets
*odified release
&apsules
,ard gelatin
Soft gelatin
Po)ders
Inhaled -erosol
*etered dose inhalers
Dry po)der inhalers
Singh. aini "0110#. Dosage 2orms3 on+Parenteral. ncyclopedia of Pharmaceutical %echnology
-
8/9/2019 Solid Dosage Processing
6/60
Quality factors for solid dosage forms
Functional quality factors
-Disintegrates to desired size 4uic5ly-%he constituent particle size of the dosage form should dissolve and beabsorbed in the 6I tract at a pre+determined rate
Physical quality factors
-*ust not brea5 up on processing. pac5aging. transportation. dispensingor handling-Surface of tablet or capsule must be free of defects-*ust be stable under anticipated environmental conditions-,ave the same )eight and composition for each tablet or capsule
Sensorial quality factors
-asy and pleasant to s)allo)
2ung and g "0117#. -I&h 8ournal. 9:";#.
-
8/9/2019 Solid Dosage Processing
7/60
*odels at different scales
Scale Subject Problems
nterprise $usiness process Sourcing. contractmanufacturing. capacity planning
Plant Process synthesis. simulation.development
6eneration of processalternatives. process optimization
4uipment 4uipment selection.performance. sizing. costing
*ixing. classification.granulation. milling
&ontinuum 2lo) and handling of po)ders 6ranular flo)
Particle Particle attributes3 composition.size distribution. density.strength. shape
Interparticle forces. brea5age
*olecule nantiomers and polymorphs.material properties
Polymorph prediction. predictionof physical and chemicalproperties
g "0110#. Po)der %echnology.
-
8/9/2019 Solid Dosage Processing
8/60
Product and process functions
Product function
Product property3 &ontent uniformity. dissolution. flo)ability. dust
formation Particle Properties3 Particle size. particle shape. surface
characteristics
Process function
Process parameters3 %ype of unit operation. operational
parameters
Product property = F(particle properties, formulation)
Particle properties = F(process parameters, raw material/intermediate properties)
-
8/9/2019 Solid Dosage Processing
9/60
Particle properties
Potential Impact
Processing $ehavior
Product Quality 2actors
Property 2lo) $lending Wetting Drying *echanical Dissolution Stability
Particle Size > > > > > > >
Surface -rea > > > > > > >
Particle Shape >
Surface nergy > > >
$ul5 Density > > >
Pore Size > > >
Internal 2riction > >
Wall 2riction > >
,ygroscopicity > > >
,lina5 et al. 8ournal of Pharmaceutical Innovation. < "011=#
Product property = F(particleproperties, formulation)
-
8/9/2019 Solid Dosage Processing
10/60
*ean particle size and flo)ability
$odhmage. -? "011=#? &orrelation bet)een physical properties and flo)ability indicators for fine po)ders? *S%hesis. Department of &hemical ngineering. !niversity of Sas5atche)an?
-
8/9/2019 Solid Dosage Processing
11/60
Size distributions for various po)ders
$odhmage. -? "011=#? &orrelation bet)een physical properties and flo)ability indicators for fine po)ders? *S%hesis. Department of &hemical ngineering. !niversity of Sas5atche)an?
-
8/9/2019 Solid Dosage Processing
12/60
Po)der flo) and tablet )eight variations
,ancoc5. $runo "011@#? Dosage 2orm Specific %ests? Short course on *aterial Properties. Purdue !niversity?
-
8/9/2019 Solid Dosage Processing
13/60
xcipients
%o aid in the processing of the drug delivery system during its
manufactureA
%o protect. support. or enhance stability. bioavailability or patient
acceptabilityA
%o assist in product identificationA %o enhance any other attribute of the overall safety. effectiveness. or
delivery of the drug during storage or use?
xcipients are substances. other than the active drugsubstance. or finished dosage form. that have been
appropriately evaluated for safety and are included in
drug delivery systems3
!SP. 6eneral Information &hapter B
-
8/9/2019 Solid Dosage Processing
14/60
xcipient functions
Component Function Examples
2illers Increase size and )eight of finaldosage form
*icrocrystallinecellulose. sucrose
$inders Promote particle aggregation Pregelatinized starch.hydroxypropyl
methylcelluloseDisintegrants Promote brea5 do)n of aggregates Sodium starch glycolate
2lo) -ids Eeduce interaction bet)een particles %alc
(ubricants Eeduce interactions bet)een particlesand surfaces of processing e4uipment
*agnesium stearate
Surfactants Promotes )etting Sodium lauryl sulfate.Polysorbate
*odifiedEelease-gents
Influences the release of active ,ydroxypropylmethylcellulose.Surelease.
,lina5 "011;#
-
8/9/2019 Solid Dosage Processing
15/60
*ost popular excipients
*agnesium stearate "lubricant#
(actose "compression aid#
*icrocrystalline cellulose
"compression aid#
Starch "corn# "compression aid#
Silicon dioxide "glidant# Stearic acid "lubricant#
Sodium starch glycollate "disintegrant#
6elatin "binder#
%alc "film coating adFuvant. glidant#
Sucrose "s)eetener. coating#
&alcium stearate "lubricant#
Povidone "binder#
Pre+gelatinized starch "binder#
,ydroxypropylmethylcellulose "film
coating. binder#
'P- products "film coats and dyes#
&rosscarmelose sodium "disintegrant#
,ydroxypropylcellulose "binder. film
coating#
thylcellulose "enteric coating#
Dibasic calcium phosphate
"compression aid#
&rospovidone "disintegrant#
Shellac and 6laze "coating agent#
International pharmaceutical excipients council of the americas.
http3//)))?ipecamericas?org/public/fa4s?html
-
8/9/2019 Solid Dosage Processing
16/60
Processing routes
2ill die
&oating. Pac5aging etc??
&ompress %ablet
Direct Compression
DrugDiluent
6lidant
Disintegrant
(ubricant
Dry Granulation
Disintegrant
6lidant
(ubricant
DrugDiluent
(ubricant
*ixing
&ompression
&omminution
Screening
*ixing
*ixing
Wetting
6ranulation
Drying
Screening
*ixing
DrugDiluent
$inder
Solvent
Disintegrant
6lidant
(ubricant
Wet Granulation
ther !outes
2luidized bed granulation
xtrusion / rotary granulation
"ablet
Compression
-
8/9/2019 Solid Dosage Processing
17/60
!nit operations
Process function
Process parameters3 %ype of unit operation. operational parameters
%ype of unit operation Size reduction "*illing#
$lending
Dry granulation "Eoll compaction#
Wet granulation
Drying
%ablet compression
&oating
Particle properties = F(processparameters, feed/intermediate properties)
-
8/9/2019 Solid Dosage Processing
18/60
!nit operations
Size reduction "milling#
-dvantages and disadvantages
2orces in milling
*illing e4uipment "dry milling#
*edia mills ")et milling#
*ill selection
nergy re4uirements
-
8/9/2019 Solid Dosage Processing
19/60
Particle size reduction
*ixing is more uniform if ingredients are roughly the same size
*illing of )et granules can promote uniform and efficient drying
Increased surface area can improve dissolution rate and bioavailablity
Improved content uniformity of dosage units
xcessive heat generation can lead to degradation. change in
polymorphic form
Increase in surface energy can lead to agglomeration
*ay result in excessive production of fines or overly broad particle
size distribution
$enefits
Disadvantages
-
8/9/2019 Solid Dosage Processing
20/60
2orces in milling
Shear "cutting forces#
&ompression "crushing
forces#
Impact "high velocitycollision#
6riffith theory % G %ensile stress
H G Houngs modulus
J G Surface energy
c G fault length
YT
c
=
Eumpf "
-
8/9/2019 Solid Dosage Processing
21/60
*illing e4uipment K screen mills
&ritical parameters for a conical screen mill Screen ,ole Size/Shape
Impeller %ype
Impeller &learance
Speed
valuate impact on aspirin granulation Particle size reduction
*illing time and energy re4uirements
'verall milling performance
Milling Work Index = i!e reduction / Milling work
Milling "ime Index = i!e reduction / Milling time
$yers. Pec5 "
-
8/9/2019 Solid Dosage Processing
22/60
*illing e4uipment K screen mills
Screen hole size has largest impact on particle size
reduction. milling time and energy re4uirements
*illing )or5 index significantly lo)er for smaller screenhole sizes
Impeller type has largest effect on overall milling
performance
Impeller clearance not significant at small clearances *illing )or5 index lo)er at higher mill speeds
Deflection of material a)ay from screens
$yers. Pec5 "
-
8/9/2019 Solid Dosage Processing
23/60
*illing e4uipment K impact mills
Significant )ear on surfaces
,ammer mills
*edium to coarse size reduction
Peripheral speed 01+;1 m/sec
Pin mills
Peripheral speed up to 011 m/sec &apable of fine grinding
&an be used to mill stic5y materials
-
8/9/2019 Solid Dosage Processing
24/60
*illing e4uipment K Fet mill
Superfine to colloid size reduction
&an be used for heat sensitive products
Different configurations Panca5e "spiral# Fet mill
2ines exit from center
(oop/oval Fet mill 2ines exit from top
'pposing Fet mills Particles impact each other in opposing Fets
2luidized bed Fet mill Particles are Fetted to)ards center "lo) )ear on e4uipment#
2ixed/moving target Fet mills Particles impact on surface of target ")ear can be significant#
-
8/9/2019 Solid Dosage Processing
25/60
*illing e4uipment K stirred media mill
&ritical parameters
-gitator speed
2eed rate
Size of beads
$ead charge
Density of beads
Design of blades *ill chamber
Eesidence time
-
8/9/2019 Solid Dosage Processing
26/60
*ill selection
Wibo)o and g "
-
8/9/2019 Solid Dosage Processing
27/60
nergy based analysis K ball mill
*acroscale energy+size relationships "&hen et al?. 0119# &alculate specific energy for a given size reduction
2unctional form derived from theoretical considerations
Eittingers model
nergy re4uired for particle size reduction is proportional to the area of ne)surface created
Lic5s model nergy re4uired to brea5 a particle is proportional to the ratio of the particle
volume before reduction to the volume after reduction
&hen et al? "0119#. 8 Pharm Sci. :7"9#.
-
8/9/2019 Solid Dosage Processing
28/60
nergy based analysis K ball millLic5s (a),igh loading
(o) fre4uencyEolling attrition
Eittingers (a)(o) loading
,igh fre4uency
Impact fragmentation
1
FP
R
xx
k t=
+
exp( )p F Kx x k t=
-ttrition
2ragmentation
Size Eeduction of MK(actose *onohydrate in a $all *ill
&hen et al? "0119#. 8 Pharm Sci. :7"9#.
-
8/9/2019 Solid Dosage Processing
29/60
!nit operations
$lending
$lending e4uipment
Impact of size difference
Eadial vs axial mixing
-
8/9/2019 Solid Dosage Processing
30/60
-
8/9/2019 Solid Dosage Processing
31/60
$lending K convective mixingEibbon $lenders 'rbiting Scre) $lenders
Planetary $lenders
,orizontal Double -rm $lenders
2orberg $lenders
Nertical ,igh Intensity *ixers
,orizontal ,igh Intensity *ixers
Diffusion *ixers )ith Intensifier/-gitator
-
8/9/2019 Solid Dosage Processing
32/60
Size difference and mixing uniformity
&bell and $auer "
-
8/9/2019 Solid Dosage Processing
33/60
*ixing in a bin blender K axial mixing
Sudah et al? "0110#. Po)der %echnology.
-
8/9/2019 Solid Dosage Processing
34/60
*ixing in a bin blender K radial mixing
Sudah et al? "0110#. Po)der %echnology.
-
8/9/2019 Solid Dosage Processing
35/60
!nit operations
Dry granulation "roll compaction#
&ritical parameters
8ohansons theory
2eed system Impact of granulation on flo) properties
Wet granulation
*onitoring li4uid addition Drying
2luidised bed dryer
-
8/9/2019 Solid Dosage Processing
36/60
Eoll compaction
&ritical parameters Eoll speed and pressure
,orizontal and vertical
feed speed. deaeration
Eoll diameter and
surface
-dvantages Improve po)der flo)
Eeduce segregation
potential
o moisture addition.
drying
-
8/9/2019 Solid Dosage Processing
37/60
8ohansons theory
Slip Eegion
ip Eegion
-
8/9/2019 Solid Dosage Processing
38/60
8ohansons theory
Slip region
ip region
Hu et al? "01
-
8/9/2019 Solid Dosage Processing
39/60
8ohansons theory K nip angle
$indhumadhavan et al? "011;#. &hem ng Sci. =1"
-
8/9/2019 Solid Dosage Processing
40/60
8ohansons theory + stress profile
$indhumadhavan et al? "011;#. &hem ng Sci. =1"
-
8/9/2019 Solid Dosage Processing
41/60
ff? angle of friction and pea5 pressure
"8ohansons theory#
ff? -ngle of
2riction
-
8/9/2019 Solid Dosage Processing
42/60
ff? angle of friction and nip angle
"8ohansons theory#
ff? -ngle of
2riction
ip -ngle
-
8/9/2019 Solid Dosage Processing
43/60
ffect of lubrication on friction properties
Hu et al? "01
-
8/9/2019 Solid Dosage Processing
44/60
ffect of lubrication on pea5 roll pressure
Hu et al? "01
-
8/9/2019 Solid Dosage Processing
45/60
ffect of lubrication on nip angle
Hu et al? "01
-
8/9/2019 Solid Dosage Processing
46/60
2alzone et al? "
-
8/9/2019 Solid Dosage Processing
47/60
Impact of feed and roll speed on granule properties
*ean particle
size
,ydrous (actose
,
,2alzone et al? "
-
8/9/2019 Solid Dosage Processing
48/60
ffect of entrained air on feeding and discharging
8ohanson "
-
8/9/2019 Solid Dosage Processing
49/60
&haracterization of flo)ability
,ausner ratio G tapped density / bul5 density xcellent
-
8/9/2019 Solid Dosage Processing
50/60
Eoll compaction and flo) properties
Soares et al? "011;#.Dry granulation and compression of spray dried plant extracts. --PSPharmSci%ech
$efore
&ompaction
"poor#
-fter
&ompaction
"excellent#
-
8/9/2019 Solid Dosage Processing
51/60
,igh shear )et granulation
-dvantages Improve flo)
Improve uniformity Increase bul5 density
nhance resistance to
segregation
&ritical parameters -mount of binder
Eate of addition %ime of granulation
Speed
Mixer Blade
Bowl
Chopper Blade
Discharge
-
8/9/2019 Solid Dosage Processing
52/60
Wet granulation K monitoring li4uid addition
8orgensen et al? "0119#. 8 Pharm Sci. :7":#. 0070+0097
"-# 1?09 ml/g
Impeller %or4ue for MK(actose *onohydrate/*&& granulation
" 1?9@ ml/g
agglomeration
"$# 1?7= ml/g
nucleation
"D# 1?;7 ml/g
agglomerate gro)th
-
8/9/2019 Solid Dosage Processing
53/60
Wet granulation K monitoring li4uid addition
8orgensen et al? "0119#. 8 Pharm Sci. :7":#. 0070+0097
"-# 1?09 ml/g
"< min#
S* of MK(actose *onohydrate/*&& granules
" 1?9@ ml/g
"0 min#
agglomeration
"$# 1?7= ml/g
"
-
8/9/2019 Solid Dosage Processing
54/60
2luid bed drying
Air Flow
Inlet FilterCondensorSteamDamper
Damper Outlet Filter
Air Flow
Product
Temperature
Inlet
Temperature
OutletTemperature
From
ranulator
To !ill
Dr"in# $one
Filter %a#
Air Flow
&etainin#
Screein
-
8/9/2019 Solid Dosage Processing
55/60
!nit operations
%ablet compaction
Eelative density and compaction pressure
&oating 'bFectives
&ritical parameters
-
8/9/2019 Solid Dosage Processing
56/60
Eotary tablet press
-
8/9/2019 Solid Dosage Processing
57/60
Eelative density changes in manufacture of tablets
,ancoc5 et al? "0119#. Pharm %ech. -pril 0117. =9+C1
-
8/9/2019 Solid Dosage Processing
58/60
4uivalence of tablets made )ith different presses
,ancoc5 et al? "0119#. Pharm %ech. -pril 0117. =9+C1
P ti
-
8/9/2019 Solid Dosage Processing
59/60
Pan coating
$enefits
*as5 taste &hemical barrier
&ontrolled release
-ppearance
&ritical Parameters
-ir flo) Spray
Drum dynamics Eotational speed
2ill fraction
Air'!oisture
Dr" Air
&otation
%a((le
Spra" )o**le
Air Flow
Inlet FilterSteamInlet
Temperature
Inlet Air
Outlet AirOutlet Filter
Outlet
Temperature
-
8/9/2019 Solid Dosage Processing
60/60
Eeferences
"#eory and Practice of Industrial P#armacy. (?(achman et al? "eds# "