Solid Dosage Processing

8/9/2019 Solid Dosage Processing

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Introduction to Solid Dosage

Processing


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Stages of pharmaceutical manufacturing

API

Excipients

PrimaryPackaging

SecondaryPackaging

API FinishedProduct

Starting Materials

(Chemicals)


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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


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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


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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


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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:";#.


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*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.


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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)


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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)


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*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?


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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?


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Po)der flo) and tablet )eight variations

,ancoc5. $runo "011@#? Dosage 2orm Specific %ests? Short course on *aterial Properties. Purdue !niversity?


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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


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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;#


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*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


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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


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!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)


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!nit operations

Size reduction "milling#

-dvantages and disadvantages

2orces in milling

*illing e4uipment "dry milling#

*edia mills ")et milling#

*ill selection

nergy re4uirements


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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


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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 "


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*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 "


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*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 "


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*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


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*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#


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*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


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*ill selection

Wibo)o and g "


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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#.


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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#.


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!nit operations

$lending

$lending e4uipment

Impact of size difference

Eadial vs axial mixing


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$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


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Size difference and mixing uniformity

&ampbell and $auer "


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*ixing in a bin blender K axial mixing

Sudah et al? "0110#. Po)der %echnology.


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*ixing in a bin blender K radial mixing

Sudah et al? "0110#. Po)der %echnology.


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!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


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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


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8ohansons theory

Slip Eegion

ip Eegion


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8ohansons theory

Slip region

ip region

Hu et al? "01


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8ohansons theory K nip angle

$indhumadhavan et al? "011;#. &hem ng Sci. =1"


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8ohansons theory + stress profile

$indhumadhavan et al? "011;#. &hem ng Sci. =1"


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ff? angle of friction and pea5 pressure

"8ohansons theory#

ff? -ngle of

2riction


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ff? angle of friction and nip angle

"8ohansons theory#

ff? -ngle of

2riction

ip -ngle


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ffect of lubrication on friction properties

Hu et al? "01


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ffect of lubrication on pea5 roll pressure

Hu et al? "01


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ffect of lubrication on nip angle

Hu et al? "01


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2alzone et al? "


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Impact of feed and roll speed on granule properties

*ean particle

size

,ydrous (actose

,

,2alzone et al? "


48/60

ffect of entrained air on feeding and discharging

8ohanson "


49/60

&haracterization of flo)ability

,ausner ratio G tapped density / bul5 density xcellent


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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#


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,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


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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


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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

"


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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


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!nit operations

%ablet compaction

Eelative density and compaction pressure

&oating 'bFectives

&ritical parameters


56/60

Eotary tablet press


57/60

Eelative density changes in manufacture of tablets

,ancoc5 et al? "0119#. Pharm %ech. -pril 0117. =9+C1


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4uivalence of tablets made )ith different presses

,ancoc5 et al? "0119#. Pharm %ech. -pril 0117. =9+C1

P ti


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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


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Eeferences

"#eory and Practice of Industrial P#armacy. (?(achman et al? "eds# "

Documents

Solid Dosage Processing