Tablet and Capsules

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Tablets and Capsules:Design and Formulation

PHAR 535: Pharmaceutics

Larry L. Augsburger, Ph.D.



A. Compaction

B. Tablets as a Dosage Form

C. Minimum Running Characteristics

D. Overview of Manufacturing Methods1. Direct Compression

2. Granulation

E. Tablet Composition1. Formulation

2. Excipients: functionality and mechanism

F. Factors Affecting Drug Release

G. “Fast-Melt” Tablets

Compressed Tablets



Tableting is a COMPACTION

Process and Involves Two Steps

n CompressionèReduction in bulk volume by

eliminating voids and bringing

particles into closer contact.

n ConsolidationèIncreased mechanical strength

due to interparticulate

interactions



Rearrangement ØPlastic

Deformation

(and/or

viscous flow)ØBrittle

Stages of CompressionSingle-Ended Compression

Elastic limit

exceeded



The Role of the Compressive

Force...

n Is primarily to bring the adjacent particulate

surfaces together so that forces active active at

surfaces may form lasting linkages.èInterparticle forces are weak and only significant if t

particles are touching one another or very close

– van der Waals

– H-bonding – The mechanical strength (e.g. hardness) is a

function of the nature of the attractive forces and

the area over which they act.



Compactibility is...

n The ease with which mechanically strong tablet

can be made.

èTablet mechanical strength may be measured b – Hardness (Breaking strength)

– Friability (Resistance to abrasion and chipping)



Friabilator

Drop

The % weight loss due to chipping, abrasion

and erosion is reported as % Friability.



Measuring Hardness(Breaking Force)

FixedF

Tablet



H a r d n e s s ( k g )

Compaction Profiles of Some Direct

Compression Fillers(0.75% magnesium stearate)

Avicel PH 101(microcrystalline cell

Fast Flo Lactose

Emcompress(dicalc. phosph.

dihydrate, unmilled)

Dipac(coprocessed sucro

Starch 1500(pregelatinized starch

200 900 16000

4

8

12microcrystalline cellulose



RDWF = Residual Die

Wall Force EF = RDWF x w

Fr

N

Fr = N

Tablet Ejection and Ejection Force

DWF

EF

RDWF



Die wall lubricants reduce frictio

by interposing a film of low sheastrength between the tablet mas

and the confining die wall…

n

Magnesium stearaten Stearic Acid



The structure formed must bestrong enough to withstand the

stresses of decompression,as well as those induced by

ejection.



lElastic recovery in combination with poor

bonding

Capping Lamination



Possible cause of

capping/lamination



Upper Punch

ou e- n e ompress onRotary (Multistation) Press



Examples of Tooling



View of Punch Train



High Speed Production RotaryTablet Press

55 stations

495,000 tabs/hour



n Ease of Administration and Patient AcceptancèSwallowing

– Size

– Coating

èChewable FormulationsèElegence

n Convenience/Compactness

n Accurate Dosage

n Stability

Compressed Tablets as a Dosage Form



lControl of Release Possiblen Delayed Release

n Extended Release

ER CORE

IR DOSE

ER CORE

IR DOSE

IR DOSE

IR DOSE

Barrier

Coating

Barrier

Coated

Beads

Compressed Tablets as a Dosage For

(continued)



What can go wrong?

n Problems in attaining acceptable content

uniformity (accuracy and precision of unit dose

content) for low dose drugs.n Large dose drugs usually lack the properties to

be formed into tablets

n

Compromised bioavailability (poor drug solubilitmalformulation)



Design and Formulation of

Compressed Tablets (IR)

n Minumum running characteristicsèCompactibility

è

FluidityèLubricity

Excipients and the method of manufacture areselected to provide these characteristics.



Manufacturing Methods

n Granulation A complex process of first forming

granules from the mix and then

tableting the granules.èWet

èDry

n Direct Compression

Simply mix and compress.



n Size of Dose

n Compactibility and/or Fluidity of Drug

n Stability Characteristics of the Drug

Choice of Method Depends on

Several Factors

A C id ti f th D f



n LOW DOSE (<25MG)

(Most of the tablet will be excipients)

èContent Uniformityn High DOSE (>250mg)

(Most of the tablet will be drug)

èCompactibilityèFluidity

A Consideration of the Dose of

Drug is the Starting Point...

Is drug solubility also an important consideration? Why

Is it equally important in each case?

Lower Dose Drugs Generally Ca



Lower Dose Drugs Generally Ca

Be Directly Compressed

n Can compensate for any lack of compactibility

and/or lack of flowability by the use of special

direct compression fillers (aka: filler-binders)

n Can provide lubricity by addition of die wall

lubricant

n Can help fluidity by adding a glidant

n Can assure rapid disintegration by adding

disintegrant

Blend Compress

G l F l f Di t



DRUG 1 PARTFILLER-BINDER 2 - 3+ PARTS

DISINTEGRANT

STARCH 10 - 20%OR

SUPER DISINT. 2 - 5%

GLIDANT

COLLOIDAL SILICA 0.5 - 1%LUBRICANT

MAG. STEARATE 0.5 - 1%

General Formula for a Direct

Compression Tablet



Advantages of Direct

Compression over Granulation

n More economical (less time, space, materials,

personnel, fewer steps)

n

Avoids heat and moisture of wet granulationn Disintegrate more directly into primary particles

DC

Gran

Primary Particles

Primary ParticlesGranules

Disintegration

Disint. Deaggregation



Disadvantages of Direct

Compression

n Problem of content uniformity for low dose drug

n Not practical for large dose poorly

compactible/poorly flowing drugsn Requires tight control over physical properties

filler-binder



Generally, direct compressionFil ler-Binders are common fillersthat have been physicallymodified.



n Microcrystalline Cellulose (MCC)

(isolated from cellulose fibers by acid hydrolysi

[Avicel]èMost compactible material available for

pharmaceutical use

èWhen made from mostly MCC, tablets self-

disintegrate and require little lubricant.n Spray processed lactose [Fast Flo Lactose]

èminigranulation of lactose crystals glued togethe

by small amount amorphous lactose

Examples of Direct Compression

Filler-Binders



n Dicalcium phosphate dihydrate, unmilled [Ditab

Emcompress]è

minigranules made up of agglomerated crystallitn Spray processesd sucrose [Dipac]

èUsed in chewable tablets

èminigranulation of sugar crystals "glued" togethe

with amorphous dextrins

Examples of Direct Compression

Filler-Binders



n GranulateèGranulation is a size enlargement process:

Improves Flowability

è Addition of a BINDER that "glues " the particles

together into granules helps to hold the overall

tablet together: Improves Compactibility

When Direct Compression Is Not

Practical*...

*i.e. large-dose, poorly compactible

and/or poorly flowing drugs



The Traditional Granulation

Method is Wet Granu lat ion

n Involves wetting the powders with binder soluti

("glue") and then a drying step.è

Wet Massing Techniques – Low Shear Granulation

– High Shear Granulation

èFluid Bed Granulation

n Not practical for drugs sensitive to water or heaè Alternative: Dry Granulation

– Slugging or Roller Compaction

d e r



Fillers (General) That May Be

Used in Granulation

n lactose

n dicalcium phosphate

n sucrosen microcrystalline cellulose (adjunctive)

Standard or

conventional

forms - not

modified for DC



Typical Wet Granulation Formula

for a drug with 300 mg dose...

n Drug: 300 mg

n Filler: 182.5 mg (e.g.lactose powder)

n Disintegrant: 15 mg (3% croscarmellose)

n Lubricant: 2.5 mg (0.5%magnesium

stearate)

Per Tablet

In this example,total tablet weight = 500 mg

ØOption to reduce or omit filler and make

smaller tablets



of Selected Fillers

(mgmin-1cm2 at 37o)

Anhydrous Lactose

Purified Water – 21.9Lactose Monohydrate

Purified Water – 12.4

Dicalcium Phosphate, Dihydrate

0.1M HCl – 6.27

0.01M HCl - 0.90

Anhydrous Dicalcium Phosphate

0.1M HCl – 5.37

0.01M HCl - 0.69Calcium sulfate dihydrate

0.1M HCl – 1.15

0.01M HCl – 0.75

.D. Koparkar, L.L. Augsburger, and R.F. Shangraw. Intrinsic dissolution rates of tablet filler-binders



LUBRICANTS



The Three Lubricant Roles

n True Lubricant RoleèReducing friction between sliding surfaces,

traditionally at the tablet-die wall interface during

tablet formation and ejection. Also applies tocapsule plugs.

n Antiadhesion RoleèPreventing sticking to surfaces, e.g., the faces o

tablet punches, capsule tamping pins.n Glidant Role

èImproving flow by modifying the interaction

between particles





Concept of a "Lubricant System"

n Frequently two substances are used in a

formulation to maximize overall lubricant effect i

all three areas:èFor example, combining magnesium stearate wit

a colloidal silica



Some Lubricant Issues

n The most effective true lubricants arehydrophobic and if too much is used, they can

interfere with disintegration and dissolution

èMagnesium stearateèCalcium stearate

n Lubricant generally interfere with bonding and

can soften tabletsn Alkaline metal stearates are incompatible with

some drugs, e.g. aspirin and ascorbic acid.



Some Lubricant Issues

(cont inued)

n Laminar lubricants (magnesium stearate, calciu

stearate) are "mixing sensitive."

Ø

Under the rigors of mixing they delaminate toincrease their Nw

Ø The effect can be equivalent to adding too

much lubricant!

Laminar Structure of



Laminar Structure ofMagnesium Stearate





Glidants

n Usually added to enhance the flowability of direcompression mixtures.

n There is an optimim concentration at which flo

is bestØ Usually <1% and often 0.25 - 0.5% for the

colloidal silicasèThe optimimum concentration is related to the

amount needed to just coat the bulk powder

particles

n Higher concentrations may be needed to corre

serious adhesion (sticking) to punch faces.

Eff f C i f Glid



Effect of Concentration of Glidan

on Flow Rate

Effect of Glidant on the Flowability of Microcrystalline

Cellulose

020

40

60

80

100

120140

0 0.2 0.4 0.6 0.8 1 1.2

Percent Cab-O-Sil

F l o

w

R a t e ( g / m i n )



DISINTEGRANTS



DISINTEGRANTS

Substances routinely included in tablet formulations

and in many hard shell capsule formulations

to promote moisture penetration and dispersion of

the matrix of the dosage form in dissolution fluids to

expose primary drug particles.



GRANULES

PRIMARY

DRUG

PARTICLES

DRUG IN SOLUTION

DEAGGREGATION

D I S I N T

E G R A

T I O N

DISINTEGR ATION

Disintegration Process



Disintegrant Mechanisms

All disintegrants are hygroscopic and draw liquidinto the matrix ("liquid uptake" or "wicking

action").

èMay generate a hydrostatic pressure. As they sorb liquid, they may:èSwell extensively (Sodium Starch Glycolate, NF)

èRecover shape with little swelling (Crospovidone,

NF; Starch, NF)

èSwell radially and straighten out [fibrous material]

(Croscarmellose Sodium, NF)

Di i t t M h i



Disintegrant Mechanism

(cont inued)

n Together, these phenomena create a

disintegrating force within the matrix

The rapid buidup of a disintegrating force

promotes rapid disintegration.

èThe liquid uptake may also contribute by

initiating binder and/or matrix dissolution to

weaken the tablet.

Types and Use Levels of Disintegrants



Types and Use Levels of Disintegrants

n Starch: 5-15%

n

Croscarmellose sodium*èDC: 1-3%

èWet Granulation: 2-4%

n Crospovidone*è2-4%

n Sodium Starch Glycolate*è4-6%

___________________ * "Super-Disintegrants"

Note: For powder filled hard gelatin capsules, 4-8% is usually

used. Crospovidone and Starch not recommended for capsul

ass ca on o uper



ass ca on o uperisintegrants

odified Cellulose [Croscarmellose Sodium, NF]Sodium carboxymethyl cellulose which has been crosslinked to

ender it insoluble)

Ø AcDiSol (FMC Corp.)

rosslinked Polyvinylpyrrolidone [Crospovidone, NHigh MW and cross linking render it insoluble)

ØPolyplasdone XL (ISP Corp.)

odified Starch [Sodium Starch Glycolate, NF]Sodium carboxymethyl starch; crosslinking reduces solubility)

ØPrimojel (Generichem Corp.)

ØExplotab (Edward Mendell Co.)

S di St h Gl l t



Upon Exposure to 100% RH Air

Sodium Starch Glycolate

When formulations are granulate



When formulations are granulate(wet or dry), disintegrants are be

added...

n 1/2 before granulation (intragranular)

n 1/2 after granulation (extragranular)



D i s i n t e g r a t i o

n T i m e P

o r o s i t y

Compression Force

An interesting relationship...

Theoretical Representation of the



Theoretical Representation of the

Relationship Between Disintegrant Swelli

and Bed Porosity

Do

D1D2

Do = Mean Pore Diameter

Fast-DisintegratingTablets for th



n Can enhance compliance in patient populations

that have difficulty in swallowing conventional

tablets.èThose elderly persons or children who have

difficulty chewing or swallowing tablets and

capsulesn Bed-ridden patients

n Active working people who may not have acces

to water for swallowing solid dfs

Fast DisintegratingTablets for thMouth

Disintegrate in mouth in ~10 secs or less.



Capsules



Capsules

A. Hard Shell Capsules

1. Types, properties and manufacture of shells

2. Overview of filling equipment with emphasis

on formulation requirements.

3. Factors Affecting Drug ReleaseFormulation and Excipients

B. Soft Shell Capsules

1. Composition/excipients

2. Manufacture

3. Factors Affecting Drug Release



Hard Gelatin vs Soft Gelatin



Hard Gelatin vs Soft Gelatin"Softgels" Capsules

Criterion Soft gelatin

Capsules

Hard Gelatin

CapsulesShell Plasticized (glycerin,

propylene glycol,sorbitol)

Not plasticized

Content Usually liquids or

suspensions (dry

solids possible)

Usually dry solids

(liquids/semi-solid

matrices possible)

Manufacture Formed/filled in one

operation

Shells made in one

operation and filled in

a separate process

Hard Gelatin vs Soft Gelatin



Hard Gelatin vs Soft Gelatin"Softgels" Capsules

Criterion Soft gelatin

Capsules

Hard Gelatin

CapsulesClosure Hermetically sealed

(inherent)

Traditional friction-fit;

mechanical interlock,banding and liquid

sealing possible

Sizes and Shapes Many Limited

FormulationTechnology

Liquids Solids

Fill Accuracy 1-3% 2-5% (with modern

automatic machines

Some hard shell capsules are



Some hard shell capsules aremade from materials other than

gelatin...

n Starch hydrolysate: "Capill"

n Hydroxypropyl methyl cellulose ("Vegicaps" anothers)

Such alternatives to gelatin will be of interest to those who,

for religious, cultural or other reasons wish to avoid capsules

made from animal derived components.



HARD GELATINCAPSULES

Advantages of Hard Gelatin



Advantages of Hard GelatinCapsules

n Rapid drug release possible.

n Flexibility of formulationèEasily compounded (Rx practice).

èNo need to form a compact that must stand up t

handling.

èUnique mixed fills possible.

èRole in drug development.èRole in clinical tests.

n Sealed HGCs are good barriers to atmospheric

oxygen.

sa van ages o ar e a n



gapsules

Very bulky materials are a problem.

Filling equipment slower than tableting.

Generally more costly than tablets, but must judgeon a case-by-case basis.

Concern over maintaining proper shell moisturecontent.Ø Shell should have moisture content of 13-15%

§ If too dry – become brittle/easily fractured

§It to moist – become too soft and can get sticky

Ø Unprotected capsules are best stored at 45-65%RH.

Ø Caution using strongly hygroscopic drugs.

Cross-linking [can affect soft gelatin capsules, hard

gelatin capsules, gelatin coated tablets]

Sizes and Approximate Capacities



pp p

1041682402964005446247288161096Capacity

(mg) at

packing

density =

0.8 g/mL

0.100.210.300.370.500.680.780.911.021.37Volume

(mL)

5432100 el0000 el000Size

3

000

0

“DB”

Ca sule

Composition of Hard Gelatin



n GelatinèBone Gelatin (Type B)

èSkin Gelatin (Type A)

n Water

n Dyes and Other Colorants

n Opaquing Agent (TiO2)

n Preservative

Composition of Hard Gelatin

Shells

Most important properties of gelatin



n Bloom strengthè A measure of relevance to cohesive strength of

gelatin filmèTypically 150-280 "bloom-grams"

– The weight in g required to depress a plunger

12.7 mm diameter 4 mm into a 6.67% gel heldfor 17 hours at 10 degrees (O.T. Bloom, 1925)

n ViscosityèSingle most important factor controlling shell

thicknessèCapillary viscometer; 6.67% soln.

èTypical range 25-45 millipoise.

g

The Dipping Process of Making



pp g gHard Gelatin Capsules

anufacturers

N. Amer.Ø Shionogi Qualicaps

Ø Capsugel div.Pfizer

Ø Pharmaphil (Canada)



n Reasons/NeedèTamper resistance/tamper evidence

èPrevents inadvertent separation on

handling/shipping

èMakes liquid/semi-solid filling of hard gelatin

capsules possible

èSealed capsules are excellent barriers to O2

Sealing and Positive Closure

Mechanically Interlocking Caps



n Interlocking rings or bumps molded into the cap

and body side-wallsèPosilok (Shionogi)

èSnap-Fit and Coni-snap (Capsugel)

èLox-it (Pharmaphil)

y g pand Bodies

ec an ca n er oc - nap-



Traditional Prefit Locked

pFit (Capsugel)

S li d W ldi M th d



n BandingèOriginal banded hard

gelatin capsule - Parke

Davis' "Kapseal"

èModern bandingprocess - Shionogi's

Qualiseal

n Liquid sealing

èCapsugel's Licaps

GelatinBand

Sealing and Welding Methods



Study of Oxygen Permeation

CAPSULE TYPE cm3 O2 /24 hrs

Traditional Friction Fit

(Non-interlocking)

0.280

Posilok (interlocking) 0.0650

Posilok + Band 0.0011

Source: Shah and Augsburger (1989)

Output Capacities of Some



Semi-automatic

Output Capacities of Some

Capsule Filling Machines

No. 8 Machine

Zanasi Z-5000/R3

MG2 G100 100,000/hr

Bosch GKF 3000 180,000/hr

Osaka R-180

150,000/hr

120,000 -

140,000/Shift

165,000/hr

Fully Automatic



PLUG

TODAY, HARD GELATIN

CAPSULES ARE MOST OFTENFILLED BY AUTOMATIC

MACHINES WHICH RESEMBLE

TABLET PRESSESTO THE EXTENT THAT -

èTHEY FORM POWDER PLUGS BY

COMPRESSION , ANDèEJECT THEM INTO EMPTY

CAPSULE BODIES

Dosator Principle



Dosator Principle

MG2 FuturaDosator Machine



Dosator Machine

36,000 caps/hr

Dosing Disc Principle



g



Bosch

GKF 1500

Dosing Disc

Machine

90,000/hr

Factors Affecting Drug



n Overall Dissolution Rate is a Function of:è

Dissolution Rate of the ShellèRate of Penetration of Dissolution Medium

èRate of Deaggregation of Powder Mass

èNature of Primary Drug Particles

Dissolution From Hard Gelatin

Capsules

Except for the shell, sounds like tablets!

ormally, shell ruptures and dissolves withinhell Dissolution and Rupture



ormally, shell ruptures and dissolves withinbout 4 minutes.èRupture occurs first at the shoulders where shell

wall is thinnest.èEnds fall away and as liquid penetrates and

deaggregation occurs, formulation tend to spill

out of the two ends.

ross-linking can reduce shell solubility inater.è Aldehydes, or prolonged exposure to elevated

temperatures and/or high humidity.èIn moderate cases, not physiologically significant

since GI fluids contain proteolytic enzymes.

èTwo-tiered dissolution test recommendedto USP by Industry-FDA Working Group

Active Ingredient



n Highly water soluble drugs exhibit few formulati

problems in terms of drug release from eithertablets or capsules.

n Micronization of poorly soluble drugs can impro

dissolution from tablets and capsules.è Affect on flow and mixing

– Adsorption to surfaces of filler particles (a form

ordered mixing) may help

èEffective surface area may be reduced byagglomeration of micronized particles.Ø Addition of a wetting agents (surfactants)

may help.

Filler (Diluent)



n Fillers include lactose, starch, dicalcium phosphate.ØForms modified for direct compression tableting are usef

for flow/compactibility - especially important for plug formi

machines.

n Consideration the solubility of drug in selecting a filler.

ØWater soluble fillers are preferred for poorly soluble drug

ØIn certain instances, a large percent of soluble filler in the

formulation has slowed the dissolution of a soluble drug.

n Possible incompatibilitiesØClassic example: Tetracycline formulated with calcium

phosphate.



Lubricants



n Glidants (colloidal silicas such as Cab-O-Sil)

è Optimum concentration generally <1%, typica0.25-50%.

n True Lubricants and Antiadherents (e.g. metalli

stearates, stearic acid)èBest lubricants are hydrophobic

– Increasing concentrations usually retard

dissolution.

– Blending time an issue with laminar lubricants.l Avoid overmixing

èEffect is exacerebated at higher degrees o

compaction.

Combined Effect of MagnesiumStearate and Compaction



Dense

Packing

5% Mag.

Stearate

0% Mag. Stearate

Stearate and Compaction

Disintegrants: sodium starch



n Speed up drug dissolution by...èPromoting liquid penetration (wicking)

èPromoting deaggregationn Efficiency often improves with increased tampi

force.

n May be effectively used at levels from 4-8%.

g

glycolate; croscarmellose

sodium*

*Crospovidone not as effective in capsules at

equivalent concentrations

Surfactants: sodium docusate;



n Speed up dissolution by...è Increasing wetting of powder mass (can overco

the waterproofing effect of hydrophobic lubricants

n Typical use levelsèSLS, 1-2%

èSodium docusate, 0.1-0.5%

Surfactants: sodium docusate;

sodium lauryl sulfate

SOFT GELATIN



SOFT GELATIN

CAPSULES(aka “Softgels”

n Similar to hard gelatin shell, except

plasticizer is incorporated (sorbitol,

propylene glycol, glycerin)

n Usually filled with liquids or suspensions

(dry solids are possible, including

compressed tablets (“Geltabs”).

R e m i n d e r

Advantages of Soft Gelatin



n High Accuracy/precision possible

n Hermetically sealed (inherently)

n Possible bioavailability advantages

n Reduced dustiness; lack of compression stage i

manufacture

n Possible reduced gastric irritancy compared to

tablets and hard shell capsulesn Specialty packages available

Advantages of Soft Gelatin

Capsules

Examples of Soft Gelatin



Capsules

Seam

Suppositories

Disadvantages o o t elatinCapsules



n Generally, product is contracted out to a limited

number of specialty houses,e.g. Scherer, Bann

n Generally more costly to produce than tablets o

hard shell capsules

n More intimate contact between the shell andcontents than with dry-filled hard shell capsules

stability a concern.

n Not adaptable to incorporation of more than onekind of fill into the same capsule (compare with

hard shell capsules)

Capsules

F l ti



nPure liquids, mixtures of miscible liquids, orsolids dissoved or suspended in a liquidvehicle.

nVehiclesØ Water immiscible non-volatile liquids

n vegetable oilsn Mineral oil not recommended for drug formulations.

Ø Water-miscible, non-volatile liquidsn Low molecular weight PEG'sn Nonionic surfactants such as polysorbate 80

Formulation

Li it ti f Li id C t t



n Water cannot exceed 5% of contents

n pH must be between 2.5 and 7.5n Low molecular weight water soluble and

volatile compounds must be excludedn Aldehydes, in general, must be excluded(Cause cross-linking)

n Contents must flow under gravity at

< 35 degrees

Limitations of Liquid Contents

Most Soft Gelatin Capsules are



n Original Rotary Die Process (R.P. Scherer: 193èOnly for pumpable fills

n Accogel Process (Stern Machine) - Lederle: 19è A rotary die process for filling powders, granules

into soft gelatin capsules

p

Made Using a Rotary Die Proces



1. Gelatin ribbon

2. Rotary die

3. Filling Wedge

4. Filled capsule

5. Webbing6. Pumpingmechanism

1

2

3

4

5

6

4



Rotary Die

process

Documents

Tablet and Capsules