Tablets and Capsules: Design and Formulation

PHAR 535: Pharmaceutics

Larry L. Augsburger, Ph.D.

A. Compaction B. Tablets as a Dosage FormC. Minimum Running CharacteristicsD. Overview of Manufacturing Methods

1. Direct Compression2. Granulation

E. Tablet Composition1. Formulation2. Excipients: functionality and mechanism

F. Factors Affecting Drug ReleaseG. “Fast-Melt” Tablets

Compressed Tablets

Tableting is a COMPACTIONProcess and Involves Two Steps...

n CompressionèReduction in bulk volume by

eliminating voids and bringing particles into closer contact.

n ConsolidationèIncreased mechanical strength

due to interparticulateinteractions

Rearrangement ØPlasticDeformation (and/orviscous flow) ØBrittle Fracture

Stages of CompressionSingle-Ended Compression

Elastic limitexceeded

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 the

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 tablets can be made.èTablet mechanical strength may be measured by...

– 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

Compression Force ( kg )

Har

dnes

s (

kg )

Compaction Profiles of Some Direct Compression Fillers

(0.75% magnesium stearate)

Avicel PH 101(microcrystalline cellulose)

Fast Flo Lactose

Emcompress(dicalc. phosph.dihydrate, unmilled)

Dipac(coprocessed sucrose)

Starch 1500(pregelatinized starch)

200 900 1600

0

4

8

12microcrystalline cellulose

RDWF = Residual Die Wall ForceEF = Ejection Force

EF = RDWF x = coeff. friction at die wallw

w

Fr

NFr = N

Tablet Ejection and Ejection Force

RDWF

EF

RDWF

Die wall lubricants reduce friction by interposing a film of low shear strength between the tablet mass and the confining die wall…

n Magnesium stearaten Stearic Acid

The structure formed must be strong 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

Lower Punch

Double-Ended CompressionRotary (Multistation) Press

Examples of Tooling

View of Punch Train

High Speed Production Rotary Tablet Press

55 stations495,000 tabs/hour

n Ease of Administration and Patient AcceptanceèSwallowing

– Size– Coating

èChewable FormulationsèElegence

n Convenience/Compactnessn Accurate Dosagen Stability

Compressed Tablets as a Dosage Form

lControl of Release Possiblen Delayed Releasen Extended Release

ER CORE

IR DOSE

ER CORE

IR DOSE

IR DOSE

IR DOSE

BarrierCoating

BarrierCoatedBeads

Compressed Tablets as a Dosage Form(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 solubility;malformulation)

Design and Formulation of Compressed Tablets (IR)n Minumum running characteristicsèCompactibilityèFluidityèLubricity

Excipients and the method of manufacture are selected to provide these characteristics.

Manufacturing Methodsn GranulationA complex process of first forminggranules from the mix and then tableting the granules.èWetèDry

n Direct CompressionSimply mix and compress.

n Size of Dosen Compactibility and/or Fluidity of Drugn Stability Characteristics of the Drug

Choice of Method Depends on Several Factors

n LOW DOSE (<25MG)(Most of the tablet will be excipients)èContent Uniformity

n 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 Can 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 glidantn Can assure rapid disintegration by adding disintegrant

Blend Compress

DRUG 1 PARTFILLER-BINDER 2 - 3+ PARTS

DISINTEGRANTSTARCH 10 - 20%

ORSUPER DISINT. 2 - 5%

GLIDANTCOLLOIDAL SILICA 0.5 - 1%

LUBRICANTMAG. STEARATE 0.5 - 1%

General Formula for a Direct Compression Tablet

Advantages of Direct Compression over Granulationn 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 Compressionn Problem of content uniformity for low dose drugsn Not practical for large dose poorly compactible/poorly flowing drugs

n Requires tight control over physical properties of filler-binder

Generally, direct compression Filler-Binders are common fillers that have been physically modified.

n Microcrystalline Cellulose (MCC)(isolated from cellulose fibers by acid hydrolysis) [Avicel]èMost compactible material available for

pharmaceutical useèWhen made from mostly MCC, tablets self-

disintegrate and require little lubricant.n Spray processed lactose [Fast Flo Lactose]èminigranulation of lactose crystals glued together

by small amount amorphous lactose

Examples of Direct Compression Filler-Binders

n Dicalcium phosphate dihydrate, unmilled [Ditab,Emcompress]èminigranules made up of agglomerated crystallites

n Spray processesd sucrose [Dipac]èUsed in chewable tabletsèminigranulation of sugar crystals "glued" together

with amorphous dextrins

Examples of Direct Compression Filler-Binders

n GranulateèGranulation is a size enlargement process:

Improves FlowabilityèAddition 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 compactibleand/or poorly flowing drugs

The Traditional Granulation Method is Wet Granulationn Involves wetting the powders with binder solution ("glue") and then a drying step.èWet Massing Techniques

– Low Shear Granulation– High Shear Granulation

èFluid Bed Granulationn Not practical for drugs sensitive to water or heat.èAlternative: Dry Granulation

– Slugging or Roller Compaction

Reminder

Fillers (General) That May Be Used in Granulation

n lactosen dicalcium phosphaten sucrosen microcrystalline cellulose (adjunctive)

Standard orconventionalforms - 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 mgØOption to reduce or omit filler and make smaller tablets

Intrinsic Dissolution Ratesof Selected Fillers

(mgmin-1cm2 at 37o)

Anhydrous Lactose Purified Water – 21.9 Lactose 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 - 0.69 Calcium sulfate dihydrate 0.1M HCl – 1.15 0.01M HCl – 0.75

A.D. Koparkar, L.L. Augsburger, and R.F. Shangraw. Intrinsic dissolution rates of tablet filler-bindersand their influence on the dissolution of drugs from tablet formulation. Pharm Res 7: 80-86, 1990.

LUBRICANTS

The Three Lubricant Rolesn True Lubricant RoleèReducing friction between sliding surfaces,

traditionally at the tablet-die wall interface during tablet formation and ejection. Also applies to capsule plugs.

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

tablet punches, capsule tamping pins.n Glidant RoleèImproving flow by modifying the interaction

between particles

LubricantsIn a general sense

Lubricant Typical Level

True Lubricant Activity

Anti-adherentActivity

GlidantActivity

MetallicStearates

e.g. mag. st., calcium st.

0.5 - 1% Excellent Good Poor*

Stearic Acid 1-5% Good Good Nil

Colloidal Silicas <1% Nil Good Excellent

Talc 1-5% Poor Excellent Good

Concept of a "Lubricant System"

n Frequently two substances are used in a formulation to maximize overall lubricant effect in all three areas:èFor example, combining magnesium stearate with

a colloidal silica

Some Lubricant Issuesn The most effective true lubricants are hydrophobic and if too much is used, they can interfere with disintegration and dissolutionèMagnesium stearateèCalcium stearate

n Lubricant generally interfere with bonding and can soften tablets

n Alkaline metal stearates are incompatible with some drugs, e.g. aspirin and ascorbic acid.

Some Lubricant Issues(continued)n Laminar lubricants (magnesium stearate, calcium stearate) are "mixing sensitive." Ø Under the rigors of mixing they delaminate to

increase their Nw Ø The effect can be equivalent to adding too

much lubricant!

Laminar Structure of Magnesium Stearate

Some Lubricant Issues(continued)n Lubricants are always added last after all other components have been thoroughly mixed.èMixing time of 2-5 minutes

n Water soluble lubricants are not nearly as effective as the hydrophobic lubricants.èUsed when a tablet must be completely water

soluble (e.g., effervescent tablets)èExamples: DL Leucine, sodium benzoate,

polyethylene glycol 8000

Glidantsn Usually added to enhance the flowability of direct compression mixtures.

n There is an optimim concentration at which flow 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 correct serious adhesion (sticking) to punch faces.

Effect of Concentration of Glidanton Flow Rate

Effect of Glidant on the Flowability of Microcrystalline Cellulose

020406080

100120140

0 0.2 0.4 0.6 0.8 1 1.2

Percent Cab-O-Sil

Flo

w R

ate

(g/m

in)

Source: S.T. David and L.L. Augsburger

DISINTEGRANTS

DISINTEGRANTS

Substances routinely included in tablet formulations and in many hard shell capsule formulationsto 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

DISINTEGRATION

DISINTEGRATION

Disintegration Process

Disintegrant Mechanismsn All disintegrants are hygroscopic and draw liquid into the matrix ("liquid uptake" or "wicking action").èMay generate a hydrostatic pressure.

n 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)

Disintegrant Mechanism(continued)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 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 capsules.

Classification of Super Disintegrants

n Modified Cellulose [Croscarmellose Sodium, NF](Sodium carboxymethyl cellulose which has been crosslinked to render it insoluble)ØAcDiSol (FMC Corp.)

n Crosslinked Polyvinylpyrrolidone [Crospovidone, NF)(High MW and cross linking render it insoluble)ØPolyplasdone XL (ISP Corp.)

§Modified Starch [Sodium Starch Glycolate, NF](Sodium carboxymethyl starch; crosslinking reduces solubility) ØPrimojel (Generichem Corp.)ØExplotab (Edward Mendell Co.)

Upon Exposure to 100% RH Air

Sodium Starch Glycolate

When formulations are granulated (wet or dry), disintegrants are best added...

n 1/2 before granulation (intragranular)n 1/2 after granulation (extragranular)

Dis

inte

grat

ion

Tim

e Porosity

Compression Force

An interesting relationship...

An optimum porosity for best disintegration

Theoretical Representation of the Relationship Between Disintegrant Swelling and Bed Porosity

Do

D1D2

Do = Mean Pore Diameter

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 capsules

n Bed-ridden patientsn Active working people who may not have access to water for swallowing solid dfs

Fast-DisintegratingTablets for the Mouth

Disintegrate in mouth in ~10 secs or less.

Formulating Fast-Disintegrating Tablets for the Mouthn Rapidly soluble components èAmorphous sucroseèMannitol (imparts cooling sensation due to uptake

of heat of solution) [Also used in chewable tabs]èAmorphous or partially amorphous lactose

n Superdisintegrants (some formulations, up to 10%)

n Moderate compression force to achieve high tablet porosity and adequate hardness/friability.

n Freeze-drying to produce a porous matrix

Capsules

A. Hard Shell Capsules1. Types, properties and manufacture of shells2. Overview of filling equipment with emphasis

on formulation requirements.3. Factors Affecting Drug ReleaseFormulation and Excipients

B. Soft Shell Capsules1. Composition/excipients2. Manufacture3. Factors Affecting Drug Release

The capsule can be viewed as a container dosage form...n Odorlessn Tastelessn Easily swallowedn Elegant

Hard Gelatin vs Soft Gelatin "Softgels" CapsulesCriterion Soft gelatin

CapsulesHard Gelatin Capsules

Shell 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 "Softgels" Capsules

Criterion Soft gelatin Capsules

Hard Gelatin Capsules

Closure Hermetically sealed (inherent)

Traditional friction-fit; mechanical interlock, banding and liquid sealing possible

Sizes and Shapes Many Limited

Formulation Technology

Liquids Solids

Fill Accuracy 1-3% 2-5% (with modern automatic machines)

Some hard shell capsules are made from materials other than gelatin...

n Starch hydrolysate: "Capill" n Hydroxypropyl methyl cellulose ("Vegicaps" and others)

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 GELATIN CAPSULES

Advantages of Hard Gelatin Capsulesn Rapid drug release possible.n Flexibility of formulationèEasily compounded (Rx practice).èNo need to form a compact that must stand up to

handling.èUnique mixed fills possible.èRole in drug development.èRole in clinical tests.

n Sealed HGCs are good barriers to atmospheric oxygen.

Disadvantages of Hard Gelatin Capsulesn Very bulky materials are a problem.n Filling equipment slower than tableting.n Generally more costly than tablets, but must judge

on a case-by-case basis.n Concern over maintaining proper shell moisture

content.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.

n Cross-linking [can affect soft gelatin capsules, hard gelatin capsules, gelatin coated tablets]

Sizes and Approximate Capacities

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” Capsule

n Gelatin èBone Gelatin (Type B)èSkin Gelatin (Type A)

n Water n Dyes and Other Colorantsn Opaquing Agent (TiO2) n Preservative

Composition of Hard Gelatin Shells

n Bloom strengthèA 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 held for 17 hours at 10 degrees (O.T. Bloom, 1925)

n Viscosity èSingle most important factor controlling shell

thicknessèCapillary viscometer; 6.67% soln.èTypical range 25-45 millipoise.

Most important properties of gelatin

The Dipping Process of Making Hard Gelatin Capsules

nManufacturersin N. Amer.Ø Shionogi QualicapsØ Capsugel div.PfizerØ Pharmaphil (Canada)

n Reasons/NeedèTamper resistance/tamper evidenceèPrevents inadvertent separation on

handling/shippingèMakes liquid/semi-solid filling of hard gelatin

capsules possibleèSealed capsules are excellent barriers to O2

Sealing and Positive Closure

n Interlocking rings or bumps molded into the cap and body side-wallsèPosilok (Shionogi)èSnap-Fit and Coni-snap (Capsugel) èLox-it (Pharmaphil)

Mechanically Interlocking Caps and Bodies

Traditional Prefit Locked

Mechanical Interlock - Snap-Fit (Capsugel)

n BandingèOriginal banded hard

gelatin capsule - ParkeDavis' "Kapseal"èModern banding

process - Shionogi'sQualiseal

n Liquid sealingèCapsugel's Licaps

GelatinBand

Sealing and Welding Methods

Study of Oxygen Permeation

CAPSULE TYPE cm3 O2 /24 hrsTraditional Friction Fit

(Non-interlocking)0.280

Posilok (interlocking) 0.0650

Posilok + Band 0.0011

Source: Shah and Augsburger (1989)

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 OFTEN FILLED BY AUTOMATIC MACHINES WHICH RESEMBLE TABLET PRESSESTO THE EXTENT THAT -

èTHEY FORM POWDER PLUGS BY COMPRESSION, ANDèEJECT THEM INTO EMPTY

CAPSULE BODIES

Dosator Principle

MG2 FuturaDosator Machine

36,000 caps/hr

Dosing Disc Principle

BoschGKF 1500

Dosing Disc Machine90,000/hr

n Overall Dissolution Rate is a Function of: èDissolution Rate of the Shell èRate of Penetration of Dissolution Medium èRate of Deaggregation of Powder Mass èNature of Primary Drug Particles

Factors Affecting Drug Dissolution From Hard Gelatin Capsules

Except for the shell, sounds like tablets!

n Normally, shell ruptures and dissolves within about 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.

n Cross-linking can reduce shell solubility in water.èAldehydes, 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 recommended

to USP by Industry-FDA Working Group

Shell Dissolution and Rupture

n Highly water soluble drugs exhibit few formulation problems in terms of drug release from either tablets or capsules.

n Micronization of poorly soluble drugs can improve dissolution from tablets and capsules.è Affect on flow and mixing

– Adsorption to surfaces of filler particles (a form of ordered mixing) may help

èEffective surface area may be reduced by agglomeration of micronized particles.ØAddition of a wetting agents (surfactants)

may help.

Active Ingredient

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

for flow/compactibility - especially important for plug forming machines.

n Consideration the solubility of drug in selecting a filler.

ØWater soluble fillers are preferred for poorly soluble drugsØIn 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.

Filler (Diluent)

Interesting Case History

(Tyrer et al.)

n Glidants (colloidal silicas such as Cab-O-Sil) è Optimum concentration generally <1%, typically

0.25-50%.n True Lubricants and Antiadherents (e.g. metallicstearates, 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 of compaction.

Lubricants

(Samyn & Jung)

Dense Packing

5% Mag. Stearate

0% Mag. Stearate

Combined Effect of Magnesium Stearate and Compaction

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

n Efficiency often improves with increased tamping force.

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

Disintegrants: sodium starch glycolate; croscarmellosesodium*

*Crospovidone not as effective in capsules atequivalent concentrations

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

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 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”).

Reminder

n High Accuracy/precision possible n Hermetically sealed (inherently) n Possible bioavailability advantages n Reduced dustiness; lack of compression stage in manufacture

n Possible reduced gastric irritancy compared to tablets and hard shell capsules

n Specialty packages available

Advantages of Soft Gelatin Capsules

Examples of Soft Gelatin Capsules

Seam

Suppositories

n Generally, product is contracted out to a limited number of specialty houses,e.g. Scherer, Banner.

n Generally more costly to produce than tablets or hard shell capsules

n More intimate contact between the shell and contents than with dry-filled hard shell capsules -stability a concern.

n Not adaptable to incorporation of more than one kind of fill into the same capsule (compare with hard shell capsules)

Disadvantages of Soft Gelatin Capsules

nPure liquids, mixtures of miscible liquids, or solids dissoved or suspended in a liquid vehicle.nVehicles

Ø Water immiscible non-volatile liquidsn 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

n Water cannot exceed 5% of contents n pH must be between 2.5 and 7.5 n 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

n Original Rotary Die Process (R.P. Scherer: 1933) èOnly for pumpable fills

n Accogel Process (Stern Machine) - Lederle: 1948èA rotary die process for filling powders, granules

into soft gelatin capsules

Most Soft Gelatin Capsules are Made Using a Rotary Die Process

1. Gelatin ribbon2. Rotary die3. Filling Wedge4. Filled capsule5. Webbing6. Pumping mechanism

1

2

3

4

5

6

4

Rotary Die Process

Rotary Die process