tablets and capsules: design and formulation
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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 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
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