Hard and Soft Shell Capsules

Design,Formulation and Manufacture

Larry L. Augsburger University of Maryland Baltimore, MD

Outline
Types and Properties of Capsules Hard Shell Capsules 1. Properties and shell manufacture 2. Filling equipment 3. Instrumented Filling Machines 4. Formulation and Excipients 5. Factors Affecting Drug Release III. Soft Shell Capsules 1. Shell Composition 2. Formulation and Excipients 3. Factors Affecting Drug Release
I. II.

The capsule can be viewed as a container dosage form...

Odorless Tasteless Easily swallowed Elegant

Hard Gelatin vs Soft Gelatin "Softgels" Capsules

Criterion
Shell Content

Soft gelatin Capsules

Plasticized (glycerin, propylene glycol, sorbitol) Usually liquids or suspensions (dry solids possible)

Hard Gelatin Capsules

Not plasticized Usually dry solids (liquids/semi-solid matrices possible)

Manufacture

Formed/filled in one Shells made in one operation operation and filled in a separate process

Hard Gelatin vs Soft Gelatin "Softgels" Capsules

Criterion
Closure

Soft gelatin Capsules

Hermetically sealed (inherent)

Hard Gelatin Capsules

Traditional friction-fit; mechanical interlock, banding and liquid sealing possible Limited Solids 2-5% (with modern automatic machines)

Sizes and Shapes Formulation Technology Fill Accuracy

Many Liquids 1-3%

Some hard shell capsules are made from materials other than gelatin...
Starch hydrolysate: "Capill" Hydroxypropyl methyl cellulose: eg. "Vegicaps (Vegicaps Technologies, div. American Home Products ), V-caps (Capsugel div. Pfizer)

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 Capsules

Rapid drug release possible. Flexibility of formulation

No need to form a compact that must stand up to

handling. Unique mixed fills possible. Role in drug development. Role in clinical tests.

Sealed HGCs are good barriers to atmospheric oxygen.

Disadvantages of Hard Gelatin Capsules

Very bulky materials are a problem. Filling equipment slower than tableting. Generally more costly than tablets, but must judge on a case-by-case basis. Concern over maintaining proper shell moisture content.

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 Unprotected capsules are best stored at 45-65%RH. Caution using strongly hygroscopic drugs.

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

Composition of Hard Gelatin Shells

Gelatin
Bone Gelatin (Type B) Skin Gelatin (Type A)

Water Dyes and Other Colorants Opaquing Agent (TiO ) 2 Preservative

Most important properties of gelatin

Bloom strength
A measure of cohesive strength of gelatin film Typically 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)

Viscosity
Single most important factor controlling shell

thickness Capillary viscometer; 6.67% soln. Typical range 25-45 millipoise.

Sealing and Positive Closure

Reasons/Need
Tamper resistance/tamper evidence Prevents inadvertent separation on

handling/shipping Makes liquid/semi-solid filling of hard gelatin capsules possible Sealed capsules are excellent barriers to O2

Mechanically Interlocking Caps and Bodies

Interlocking rings or bumps molded into the cap and body side-walls
Posilok (Shionogi) Snap-Fit and Coni-snap (Capsugel) Lox-it (Pharmaphil)

Study of Oxygen Permeation

CAPSULE TYPE
Traditional Friction Fit (Non-interlocking) Posilok (interlocking) Posilok + Band

cm2 O2 /24 hrs

0.280

0.0650 0.0011

Source: Shah and Augsburger (1989)

Hard Gelatin Filling Machines

Output Capacities of Some Capsule Filling Machines

Semi-automatic No. 8 Machine 120,000 140,000/Shift

Fully Automatic Zanasi Z-5000/R3 150,000/hr MG2 G100 100,000/hr

Bosch GKF 3000 180,000/hr Osaka R-180 165,000/hr

DIFFERENCES BETWEEN TABLETS AND PLUGS

Compression forces generally 50 - 200N -Tablets: up to 50 KN High Height-to-Diameter Ratios (e.g. 5:1)
Tablets: <1 (e.g. 0.3)

Breaking Strength ["Hardness] typically under 1N

Tablets: typically ~100N in diametral compression

DOSATOR MACHINES
BASIC FORMULATION REQUIREMENTS
Flowability Lubricity Compactibility

FILL WEIGHT
Piston Height

(Primary)
Powder Bed Height

A stable arch across dosator outlet is necessary to prevent loss of powder.

DOSING DISK MACHINES

BASIC FORMULATION REQUIREMENTS
Flowability Lubricity Compactibility

FILL WEIGHT
Disk Thickness Powder Height Tamp Force Number of Tamps

Instrumented Filling Machines

NEW ERA OF FORMULATION RESEARCH FOR CAPSULES

Interplay of formulation and machine operating variables
Effect on capsule running Effect on performance of the capsule as a drug delivery system

Identification of critical variables Selection of excipients and their levels Validation and Scale up

INSTRUMENTED DOSATOR MACHINES

DATE
1972, 1975 1975, 1977 1977 1980 1980 1983

INVESTIGATORS
Cole & May Small & Augsburger Mony, Sambeat, & Cousin Greenberg Mehta & Augsburger Rowley, Hendry, Ward & Timmins Maury, Heraud, Etienne, Aumonier Casahoursat Hauer, Remele & Sucker

MACHINE
Zanasi LZ-64 Zanasi LZ-64 Zanasi LZ-64 Zanasi AZ-20 Zanasi LZ-64 Zanasi LZ-64

METHODS
Strain gaged piston; Planetary gear system Strain gaged piston; Mercury pool swivel Piezoelectric load washer on piston end Strain gaged piston; slip ring LVDT added Piezoelectric load washer mounted on ejection knob Piezoelectric load cells mounted on ejection knob & in overload mechansism. Strain gaged piston

1986

Zanasi LZ-64

1993

Zanasi LZ-64

INSTRUMENTED DOSING DISK MACHINES

DATE
1983

INVESTIGATORS
Shah, Augsburger, Small & Polli Shah, Augsburger, & Marshall Botzolakis, Harris & Weiss Cropp, Augsburger & Marshall Podczeck

MACHINE
Hofliger & Karg GKF 330 Hofliger & Karg GKF 330 Hofliger & Karg GKF 330 Hofliger & Karg GKF 330 Bosch GKF 400S

METHODS
Strain gaged pistons (two stations) Strain gaged pistons (all stations) Strain gaged load cell mounted above piston LVDT's added Piezoelectric force transducer - instrumented tamping block

1986

1988 1988 2000

Force - Time / Force - Displacement Profiles from a GKF 330

80 70 60 50 1 0 -1

Displacement (mm)
0 100 200 300 400 500 600

-2 -3 -4 -5 -6 -7 -8 0 100 200 300 400 500

Force (N)

40 30 20 10 0 -10

Time (ms)

Time (ms)

(Cropp, Augsburger, & Marshall, 1988)

Formulation Principles

Formulation Design Goals and Issues

Successful running characteristics
Requirements of fluidity and lubrication similar to tableting Blending & homogeneity Compactibility May be required to run on different machines

Drug delivery
Proper accounting of the interplay of formulation and process variables is required to assure that performance as a drug delivery system will not be compromised.

Product Stability/Compatibility of components

Factors Affecting Drug Dissolution From Hard Gelatin Capsules

Overall Dissolution Rate is a Function of:

Dissolution Rate of the Shell Rate of Penetration of Dissolution Medium Rate of Deaggregation of Powder Mass Nature of Primary Drug Particles

Except for the shell, sounds like tablets!

Active Ingredient
Highly water soluble drugs exhibit few formulation problems in terms of drug release from either tablets or capsules. Micronization of poorly soluble drugs can improve dissolution from tablets and capsules.

Affect on flow and mixing

to surfaces of filler particles (a form of ordered mixing) may help Effective surface area may be reduced by tendency of micronized particles to agglomerate.
Addition of a wetting agents (surfactants) may help.

Adsorption

Filler (Diluent)

Fillers include lactose, starch, dicalcium phosphate.

Forms modified for direct compression tableting are useful for flow/compactibility - especially important for plug forming machines.
Anhydrous Lactose (Direct tableting Grade); Fast-Flo Lactose Microcrystalline Cellulose Starch 1500 Dicalcium phosphate dihydrate, unmilled (Ditab, Emcompress)

Consider the solubility of drug in selecting a filler.

Water soluble fillers are preferred for poorly soluble drugs In certain instances, a large percent of soluble filler in the formulation has slowed the dissolution of a soluble drug.

Possible incompatibilities

Interesting Case History

(Tyrer et al.)

Intrinsic Dissolution Rates of Fillers

(mg/min/cm2 @ 37o) Anhydrous Lactose (water) - 21.9 Hydrous Lactose (water) - 12.4 Dicalcium phosphate dihydrate 0.1M HCl - 6.27
0.01M HCl - 0.90

Anhydrous dicalcium phosphate

0.1 M HCl - 5.37 0.01 M HCl - 0.69

Calcium sulfate dihydrate (Terra Alba)

0.1 M HCl - 1.15 0.01 M HCl - 0.75

Source: Koparkar, Augsburger, Shangraw, Pharm. Res., 7, 80 (1990)

Lubricants

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

Optimum concentration generally <1%,

typically

0.25-50%.

True Lubricants and Antiadherents (e.g. metallic stearates, stearic acid)

Best lubricants are hydrophobic
Increasing

concentrations usually retard dissolution. Blending time an issue with laminar lubricants (calcium and magnesium stearates)

Avoid overmixing

Effect is exacerebated at higher degrees of

compaction.

Combined Effect of Magnesium Stearate and Compaction

0% Mag. Stearate 5% Mag. Stearate

Dense Packing

(Samyn & Jung)

Effect of Magnesium Stearate Level on HCTZ Dissolution

HCTZDissolution (T-60%)
45 40 35 30 25 20 15 10 5 0 0.5 1 1.5 2 2.5

% Magnesium Stearate
Filler: Microcrystalline cellulose Tamping force: 100N Source: Mehta & Augsburger

Effect of Magnesium Stearate on Plug Breaking Force and Dissolution*

*Hydrochlorothiazide
T-60% % MS

Microcrystalline Cellulose
% MS Plug Strength [N] 84 (1.7) 76 (1.1) 27 (1.5) 4.0 (0.36) 1.8 (0.06)

Anhydrous Lactose Plug T-60% Strength [min.] [N] 18 (2.0) 12 (1.0) 15 (1.2) 15 (1.4) 14 (1.6) 13 (1.2) 13 (0.90) 13 (0.70) 13 (0.59) 18 (1.2)

0.05 0.10 0.20 0.05 0.75

55 (1.2) 36 (0.82) 16 (2.0) 14 (1.6) 12 (0.98)

0.05 0.10 0.20 0.05 0.75

Source: Mehta & Augsburger

Rifampicin Capsules
0.1% Mag. St.
5 min. 30 min. 15 min. Control (No Mag. St.)

Nakagawa, H. et al., Yakagaku Zasshi, 100, 1111-1117 (1980).

Effect of Concentration of Glidant on Flow Rate

Effect of Glidant on the Flowability of Microcrystalline Cellulose
140 120 100 80 60 40 20 0 0 0.2 0.4 0.6 0.8 1 1.2 Percent Cab-O-Sil

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

Flow Rate (g/min)

Disintegrants: sodium starch glycolate; croscarmellose sodium*

Speed up drug dissolution by...

Promoting liquid penetration (wicking) Promoting deaggregation

Efficiency often improves with increased tamping force. May be effectively used at levels from 4-8%.

*Crospovidone not as effective in capsules at equivalent concentrations

Surfactants: sodium docusate; sodium lauryl sulfate

Speed up dissolution by...

Increasing wetting of powder mass (can overcome

the waterproofing effect of hydrophobic lubricants)

Typical use levels

SLS, 1-2% Sodium docusate, 0.1-0.5%

Soft Gelatin Capsules

SOFT GELATIN CAPSULES R

(aka Softgels)

Similar to hard gelatin shell, except plasticizer is incorporated (sorbitol, propylene glycol, glycerin) Usually filled with liquids or suspensions (dry solids are possible, including compressed tablets (Geltabs).

emi nde r

Advantages of Soft Gelatin Capsules

High Accuracy/precision possible Hermetically sealed (inherently) Possible bioavailability advantages Reduced dustiness; lack of compression stage in manufacture Possible reduced gastric irritancy compared to tablets and hard shell capsules Specialty packages available

Disadvantages of Soft Gelatin Capsules

Generally, product is contracted out to a limited number of specialty houses,e.g. Scherer, Banner. Generally more costly to produce than tablets or hard shell capsules More intimate contact between the shell and contents than with dry-filled hard shell capsules stability a concern. Not adaptable to incorporation of more than one kind of fill into the same capsule (compare with hard shell capsules)

Formulation
Pure liquids, mixtures of miscible liquids, or solids dissoved or suspended in a liquid vehicle. Vehicles

Water immiscible non-volatile liquids

Water-miscible, non-volatile liquids

vegetable oils Mineral oil not recommended for drug formulations. Low molecular weight PEG's Nonionic surfactants such as polysorbate 80

Limitations of Liquid Contents

Water cannot exceed 5% of contents pH must be between 2.5 and 7.5 Low molecular weight water soluble and volatile compounds must be excluded Aldehydes, in general, must be excluded (Cause cross-linking) Contents must flow under gravity at < 35 degrees

Most Soft Gelatin Capsules are Made Using a Rotary Die Process

Original Rotary Die Process (R.P. Scherer: 1933)

Only for pumpable fills

Accogel Process (Stern Machine) - Lederle: 1948

a rotary die process for filling powders, granules

into soft gelatin capsules

Rotary Die process

General Bibliography
L.L. Augsburger, "Hard and Soft Gelatin Capsules," Chapter 11 in Modern Pharmaceutics, 3nd Edition, G. Banker and C.T. Rhodes (Editors), Marcel Dekker, Inc., New York, NY, 1995. Hostetler, V. and Bellard, J.Q., Capsules I. Hard Capsules, in Lachman, L., Lieberman, H.A., and Kanig, J.L. (eds), The Theory and Practice of Industrial Pharmacy, 2nd ed., pp. 389-404, Lea and Febiger, Philadelphia, PA, 1976. Stanley, J.P., Capsules II. Soft Gelatin Capsules. In Lachman, L., Lieberman, H.A. and Kanig, J.L. (eds.), Theory and Practiceof Industrial Pharmacy, 2nd ed., pp. 404-420 (1976), Lea and Febiger, Philadelphia, PA, 1976.