Hard and Soft Shell CapsulesDesign,Formulation and Manufacture

Larry L. AugsburgerUniversity of Maryland

Baltimore, MD���������������

������������������

���������

������������

OutlineI. Types and Properties of CapsulesII. Hard Shell Capsules

1. Properties and shell manufacture 2. Filling equipment3. Instrumented Filling Machines4. Formulation and Excipients5. Factors Affecting Drug Release

III. Soft Shell Capsules1. Shell Composition2. Formulation and Excipients3. Factors Affecting Drug Release

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

■ Odorless■ Tasteless■ Easily swallowed■ 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" CapsulesCriterion Soft gelatin

CapsulesHard 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...

■ 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 fracturedIt 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]

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

■ Water ■ Dyes and Other Colorants■ Opaquing Agent (TiO2) ■ Preservative

Composition of Hard Gelatin Shells

■ 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.

Most important properties of gelatin

■ 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

Sealing and Positive Closure

■ Interlocking rings or bumps molded into the cap and body side-walls

➨ Posilok (Shionogi)➨ Snap-Fit and Coni-snap (Capsugel) ➨ Lox-it (Pharmaphil)

Mechanically Interlocking Caps and Bodies

Study of Oxygen PermeationCAPSULE TYPE cm2 O2 /24 hrsTraditional Friction Fit

(Non-interlocking)0.280

Posilok (interlocking) 0.0650Posilok + Band 0.0011

Source: Shah and Augsburger (1989)

Hard Gelatin Filling Machines

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

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 diametralcompression

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 FORMULATIONRESEARCH 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 INVESTIGATORS MACHINE METHODS1972, 1975

Cole & May Zanasi LZ-64 Strain gaged piston;Planetary gear system

1975,1977

Small & Augsburger Zanasi LZ-64 Strain gaged piston;Mercury pool swivel

1977 Mony, Sambeat, & Cousin Zanasi LZ-64 Piezoelectric load washer on piston end

1980 Greenberg Zanasi AZ-20 Strain gaged piston; slip ring

1980 Mehta & Augsburger Zanasi LZ-64 LVDT added

1983 Rowley, Hendry, Ward &Timmins

Zanasi LZ-64 Piezoelectric load washer mounted on ejection knob

1986 Maury, Heraud, Etienne, Aumonier Casahoursat

Zanasi LZ-64 Piezoelectric load cells mounted on ejection knob & in overload mechansism.

1993 Hauer, Remele & Sucker Zanasi LZ-64 Strain gaged piston

INSTRUMENTEDDOSING DISK MACHINES

DATE INVESTIGATORS MACHINE METHODS1983 Shah, Augsburger,

Small & PolliHofliger & Karg GKF 330

Strain gaged pistons (two stations)

1986 Shah, Augsburger, & Marshall

Hofliger & Karg GKF 330

Strain gaged pistons (all stations)

1988 Botzolakis, Harris & Weiss

Hofliger & Karg GKF 330

Strain gaged load cell mounted above piston

1988 Cropp, Augsburger &Marshall

Hofliger & Karg GKF 330

LVDT's added

2000 Podczeck Bosch GKF 400S Piezoelectricforce transducer - instrumented tamping block

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

0 100 200 300 400 500 600

Time (ms)

-10

0

10

20

30

40

50

60

70

80

Forc

e (N

)

0 100 200 300 400 500

Time (ms)

-8

-7

-6

-5

-4

-3

-2

-1

0

1

Dis

plac

emen

t (m

m)

(Cropp, Augsburger, & Marshall, 1988)

Formulation Principles

Formulation Design Goalsand Issues

• Successful running characteristics– Requirements of fluidity

and lubrication similar totableting

– Blending & homogeneity– Compactibility– May be required to run on

different machines• Product

Stability/Compatibility of components

• 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.

■ 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

Factors Affecting Drug Dissolution From Hard Gelatin Capsules

Except for the shell, sounds like tablets!

■ 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– Adsorption 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.

Active Ingredient

■ 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 LactoseMicrocrystalline CelluloseStarch 1500Dicalcium phosphate dihydrate, unmilled (Ditab, Emcompress)

Consider the solubility of drug in selecting a filler.Water soluble fillers are preferred for poorly soluble drugsIn certain instances, a large percent of soluble filler in the formulation has slowed the dissolution of a soluble drug.

■ Possible incompatibilities

Filler (Diluent)

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)

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

0.25-50%.■ True Lubricants and Antiadherents (e.g. metallicstearates, 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.

Lubricants

(Samyn & Jung)

Dense Packing

5% Mag. Stearate

0% Mag. Stearate

Combined Effect of MagnesiumStearate and Compaction

Effect of Magnesium Stearate Level on HCTZ Dissolution

Filler: Microcrystalline celluloseTamping force: 100NSource: Mehta & Augsburger

0 0.5 1 1.5 2 2.55

10

15

20

25

30

35

40

45

% Magnesium Stearate

HCTZDissolution (T-60%)

Effect of Magnesium Stearate on Plug Breaking Force and Dissolution*

*Hydrochlorothiazide

% MS Plug Strength

[N]

T-60%

0.05 84 (1.7)

55 (1.2)

0.10 76 (1.1)

36 (0.82)

0.20 27 (1.5)

16 (2.0)

0.05 4.0 (0.36) 14 (1.6)

0.75 1.8 (0.06) 12 (0.98)

Microcrystalline Cellulose% MS Plug

Strength[N]

T-60%[min.]

0.05 18 (2.0) 12 (1.0)

0.10 15 (1.2) 13 (0.90)

0.20 15 (1.4) 13 (0.70)

0.05 14 (1.6) 13 (0.59)

0.75 13 (1.2) 18 (1.2)

Anhydrous Lactose

Source: Mehta & Augsburger

Rifampicin Capsules0.1% Mag. St.

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

5 min.

15 min.

30 min.

Control(No Mag. St.)

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

Flow

Rat

e (g

/min

)

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

■ 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%.

Disintegrants: sodium starchglycolate; croscarmellosesodium*

*Crospovidone not as effective in capsules atequivalent concentrations

■ 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%

Surfactants: sodium docusate; sodium lauryl sulfate

Soft Gelatin Capsules

SOFT GELATIN CAPSULES

(aka “Softgels”)

■ Similar to hard gelatin shell, exceptplasticizer is incorporated (sorbitol, propylene glycol, glycerin)

■ Usually filled with liquids or suspensions (dry solids are possible, including compressed tablets (“Geltabs”).

Reminder

■ 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

Advantages 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)

Disadvantages of Soft Gelatin Capsules

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

■ VehiclesWater immiscible non-volatile liquids

■ vegetable oils■ Mineral oil not recommended for drug formulations.

Water-miscible, non-volatile liquids■ Low molecular weight PEG's■ Nonionic surfactants such as polysorbate 80

Formulation

■ 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

Limitations of Liquid Contents

■ 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

Most Soft Gelatin Capsules are Made Using a Rotary Die Process

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”, inLachman, 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 PracticeofIndustrial Pharmacy, 2nd ed., pp. 404-420 (1976), Lea andFebiger, Philadelphia, PA, 1976.