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Hard and Soft Shell CapsulesDesign,Formulation and Manufacture
Larry L. AugsburgerUniversity of Maryland
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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.