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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.
Manufacture
Formed/filled in one Shells made in one operation operation and filled in a separate process
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.
handling. Unique mixed fills possible. Role in drug development. Role in clinical tests.
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]
Gelatin
Bone Gelatin (Type B) Skin Gelatin (Type A)
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
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
Interlocking rings or bumps molded into the cap and body side-walls
Posilok (Shionogi) Snap-Fit and Coni-snap (Capsugel) Lox-it (Pharmaphil)
0.0650 0.0011
DOSATOR MACHINES
BASIC FORMULATION REQUIREMENTS
Flowability Lubricity Compactibility
FILL WEIGHT
Piston Height
(Primary)
Powder Bed Height
FILL WEIGHT
Disk Thickness Powder Height Tamp Force Number of Tamps
Identification of critical variables Selection of excipients and their levels Validation and Scale up
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
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
Displacement (mm)
0 100 200 300 400 500 600
Force (N)
40 30 20 10 0 -10
Time (ms)
Time (ms)
Formulation Principles
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.
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.
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)
Possible incompatibilities
(Tyrer et al.)
Lubricants
typically
0.25-50%.
concentrations usually retard dissolution. Blending time an issue with laminar lubricants (calcium and magnesium stearates)
Avoid overmixing
compaction.
Dense Packing
% Magnesium Stearate
Filler: Microcrystalline cellulose Tamping force: 100N Source: Mehta & Augsburger
*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)
Rifampicin Capsules
0.1% Mag. St.
5 min. 30 min. 15 min. Control (No Mag. St.)
Efficiency often improves with increased tamping force. May be effectively used at levels from 4-8%.
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
Formulation
Pure liquids, mixtures of miscible liquids, or solids dissoved or suspended in a liquid vehicle. Vehicles
vegetable oils Mineral oil not recommended for drug formulations. Low molecular weight PEG's Nonionic surfactants such as polysorbate 80
Most Soft Gelatin Capsules are Made Using a 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.