PF6026 - Lecture 13 - Encapsulation PDF

Capsule Filling Dr Joseph O’Shea ✉ [email protected] ☎ 1665 Capsules Capsules are solid dosage forms that are available in two types: Hard (two piece) Soft (one piece) They represent an advancement over unit dose powders Dosage contained in the capsule is swallowed as a whol...

Capsule Filling Dr Joseph O’Shea ✉ [email protected] ☎ 1665 Capsules Capsules are solid dosage forms that are available in two types: Hard (two piece) Soft (one piece) They represent an advancement over unit dose powders Dosage contained in the capsule is swallowed as a whole with water Convenient to the patient. The major component of the capsule shell is gelatin Derived from animal collagen Excellent physicochemical and biological properties Non toxic Good mechanical properties Soluble in biological fluids HPMC is becoming widely used as a vegan alternative Capsules may be filled with a range of formulation types including: Powders Tablets Pellets Semi solids Liquids (non aqueous liquids in soft capsules) Pharmaceutical Capsules advantages Advantages Advantages of oral drug delivery Convenient for oral administration of drugs with unpleasant odor or taste Better bioavailability vs tablets Easier to formulate vs tablets Drug is give reasonable protection vs air and moisture and can be protected from light May dispense exact dose for individual patient Controlled release capability Easy product identity Disadvantages Automatic capsule filling machines output is only ~ one-fifth that of high speed tablet presses Rapid drug release (highly soluble salts) may cause gastric irritation, high local concentration Potential for oesophageal adhesion, remain standing 90 secs and swallow with at least 100ml water Pharmaceutical Capsules Pharmaceutical capsules 2 types Hard gelatin caps, two-piece Soft gelatin caps (Softgels), one-piece Hard Capsules Hard gelatin capsules consist of 2 halves “cap” and “body” and come in a variety of different sizes The formulation is filled into the body and cap is pushed into place, overlapping the body. Sealing of capsules may be performed Capsule formulation: Gelatin –capsule formation Colourants –aesthetics, identification Wetting agents Lubricants Capsule fill: Powders: Diluents e.g. lactose, maize starch, microcrystalline cellulose (MCC) Lubricants e.g. magnesium stearate Glidant - decrease inter-particulate friction, aid powder flow (colloidal silicon dioxide) Disintegrant –maize starch, microcrystalline cellulose, sodium starch glycolate Liquid/semi-solids: Surface-active agents –solubilise, stabilise, dissolution enhancers Viscosity modifying agents –stabilise suspensions, optimise filling Stabilisers - antioxidants Hard Capsule Formulation Factors Powder fills Homogeneity of mix Powder flowability Powder packing properties - Density Powder compatibility and compatibility with the capsule Liquid/semi-solid -Contain dissolved or dispersed drug Lipophilic oils : vegetable oils (sunflower, arachis) or fatty acid esters Water-miscible liquids: PEGs, liquid Pluronics Impact on capsule stability important Equilibrium moisture content 13-16% for optimal mechanical properties Hygroscopic solvents can destabilise capsule shell Example Hard Capsule Prozac 20 mg hard capsules Each capsule contains 20 mg of fluoxetine (as fluoxetine hydrochloride) Description: The capsules are green and yellow, printed 'Lilly 3105’ The capsules contain: Maize starch flowable Dimeticone Capsule components: Patent blue V (E131) Yellow iron oxide (E172) Titanium dioxide (E171) Gelatin Hard capsule shell Traditionally made from gelatin – animal origin Transition to non-aninal source materials - HPMC (hydroxypropylmethylcellulose) Colourants Opacifying agents e.g. titanium dioxide Preservatives e.g. sulphur dioxide or benzoic acid Water 13-16%, depends on storage conditions Plasticizers Other markings; company logo, symbol, banding, number (code) Gelatin Non-toxic Readily soluble in biological fluids at body temp, not pH dependent It is a good film-forming material, giving a strong film Solutions of high conc 40%w/v are mobile at 50oC: suitable for processing A solution in water undergoes a reversible change from a gel to a sol at temp only a few degrees above ambient Manufacture Prepared by hydrolysis of collagen: animal skin and bones are used as source After hydrolysis, gelatin extracted using hot water Solutions of gelatin are concentrated and chilled to form a gel The gel is extruded in strands & dried Graded, Bloom strength ( measure of gel rigidity) & viscosity Alternatives (BSE scare) to gelatin; HPMC Hypromellose Hydroxypropyl methylcellulose; Hypromellose; HPMC Methyl and hydroxypropyl mixed ether of cellulose Animal independent alternative polymer for capsule manufacture Semi-synthetic, inert, viscoelastic polymer Derivative of cellulose – plant origin Exhibits thermal gelation in aqueous solution – suitable for capsule formation Cellulose solution heats up to a critical temperature, the solution congeals into a non-flowable but semi-flexible mass Degree and pattern of substitution controls critical properties Critical temperature is inversely related to solution concentration of HPMC and concentration of the methoxy group Viscosity of the resulting mass is directly related to the concentration of the methoxy group - higher the concentration is, the more viscous or less flexible the resulting mass Differing grades based on concentration and pattern of substitution Hypromellose Hypromellose Soluble methylcellulose ether easily extracted by chemically modifying polymer cellulose Contains methoxy (–OCH3) and hydroxypropoxy (– OC3H6OH) groups conforming to the limits for the types of HPMC Wide range of functions Capsule shell material; coating agent; dispersing agent; emulsifying agent; film-forming agent; modified-release agent; solubilizing agent; suspending agent; tablet and capsule binder; viscosity-increasing agent Application depends on grade, chain length and concentration HPMC Capsules Capsule preparation Hard capsule size and body fill volumes Fill weight, powder = body volume x tapped density Liquid = Specific gravity liquid x body volume x 0.8 Material is filled only into the body and then cap attached Types of fill for hard capsules DRY SOLIDS: powders; pellets; granules & tablets SEMISOLIDS: Thermosoftening mixtures; Thixotropic mixtures; Pastes LIQUIDS: non-aqueous liquids Limitations in properties of materials for filling into caps Must not react with gelatin or materials in shell Must not contain a high level of free moisture: will result in a softening of the shell Volume of the unit dose must not exceed the size of caps available: can be a problem for materials of low density Temperature of fill must not affect shell Liquid fills Must ensure no leakage Industrial-scale filling hard capsules Dependent: dosing systems that use the body directly to measure the powder. Uniformity of fill weight can only be achieved if the cap is filled completely. Independent: dosing system where the powder is measured independently of the body in a special measuring device. Weight uniformity is not dependent on filling the body completely (capsule can be part filled) Most industrial processes are fully automatic and use dosing mechanisms that form a ‘plug’ of powder Soft compact formed at low compression forces - significantly less than those used in tableting Industrial-scale filling hard capsules Range of methods, differing in the means by which the formulation is dosed into the capsules Bench-scale filling, the ‘Feton’ Industrial-scale filling; Auger filling principle (dependent) Dosator filling principle (independent) Tamping finger principle (independent) Nonpowder filling, semisolid & liquid filling Steps in Capsule Filling 1. Feeding Capsules are introduced and orientated 2. Opening Capsule bodies are removed from cap – using suction 3. Dosing Capsule bodies filled Using one of principles outlined in this lecture 4. Closing Caps and placed on bodies 5. Discharge Capsules removed from capsule filling machine https://www.youtube.com/watch?v=Huq7SeTVFhk Auger filling machine Empty capsules are fed into a pair of ring holders Caps being retained in one half and the bodies being retained in the other half. Body holder is placed on turntable Powder hopper is pulled over the top of this plate - revolves underneath Revolving auger forces powder down into the capsule bodies Weight of powder with which the body is filled is dependent mainly on the time the body is underneath the hopper during the revolution of the plate holder Dosator-type machine Dosing tube with movable spring-loaded piston Variable-volume chamber in the bottom of the tube Lowered into a bed of powder which enters the tube to fill the chamber and forms a plug May be further consolidated by applying a compression force Raised from the powder bed and positioned over the capsule body. Piston is lowered, ejecting the powder plug into the capsule body. Weight of powder added can be adjusted by altering the position of the piston inside the tube, i.e. increasing or decreasing the volume, and by changing the depth of the powder bed Tamping finger principle Dosing disc forms the bottom of a revolving powder hopper Several sets of accurately drilled holes in which powder plugs are formed by several sets of tamping fingers Stainless steel rods that are lowered into them through the bed of powder. At each position the fingers compress the material in the holes Building up a plug before they index on to the next position As the disc rotates, material flows into the holes At the last position, fingers push the plugs through the disc into capsule bodies Powder fill weight can be varied by the Amount of insertion of the fingers into the disc, Thickness of the dosing disc being changed, Adjusting the amount of powder in the hopper Excipients used in powder-filled capsules Reliably capsule production on a high-speed filling machine minimally requires a formulation that (1) flows well (2) consolidates to form a plug (3) has sufficient lubricity to be efficiently ejected into the capsule body (4) when the capsule shell dissolves, the formulation must disintegrate for drug release Excipients utilise to achieve this Diluents: cohesive to enable plug formation Lubricants; reduce powder to metal adhesion during filling Gildants; improve powder flow Wetting agents: improve water penetration of powder mass Disintegrants; produce disruption of the powder mass Non-powder fills Pellets MR preparations often produced as granules or coated pellets Filled on an industrial scale by machines adapted from powder use Dosing system based on a chamber with a volume that can be changed Pellets are not compressed in the process and may have to be held inside the measuring devices by mechanical means (e.g. by applying suction to the dosing tube) Make an allowance for their size - packing restrictions Tablets Tablets are placed in hoppers and allowed to fall down tubes - gate device Fall by gravity into the capsule bodies as they pass underneath the hopper Mechanical probe to check that the correct number of tablets have transferred Liquid Filled using volumetric pumps Similar fill materials to those for soft capsules Challenge is to prevent leakage Semisolid & Liquid Filling Challenge is to prevent leakage from the closed capsule: Formulation to avoid materials that undermine mechanical strength of capsule shells Sealing of the capsule Increased number of dimples Tighter fit of body and cap Banding can be used Semisolid & Liquid Filling Sealing process Stage 1: sealing solution is sprayed in between thecap and body and lowers the melting point of gelatin inthese areas Semisolid & Liquid Filling Stage 2: Warm air is blown across the sealing area to complete melting and fusion Stage 3: Gelatin hardens and seals Soft Capsules Soft gelatin capsules Flexible capsules May be spherical, ovoid or cylindrical in shape. Mechanical properties of gelatin are manipulated by the addition of a plasticiser e.g. Glycerol, sorbitol Usually manufactured, filled and sealed in one operation There are several categories of fill material Lipophilic liquids vegetable oils and fatty acid esters Self emulsifying systems emulsify in GIT, contain non ionic emulsifiers (Tween) Water miscible liquids High molecular weight alcohols PEG 400, non ionic surfactants (Tween) The fill tends to be liquid oils, gels. Water is not employed as it physically destabilises the capsule. Excipients: Viscosity modifying agents Surfactants Colours Co solvents Soft gelatin capsules useful: Formulation of poorly water soluble drugs Formulating drugs of abuse. Softgel capsules Softgel capsules Softgel Capsule - Example Avodart 0.5 mg soft capsules Each capsule contains 0.5 mg dutasteride Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH) Capsule contents: Mono- and diglycerides of caprylic/capric acid Butylhydroxytoluene (E321). Capsule shell: Gelatin Glycerol Titanium dioxide (E171) Iron oxide yellow (E172) Triglycerides Medium chain lecithin (may contain soya oil) Soft Gelatin Capsules - Softgels Hydrophobic drugs, poorly water soluble, liquid formula encapsulated in soft gel capsule Liquid or semisolid matrix Ingredients solid at room temp Drug in solution or in suspension in the capsule-fill matrix Fill matrix, hydrophilic (polyethylene glycols) or lipophilic (triglycerides) Similar to formulation of fills for liquid filled hard gelatin Softgels - Types Orally administered Softgels containing solutions or suspensions that release their contents in the stomach in an easy-to-swallow, convenient unit dose form Chewable softgels where a highly flavoured shell is chewed to release the drug liquid fill matrix. The drug(s) may be present in both the shell and the fill matrix. Suckable softgels Consist of a gelatin shell containing the flavoured medicament to be sucked and a liquid matrix or just air inside the capsule. Twist-off softgels designed with a tag to be twisted or snipped off, thereby allowing access to the fill material. This type of softgel can be used for unit dosing of topical medication, inhalations or oral dosing of a paediatric product Meltable softgels Designed for use as pessaries or suppositories. Softgels – shell formulation Gelatin Different formulations are available depending on the nature of the liquid fill matrix Plasticizers, Plasticizers are used to make the softgel shell elastic and pliable 20 -30 % of wet gel formulation Glycerol, sorbitol and propylene glycol Conc and choice can affect dissolution or disintegration Compatibility with the fill formulation Water 30% to 40% of the wet gel formulation - ensure proper processing Excess water is removed from the softgels through controlled drying; equilibrium, 5-8% Colourants / Opacifiers Move towards vegetable-based alternatives Vegicaps Softgels – fill matrix, choice of excipients? Capacity to dissolve the drug if possible otherwise suspend Rate of dispersion in the GIT after rupture of shell and release of fill-matrix Capacity to retain the drug in solution in the GI fluid: hydrophobic drugs Compatibility with the softgel shell Ability to optimise rate, extent and consistency of drug absorbed Softgels – fill matrix, choice of excipients? Lipophilic liquids/oils: Drug may also be suspended in oils with appropriate excipients to ensure homogeneity during the manufacturing process. e.g. triglyceride oils Hydrophilic liquids: Polar liquids with a sufficiently high molecular weight are commonly used in softgel formulation either to dissolve or to suspend the drug. Polyethylene glycol (PEG) is the most frequently used, for example PEG 400 Ethanol can be used at low concentrations – may interact with shell Self-emulsifying oils (SEDDS): Oil plus Non-ionic surfactants (droplet size