PHAR:8136 Pellets and Capsules

while pills are an outdated dosage form, there is another dosage form that is prepared in a manner that is very similar

pellets

pellets

form of multi-particulate dosage form → consists of many small, discrete particles (ie multi-particulates)

types of multi-particulates

• drug crystals

• granules

• pellets

• mini tablets

multi-particulate dosage forms

• filled into capsules

• compressed into tablets

• packaged in sachets

why choose multi-particulate dosage forms?

for the patients and for product functionality

why choose multi-particulate dosage forms for patients?

• maximize absorption

• more predictable gastric emptying

• reduce inter-/intra- subject variability

• minimize local irritation

• decrease risk of dose dumping

why choose multi-particulate dosage forms for product functionality?

• improve therapeutic options / flexibility

  • customization of overall drug release pattern

  • drug delivery to the same site or different sites in the GI tract

  • combine chemically incompatible drugs into single dosage form

pelletization techniques

• direct pelletization

• pelletization through extrusion step: extrusion-spheronization

• pelletization by layering onto starter seeds: solution layering + suspension layering

• pelletization through formation of droplets

extrusion-spheronization

multistep process

• dry blending of materials (api + excipients)

• wet massing

• spheronization

• drying

changes in extrudate shape with spheronization time

more round

formulation consideration for pelletization

• specific requirement for extrusion

  • cohesive plastic, wet mass with inherent fluidity and self-lubricating properties

• specific requirement for spheronization

  • extrudates with sufficient plasticity

pelletization aid

microcrystalline cellulose

pros of extrusion-spheronization

• high throughput with low wastage

• produces highly spherical particles with a narrow size distribution

• produces pellets with smooth surface

• produces pellets with low friability

cons of extrusion-spheronization

• requires 2 specialized equipment (extruder and spheronizer)

• may not be suitable for moisture/heat sensitive APIs (wetting and drying steps involved)

fluidized bed coating

• pellets (drug-containing core, or inert sugar/MCC sphere with a drug layer) are coated in a Wurster-type fluidized bed coater, which separates the coating zone, drying zone and staging area

• spherical pellets coat very evenly

• multi-particulates oftened coated with polymers using this

polymers used in film coating

• cellulosics

  • hypromellose (hpmc)

  • ethylcellulose

• vinyls

  • polyvinyl alcohol (PVA)

• glycols

• acrylics — methacrylic acid copolymers

what was gelatin first used for?

as a taste masking material for obnoxious medicines

types of capsules

• hard gelatin capsules

• soft gelatin capsules

hard gelatin capsule

• shell

  • rigid, composed of gelatin, sugar, and water; not intentionally plasticized

• content

  • mostly solids (powders, granules, pellets or mini tablets); semisolids and thixotropic fluids possible but rare

• closure

  • 2 parts — cap and body, sealed by banding or mechanical interlocking

soft gelatin capsules

• shell

  • flexible, plasticized gelatin (common are glycerin or propylene glycol)

• content

  • mostly liquids (soln, suspensions, or semisolids); dry powder are possible but rare

• closure

  • hermetically sealed

hard capsule sizes

• provide a greater flexibility in formulation partly because of range of available sizes

• smaller # → larger volume

concerns with gelatin capsules

• an animal protein (bovine, fish)

  • derived from animal collagen

  • may have religious objections

  • may be associated with animal diseases

• moisture sensitive

• properties may change with adsorbed constituents (eg aldehydes)

  • usual concern is cross-linking

gelatin cross-linking

• gelatin structure: protein with some potentially reactive side chains

• cross-linking refers to the formation of strong chemical linkages beyond simple hydrogen and ionic bonding between gelatin chains

• rxn is generally irreversible

• renders gelatin insoluble

• rxn catalyzed by several chemical and environmental factors

what are the factors that cause cross-linking in gelatin?

• aldehydes and ketones

• API with carbonyl grps

• oxidizing agents

• sugars

• light

• heat

• humidity

• metal ions

concern with cross-linking: pellicle formation

capsule shell opening is delayed or stopped by pellicle formation on the internal or external gelatin surface

plant-based hard capsules

• made from hypromellose (HPMC), pullulan, or red seaweed

• low moisture content and water permeability compared to gelatin

• physically stable, less brittle than gelatin capsules

• chemically stable and does not undergo cross-linking reactions

gelatin vs HPMC capsules

• gelatin higher moisture content

• gelatin has maillard reaction with fillings

• gelatin degradation by light and heat (above 60C for denaturation)

formulation consideration for capsules

• drug, filler/diluent, glidant, lubricant, disintegrant, surfactant

• all formulations must:

  • be capable of being filled uniformly to give a stable product

  • must release their active contents in a form that is available for dissolution and subsequent absorption thru GI tract

  • must comply with requirements of usp and government regulatory authorities

• the type and concentration of disintegrant added can impact dissolution

enteric coated capsules

• acid resistant (will not dissolve in stomach)

• will quickly dissolve in the intestinal environment

• usually combines a neutral polymer (hypromellose) with an enteric polymer (hypromellose acetate succinate, hypromellose phthalate)

pros of hard gelatin capsules

• great formulation flexibility

• able to mask bitter taste and pleasant odor of drugs

• slippery when wetted and aids with swallowing

• convenient to carry/transport

• can be used for modified drug release

cons of hard gelatin capsules

• requires powder blending, homogeneity of powder blend, adequate powder flow, and lubrication

• slower filling

• not suitable for highly-soluble salts — rapid release will cause GI irritation

• high moisture content/humidity can promote microbial growth, affect in vitro dissolution, and increase chemical instability for moisture-sensitive drugs

soft gelatin capsules

• aka soft elastic gelatin capsule or softgel

• formed, filled, and sealed in one operation and may be of different shapes and sizes

• flexible and can be formulated as:

  • oral softgels - containing soln/susp for release in stomach

  • chewable softgels - flavored and can be chewed prior to swallowing

  • twist-off softgels - tag to be snapped off to release contents (mostly for topicals and cosmetics)

softgel capsule sizes

• opposite of hard capsules

• size number positively correlates with physical size

• larger number → larger volume

formulation considerations for softgels

fill materials

• water-immiscible oils (volatile and non-volatile oils)

• water-misicble liquids (hydrophilic liquids)

pros of softgels

• accurate and precise (content uniformity)

• rapid filling

• rapid dissolution with potentially enhanced bioavailability (largely stems from softgels delivering lq cargo)

• lq fill avoids powder flow and mixing problems

• no dust problem during manufacturing

cons of softgels

• need specialized equipment (cannot be extemporaneously compounded)

• migration of drug into shell is possible