Solid preparations

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Solid preparations

• Chapter 4

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I.Introduction

• A.characteristics
• (1)better stability when compared with liquid
  preparations
• (2)similar preparation process
• (3)absorbed into blood circulation only after
  released from preparations

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• B.Flow profiles of preparation process
• raw materials
• crushing
• sieving
• mixing powder
• granulation granule capsule
• pressure tablet

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• C.process of absorption in vivo of solid
  preparations
• oral administration
• disintegration (coarse particles) (tablet and
  capsule)
• dissolution(fine particles)
• absorption into blood(biological membrane)

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• order of absorption speed
• solutiongtsuspensiongtpowdergtgranulegtcapsulegttab
  letgtpill

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• D.Noyes-Whitney equation
• dC/dtKS(Cs-C), KD/(Vd)
• at the sink condition, C 0
• then dC/dtKSCs
• dC/dtdissolution rate
• Kconstant of dissolution rate
• Sinterface area of dissolution
• Cs solubility(saturated concentration) of drug
• Cdrug concentration in release solvent at time
  of t
• Ddiffusion coefficient
• Vvolume of release solvent
• dthickness of diffusion layer

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• ? S, ?K and (or) ? Cs in order to ?dC/dt
• ? S depends on ?size
• ?K depends on stirring
• ? Cs is better and more frequently used which
  depends on modern techniques

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II. Powders

• A.definition
• drug(s) excipient(s), mixing
• B.properties
• (1)quick effect and large effect area
• (2)easy preparation
• (3)poor stability

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• C.preparation process
• raw materials
• crushing
• sieving
• mixing
• quality evaluation
• dosage and package

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• (1)crushing
• aims ? dissolution rate and bioavailability
• improving mixing process
• mechanism energy exchange(mechanical energy
  surface energy)
• evaluating parameter comminution degree
  nD1/D2
• equipment mortar, ball mill(P100), fluid-energy
  mill(P101)
• types dry and wet crushing
• occlusion crushing and free crushing
• open crushing and recirculating
  crushing
• low-temperature crushing

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• (2)sieving
• aims homogenize the size of particles
• grades No.19 sieve mesh
• the larger the number, the smaller
  the mean size
• equipment sieves

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• (3)mixing
• aims homogenize the whole materials in order to
  keep uniform of drug concentration
• evaluation parameters
• s, s2 the smaller the better ( 0)
• M the larger the better (01)
• mechanisms convective, shear, diffusion
• along with segregation

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• impact factors
• particlessize distribution(sieving)
• ratios of different
  particles(balanced progressive mixing)
• density(beginning with the
  light followed by the heavy)
• adhesive(the massive amount
  one followed by the less one)
• electrostatic(surfactants)
• liquid(absorbers)
• eutectic mixture(effectiveness
  )
• equipmentrotary (V-shaped)
• operating conditionsfilling amount, time, speed
  etc

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• D. Package
• dosageweight, volume
• note fluidity, wettability (CRH)
• E. Quality evaluation
• Chp2005 edition

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III. Granules

• Definition drugexcipients, mixing, granulation
• Types soluble, suspension, effervescent
• Properties
• (1)more stable when compared to powders
• (2)convenient to administration
• (3)be coated in order to sustained release
• (4)segregation(compound ones)

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• D. Preparation process
• drug
• crushing
• sieving
• mixing fillers,
  disintegrants, adhesives
• soft materials extrusion or in
  fluiding-bed
• wet granules dry, sieving
• dry granules quality control(Chp2005
  edition)
• dosage and package

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IV. Tablets

• Definition drugadjuvants, mixing,
  (granulation), pressure
• Properties
• (1)homogeneous dosage
• (2)promising stability
• (3)low cost (mechanization and automation)
• (4)many types
• (5)difficult to swallow

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• C. Types
• (1)tablets for oral administration
• compressed
• coated (sugar, film, enteric)
• effervescent
• chewable
• dispersible
• sustained or controlled release
• multilayer

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• (2)tablets for oral cavity
• sublingual
• toroches
• buccal
• (3)tablets for hypodermis
• implant
• hypodermic (disappeared)
• (4)tablets for external use
• solution
• vaginal

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• D.adjuvants(excipients)
• (1)diluents or fillers
• aims to produce tablets with a reasonable size
• types starch, sugar, dextrin, lactose,
  pregelatinized starch, MCC, inorganic salts etc

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• (2)moistening agents and adhesives
• moistening agents induce the adhesion of other
  materials
• distilled water, ethanol with different
  concentration
• adhesives have adhesion themselves
• starch paste, MC, HPC, HPMC, CMC-Na, EC, PVP,
  PEG, gelatin solution etc

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• (3)disintegrants
• aims disintegrate the tablets into small
  particles
• mechanisms capillary, swelling, heat of
  wetting, gas
• types starch, CMS-Na, L-HPC, CCNa, PVPP,
  NaHCO3weak acid
• addition methods in the raw materials(inside
  the particles), before pressure (outside the
  particles), combination of the two (the best)

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• (4)lubricants
• glidants reduce the friction among particles
• such as MgO, starch, talc, aerosil, MgCO3
• antiadherents reduce the adhesion between
  materials and punches
• such as most lubricants, starch, talc
• lubricants reduce the friction between the
  tablets and punches
• soluble PEG, sodium benzoate
• insoluble calcium, magnesium and zinc salts of
  stearic acid, talc, light mineral oil, paraffin
  

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• (5)others
• pigments soluble, insoluble (Lake)
• flavors essences
• note no addition or lower the amount

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• E. Preparation techniques
• wet
• granulation
• dry
• powder compact
• direct compression
• blank
  granulation

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• (1)wet granulation (the most frequently used)
• drugsadjuvants
• crushing
• sieving blending of dry
  ingredients
• mixing
• wet granules moistening agents or
• adhesives
• dry
• screening lubricants
• blending
• compression

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• (2)dry granulation (heat-sensitive materials)
• drugsadjuvants
• crushing
• sieving
• mixing
• compression large tablets
• crushing
• screening lubricants
• blending
• pressure

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• (3)direct compression ( powder or crystal with
  good pressing ability and fluidity)
• It is always necessary to employ
  promising excipients, such as MCC, lactose,
  aerosil etc (so-called compression aids)

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• (4)blank granulation (heat- and
  humidity-sensitive drugs with poor compression
  ability)
• drugs
• crushing
• sieving
• mixing blank granules
• blending lubricants
• compression

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• F. Tableting equipment
• (1)granulators
• extruding (p121)
• rolling (p122)
• high-speed stirring (p123)
• fluidized bed (p124)
• spray-drying (p126)
• microwave vacuum drying

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• (2)tablet presses
• single-station (single-punch) (p134)
• multistation (rotary) (p136)
• the same steps
• filling compression ejection
• Feed shoe upper (and lower) punches lower
  punches

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• G.Coating of tablets
• (1)aims increase stability
• enhance patient compliance
• separate different medicines
• optimize appearance
• control release site and rate
• (2)types sugar coating
• film coating (including enteric
  coating)

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• (3)coating process
• sugar coating
• core(using tooling with deep concave geometry,
  note the friability)
• sealing coat(moisture barriers, shellac, CAP
  etc, 3-5)
• subcoat(a good bridge between the main coating
  and the sealed coat, as well as rounding off any
  sharp corners, warm subcoat syrupsubcoat powder,
  acacia or gelatin talc, starch, calcium
  carbonate, 15-18)
• sugar coat(produce a smooth surface, a syrup
  free from suspended powders, 10-15)
• colored coat(convenient to reorganization and
  beautiful appearance, colorants in syrup, 8-15)
• polishing(high luster and evaporated any traces
  of solvent, canvas side walls dilute wax
  solution or powder)

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• equipment a revolving pan
• properties beautiful appearance
• cover nasty taste and smell
• good moisture barriers
• complexity and
  time-consuming(more than 50 weight gains)
• Efforts were made to develop film coatings!

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• film coating
• core
• film coat and dry(weight gains of only 2-6)
• solidify(the film coating, 6-8h)
• dry slowly(evaporate any traces of solvent,
  12-24h)
• equipment a revolving pan, fluidized beds,
  spray-drying etc
• properties simpler and easier to automate
• distinctive identification
  markings
• promising stability

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• commonly used film-coating materials
• nonentericMC, EC, HPMC, CMC-Na, PVP, PEGs etc
• entericshellac, CAP, PVAP, HPMCP, methacrylic
  acid and its eaters(Eudragit L and S)
• plasticizersglycerin, propylene glycol, citrate
  esters, PEG, triacetin etc
• agents adjusting release rate
• antiadhesives
• colorants

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• (4)coating equipment
• conventional coating pans
• fluidized beds
• compression coating presses(corefine
  free-flowing materials, especially used by
  instable drugs coating)

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• H.quality control
• Chp2005 edition
• appearance
• weight variation
• hardness and crushing strength
• disintegration testing
• dissolution rate (if done, the above can be
  omitted)
• uniformity of dosage units (if done, the
  following can be omitted)
• concentration
• I.package
• multi- and unit-dose packaging

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V.Capsules

• A.Definition solid dosage forms in which the
  drug substance is enclosed within either a hard
  or soft shell usually from gelatin
• B.properties
• (1)enhance stability and cover unpleasant taste
  and odor
• (2)quick effect
• (3)turn liquid drug into solid form
• (4)adjust drug release rate and site
• (5)note drug choice (shell effects and
  irritation) and difficult swallowing by some
  patients

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• C.Hard capsules
• (1)advantages
• better bioavailability when compared with
  tablets
• easier to formulate
• multiple fillings (beads, granules, minitablets,
  powders, semisolids) in order to overcome
  incompatibility and modify or control drug release

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• (2)disadvantages
• relative higher cost
• drug choice (such as highly soluble salts)
• difficulty in swallowing
• (3)preparation process
• empty hard shells
• filling materials
• filling and closuring
• package
• quality evaluation

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• Empty hard shell
• shell composition gelatinplasticizerscolorants
  opaquing agentspreservativeswater
• shell manufacture dippingrotationdryingstripp
  ingtrimmingjoining
• shell sizes and shapes
• 8 types (No.000,00,0,15), smaller
• self-locking closure

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• Filling materials
• dosage forms
• powders
• granules
• beads or pellets
• tablets or minitablets
• liquid or pasty materials

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• ingredients must not dissolve, alter or
  otherwise adversely affect the integrity of the
  shell
• active ingredient
• fillersincrease the bulk of the formulation
  (such as starch, lactose, dicalcium phosphate)
• glidantsimprove the fluidity of powders(such as
  talc, MS)
• lubricantsease the ejection of plugs, reduce
  filming on pistons and adhesion of powder to
  mental surfaces, reduce friction between sliding
  surfaces in contact with powder (such as MS,
  stearic acid)
• disintegrants, surfactants, hydrophilization etc

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• Filling
• rectification
• separation of caps from bodies
• dosing of fill materials
• replacement of caps and ejection of filled
  capsules
• semiautomatic or fully automatic capsule-filling
  machines (p152)

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• D.soft capsules
• (1)advantages
• more suitable to liquid or volatile drugs or
  drugs dissolved, solubilized or suspended in a
  liquid vehicle with rapid release and potential
  enhanced bioavailability
• suitable to drugs subjected to atmospheric
  oxidation because of effective barrier to oxygen
  of the shell
• a wide variety of sizes and shapes(tube form and
  bead form)

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• (2)disadvantages
• inexpensive dosage form for the need of
  necessary filling equipment and expertise
• increase the possibility of interaction between
  drugs and shell(migration of a drug into the
  shell)
• (3)composition of the shell
• gelatin(1part)water(1part)plasticizers(0.4-0.6p
  art)dyersopacifierspreservativesflav-ors

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• (4)filling materials
• a single liquid, a combination of miscible
  liquids, a solution of a drug in a liquid, or a
  suspension of a drug in a liquid (do not have an
  adverse effect on the gelatin walls and
  pH2.57.5)
• types of vehicles water-immiscible, volatile,
  or more likely nonvolatile liquids (vegetable
  oils, mineral oils etc)
• water-miscible,
  nonvolatile liquids (PEG400, PEG600)
• water(greater than 5 of contents) and low
  molecular weight organic agents cannot be
  encapsulated

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• (5)manufacture of soft capsules
• dripping process (p153)
• compacting process (p154)

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• E. Enteric capsules
• coated the surface of shell by enteric materials

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• F. Quality evaluation
• Chp2005 edition
• appearance
• water concentration
• weight variation
• disintegration or dissolution
• G. Package
• unit-dose container blister and strip packaging
• multi-dose container glass(amber) or plastic
  bottles

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VI. Dripping pills

• Definition
• drugsbases, melting, quick freezing
• shapes spherical, oval, olive etc
• B. Properties
• (1)simple operation and equipment
• (2)liquid solid
• (3)adjust drug release rate through the property
  of base
• (4)enhance stability

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• C. Preparation technique
• (1) drugs(insoluble and moderate soluble)
• melting
• water-soluble bases(PEGs, poloxamers
  etc )
• dripping freezing
• oily freezing solvent
• Key step quick freezing(solid dispersion)
• quicker release and higher bioavailability

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• (2) drugs(soluble)
• melting
• water-insoluble bases(stearic acid,
  hydrogenized vegetable oil )
• freezing
• freezing solvent(water or alcohol)
• sustained release and prolonged effective time

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• D. Equipment
• P157

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VII. Pills

• Definition
• spherical pellets with diameter below 2.5mm
• in general, enclosed with hard capsules
• drugbase(core) with film coating
• B. Properties
• (1)convenient to adjust release rate
• (2)higher drug content in capsules
• (3)more uniform absorption, higher
  bioavailability and lower irritation
• (4)easy preparation

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• C. Types
• soluble film-coated pills(gel barrier)
• insoluble film-coated pills(erosion, suitable
  for water-soluble drugs)
• insoluble film-coated pills with micropores
  (caused by water-soluble materials)

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• D. Preparation process
• drugbase pills
• 
  polymer coating
• base(blank core)drug layers
• base starch, sugar and dextrin etc
• polymer coating PVP, MC, AC, CAP etc
• Methods traditional methods, fluidized bed,
  spray-drying, spray-freezing, dry-in-liquid,
  dispersion-in-water and spherical crystallization
  etc

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VIII. Films

• Definition
• drugsfilm materials
• B. Properties
• (1)simple preparation process
• (2)great stability
• (3)easy to adjust drug release rate through
  different kinds of membrane materials
• (4)low drug-loading rate

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• C.Membrane materials and excipients
• (1)natural polymers gelatin, acacia, starch,
  dextrin etc
• (2)Synthetic polymers
• PVA PVA05-88PVA17-88(13)
• EVA
• (3)plasticizers glycerin
• (4)surfactants Tween-80, SLS-Na
• (5)fillers CaCO3, SiO2, starch
• (6)colorants pigments, TiO2
• (7)defilming agents liquid paraffin

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• D. Preparation process
• Homogenization PVA
• Thermoplast EVA
• Complex sustained release films

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• E. Quality evaluation
• Chp2005 edition
• (1)appearance
• (2)weight variation
• (3)microorganism test