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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
B.Flow profiles of preparation process
raw materials
crushing
sieving
mixing powder
granulation granule capsule
pressure tablet
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)
D.Noyes-Whitney equation dC/dt=KS(Cs-C), K=D/(Vδ) at the sink condition, C 0 then: dC/dt=KSCs
dC/dt—dissolution rateK—constant of dissolution rateS—interface area of dissolutionCs– solubility(saturated concentration) of drugC—drug concentration in release solvent at time of tD—diffusion coefficientV—volume of release solventδ—thickness of diffusion layer
↑ 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
II. Powders
A.definition
drug(s) +excipient(s), mixing
B.properties
(1)quick effect and large effect area
(2)easy preparation
(3)poor stability
(1)crushing aims: ↑ dissolution rate and bioavailability improving mixing process mechanism: energy exchange(mechanical energy
surface energy) evaluating parameter: comminution degree:
n=D1/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
(2)sieving
aims: homogenize the size of particles
grades: No.1~9 sieve mesh
the larger the number, the smaller the mean size
equipment: sieves
(3)mixing
aims: homogenize the whole materials in order to keep uniform of drug concentration
evaluation parameters:
σ, σ2: the smaller the better ( 0)
M: the larger the better (0~1)
mechanisms: convective, shear, diffusion
along with segregation
impact factors: particles—size 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) equipment—rotary (V-shaped) operating conditions—filling amount, time,
speed etc
D. Package
dosage—weight, volume
note: fluidity, wettability (CRH%)
E. Quality evaluation
Chp2005 edition
III. Granules
A. Definition: drug+excipients, mixing, granulation
B. Types: soluble, suspension, effervescent
C. Properties
(1)more stable when compared to powders
(2)convenient to administration
(3)be coated in order to sustained release
(4)segregation(compound ones)
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
IV. Tablets
A. Definition: drug+adjuvants, mixing, (granulation), pressure
B. Properties
(1)homogeneous dosage
(2)promising stability
(3)low cost (mechanization and automation)
(4)many types
(5)difficult to swallow
C. Types
(1)tablets for oral administration
compressed
coated (sugar, film, enteric)
effervescent
chewable
dispersible
sustained or controlled release
multilayer
(2)tablets for oral cavity sublingual toroches buccal(3)tablets for hypodermis implant hypodermic (disappeared)(4)tablets for external use solution vaginal
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
(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
(3)disintegrants
aims: disintegrate the tablets into small particles
mechanisms: capillary, swelling, heat of wetting, gas
types: starch, CMS-Na, L-HPC, CCNa, PVPP, NaHCO3+weak acid
addition methods: in the raw materials(inside the particles), before pressure (outside the particles), combination of the two (the best)
(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
(5)others
pigments: soluble, insoluble (Lake)
flavors: essences
note: no addition or lower the amount
(1)wet granulation (the most frequently used) drugs+adjuvants crushing sieving blending of dry ingredients mixing wet granules moistening agents or adhesives dry screening lubricants blending compression
(2)dry granulation (heat-sensitive materials) drugs+adjuvants crushing sieving mixing compression large tablets crushing screening lubricants blending pressure
(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”)
(4)blank granulation (heat- and humidity-sensitive drugs with poor compression ability)
drugs
crushing
sieving
mixing + blank granules
blending lubricants
compression
F. Tableting equipment
(1)granulators
extruding (p121)
rolling (p122)
high-speed stirring (p123)
fluidized bed (p124)
spray-drying (p126)
microwave vacuum drying
(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
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)
(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 syrup+subcoat 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)
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!
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
commonly used film-coating materials: nonenteric—MC, EC, HPMC, CMC-Na,
PVP, PEGs etc enteric—shellac, CAP, PVAP, HPMCP,
methacrylic acid and its eaters(Eudragit L and S)
plasticizers—glycerin, propylene glycol, citrate esters, PEG, triacetin etc
agents adjusting release rate antiadhesives colorants
(4)coating equipment
conventional coating pans
fluidized beds
compression coating presses(core+fine free-flowing materials, especially used by instable drugs’ coating)
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) concentrationI.package multi- and unit-dose packaging
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
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
(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
Empty hard shell
shell composition: gelatin+plasticizers+colorants+opaquing agents+preservatives+water
shell manufacture: dipping+rotation+drying+stripping+trimming+joining
shell sizes and shapes:
8 types (No.000,00,0,1~5), smaller
self-locking closure
Filling materials
dosage forms:
powders
granules
beads or pellets
tablets or minitablets
liquid or pasty materials
ingredients: must not dissolve, alter or otherwise adversely affect the integrity of the shell
active ingredient fillers—increase the bulk of the formulation
(such as starch, lactose, dicalcium phosphate) glidants—improve the fluidity of powders(such
as talc, MS) lubricants—ease 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
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)
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)
(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-
0.6part)+dyers+opacifiers+preservatives+flav-ors
(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 pH2.5~7.5)
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
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
VI. Dripping pills
A. Definition drugs+bases, 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
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
(2) drugs(soluble)
melting + water-insoluble bases(stearic acid, hydrogenized
vegetable oil )
freezing
freezing solvent(water or alcohol)
sustained release and prolonged effective time
VII. Pills
A. Definition spherical pellets with diameter below 2.5mm in general, enclosed with hard capsules drug+base(core) with film coatingB. 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
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)
D. Preparation process drug+base pills polymer coating
base(blank core)+drug layers base: starch, sugar and dextrin etc polymer coating: PVP, MC, AC, CAP etcMethods: traditional methods, fluidized bed,
spray-drying, spray-freezing, dry-in-liquid, dispersion-in-water and spherical crystallization etc
VIII. Films
A. Definition
drugs+film 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
C.Membrane materials and excipients(1)natural polymers: gelatin, acacia, starch,
dextrin etc (2)Synthetic polymers: PVA: PVA05-88+PVA17-88(1:3) EVA(3)plasticizers: glycerin(4)surfactants: Tween-80, SLS-Na(5)fillers: CaCO3, SiO2, starch(6)colorants: pigments, TiO2
(7)defilming agents: liquid paraffin
D. Preparation process
(1) Homogenization: PVA
(2) Thermoplast: EVA
(3) Complex: sustained release films