Transcript Document

Solid preparations
Chapter 4
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)
order of absorption speed :
solution>suspension>powder>granu
le>capsule>tablet>pill
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 rate
K—constant of dissolution rate
S—interface area of dissolution
Cs– solubility(saturated concentration) of drug
C—drug concentration in release solvent at time of t
D—diffusion coefficient
V—volume of release solvent
δ—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
C.preparation process
raw materials
crushing
sieving
mixing
quality evaluation
dosage and package
(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
E. Preparation techniques
wet
granulation
dry
powder compact
direct compression
blank granulation
(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 humiditysensitive 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 timeconsuming(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)
concentration
I.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 capsulefilling 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(0.40.6part)+dyers+opacifiers+preservatives+flavors
(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
(5)manufacture of soft capsules
dripping process (p153)
compacting process (p154)
E. Enteric capsules
coated the surface of shell by enteric
materials
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)
melting
drugs(soluble)
+
water-insoluble bases(stearic acid, hydrogenized
vegetable oil )
freezing
freezing solvent(water or alcohol)
sustained release and prolonged effective time
D. Equipment
P157
VII. Pills
A. Definition
spherical pellets with diameter below 2.5mm
in general, enclosed with hard capsules
drug+base(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
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 etc
Methods: 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
E. Quality evaluation
Chp2005 edition
(1)appearance
(2)weight variation
(3)microorganism test