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>granule>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 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

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 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

(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) drugs(soluble)

melting + 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 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

E. Quality evaluation

Chp2005 edition

(1)appearance

(2)weight variation

(3)microorganism test