Solid preparations

1. Solid preparations Chapter 4

2. 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

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

4. 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)

5. order of absorption speed : solution>suspension>powder>granule>capsule>tablet>pill

6. 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

7. ￪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

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

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

10. (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

11. (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

12. (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

13. 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

14. D. Package dosage—weight, volume note: fluidity, wettability (CRH%) E. Quality evaluation Chp2005 edition

15. III. Granules • Definition: drug+excipients, 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)

16. 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

17. IV. Tablets • Definition: drug+adjuvants, mixing, (granulation), pressure • Properties (1)homogeneous dosage (2)promising stability (3)low cost (mechanization and automation) (4)many types (5)difficult to swallow

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

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

20. 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

21. (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

22. (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)

23. (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

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

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

26. (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

27. (2)dry granulation (heat-sensitive materials) drugs+adjuvants crushing sieving mixing compression large tablets crushing screening lubricants blending pressure

28. (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”)

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

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

31. (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

32. 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)

33. (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)

34. 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!

35. 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

36. 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

37. (4)coating equipment conventional coating pans fluidized beds compression coating presses(core+fine free-flowing materials, especially used by instable drugs’ coating)

38. 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

39. 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

40. 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

41. (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

42. 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

43. Filling materials dosage forms: powders granules beads or pellets tablets or minitablets liquid or pasty materials

44. 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

45. 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)

46. 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)

47. (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

48. (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

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

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