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T a b l e t s. ยาเม็ด. รศ.ดร.จอมใจ พีรพัฒนา คณะเภสัชศาสตร์ มหาวิทยาลัยขอนแก่น. ยาเม็ด. บทนำ ข้อดี-ข้อเสีย ชนิดของยาเม็ด แบ่งตามการบริหารยา แบ่งตามกระบวนการผลิตและการใช้ Tablet compression machines Single punch Multi-station rotary presses. กระบวนการผลิตยาเม็ด Dry methods

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t a b l e t s

Tablets

ยาเม็ด

รศ.ดร.จอมใจ พีรพัฒนา

คณะเภสัชศาสตร์

มหาวิทยาลัยขอนแก่น

slide2
ยาเม็ด
  • บทนำ
  • ข้อดี-ข้อเสีย
  • ชนิดของยาเม็ด
    • แบ่งตามการบริหารยา
    • แบ่งตามกระบวนการผลิตและการใช้
  • Tablet compression machines
    • Single punch
    • Multi-station rotary presses
slide3
กระบวนการผลิตยาเม็ด
    • Dry methods

- Direct compression

- Dry granulation

    • Wet method

- Wet granulation

slide4
บทนำ

1843 Tomas Brockedon จดลิขสิทธิ์ยาเม็ด และยาอม

1874 เครื่องตอก rotary และ eccentric

1885 glyceryl trinitrate tablets ใน BP

1980 มี 300 monographs ในเภสัชตำรับ

slide5
ข้อดี
    • การผลิต
      • ผลิตมากๆ อัตราเร็วสูง ต้นทุนต่ำ
      • อยู่ในสภาพแห้ง คงตัวดี shelf life นาน
    • ผู้ใช้ยา (แพทย์ เภสัชกร และผู้ป่วย)
      • สะดวกในการจ่ายแก่ผู้ป่วย
      • ปริมาตร, น้ำหนักน้อย สะดวกในการพกพา
      • ขนาดยาสม่ำเสมอ
      • ยาเม็ดเคลือบกลบกลิ่นรสได้
disadvantages
Disadvantages

Some drugs resist compression into dense compacts

Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability

Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating

ingredients used in tablet formulations
Ingredients used in tablet formulations

Drugs

Fillers, diluent, bulking agent

To make a reasonably sized tablet

Binders

To bind powders together in the wet granulation process

To bind granule together during compression

Disintegrants

To promote breakup of the tablets

To promote rapid release of the drug

slide9
Lubricants

To reduce the friction during tablet ejection between the walls of the tablet and the walls of the die cavity

Glidants

Reducing friction between the particles

To improve the flow properties of the granulations

Antiadherants

To prevent adherence of the granules to the punch faces and dies

slide10
Dissolution (enhancers and retardants)

Wetting agents

Antioxidants

Preservatives

Coloring agents

Flavoring agents

slide11
คุณสมบัติของยาเม็ดที่ดีคุณสมบัติของยาเม็ดที่ดี
  • ขนาดของยาถูกต้อง
  • แข็งแรงเพียงพอ ต่อกระบวนการผลิต การขนส่ง
  • นำส่งยาไปบริเวณที่ออกฤทธิ์ ในปริมาณถูกต้อง
  • ขนาดเม็ด, รูปร่างลักษณะเป็นที่ยอมรับ
  • คงตัวทั้งทางเคมีและกายภาพ
slide12
ชนิดของยาเม็ด

- Route of administration

  • Oral tablets
  • Sublingual or buccal tablets
  • Vaginal tablets

- กระบวนการผลิตและการใช้

  • Compressed tablets
slide13
Multiple compressed tablets

table within a tablet : core, shell

multilayer tablet

  • Sugar-coated tablets

ปกป้องยาเม็ดจากอากาศ ความชื้น

กลบกลิ่น รส

ลักษณะน่าใช้ สวยงาม

เคลือบด้วยชั้นฟิล์มบางๆ

slide14
Film-coated tablets

ฟิล์มโพลิเมอร์ที่ละลายหรือไม่ละลายในน้ำ

แตกตัวได้เร็ว เคี้ยวก่อนกลืน

Chewable tablets

ยาเด็ก, ยาลดกรด และขับลม ออกฤทธิ์เร็ว

Effervescent tablets

ใส่ในน้ำ รับประทานขณะฟองกำลังฟู่

slide16
กระบวนการผลิตยาเม็ด

คุณสมบัติสำคัญของอนุภาค

  • Flowability
  • Compressibility

ไม่มีอนุภาคใดๆ ที่มีคุณสมบัติครบถ้วน

Tableting procedure

  • Filling
  • Compression
  • Ejection
tablet compression machines
Tablet compression machines

ส่วนประกอบพื้นฐาน

  • Hopper บรรจุแกรนูลป้อนเข้า die
  • Dies พิมพ์กำหนดรูปร่าง ขนาด
  • Punches ตอกอัดยาเม็ดภายใน die
  • Cam tracks รางควบคุมการเคลื่อนที่
  • Feeding mechanisms
slide18

Single Punch Machine (Tablets)

Upper andLower Collar

Collar locker

slide19
1. Single punch, single stroke, eccentric press

- Die 1 อัน, punches 1 คู่

- Punch บนเคลื่อนลงไปใน die เกิดการตอกอัด

- อนุภาคเกาะกลุ่มกันเป็นยาเม็ด

- Punch บนเคลื่อนที่ขึ้น punch ล่างเลื่อนขึ้น

- ยาเม็ดถูกผลักออก

slide22
2. Multi-station rotary presses

cam tracks

upper และ lower terrets

die table

pull-down cam (C)

weigh control cam (E)

wipe-off blade (D) ปลาย feed frame

lower compression roll (F)

upper compression roll (G)

slide23
upper punch raising cam (H)

cam (I)

ejector knob

เพิ่มอัตราการผลิต (production rate)

จำนวน station สำหรับตอก

slide26
Production rate ถูกควบคุมโดย
    • จำนวนชุดของเครื่องมือ (tooling sets)
    • จำนวน compression stations
    • ความเร็วรอบของการตอก

ยาเม็ดหลายชั้น

ยาเม็ดตอกเคลือบ (coated tablets)

มีส่วนให้ความเย็น ตอกสาร MP ต่ำ เช่น waxes

slide27
การเตรียมยาเม็ด

การเตรียมยาเม็ด แบ่งได้เป็น 2 วิธีใหญ่ๆ คือ

1. Dry method

1.1 Direct compression

1.2 Dry granulation

2. Wet method

2.1 Wet granulation

slide29
Advantages

Economy

Machine: fewer manufacturing steps and pieces of equipment

Labor: reduce labor costs

Less process validation

Lower consumption of power

slide30
Elimination of granulation process

Heat (wet granulation)

Moisture (wet granulation)

High pressure (dry granulation)

Processing without the need for moisture and heat which is inherent in most wet granulation procedures

slide31
Avoidance of high compaction pressures involves in producing tablets by slugging or roll compaction

Elimination of variabilities in wet granulation processing

Binders (temp, viscous, age)

Viscosity of the granulating solution (depend on its temp),

How long it has been prepared,

Rate of binder addition and kneadingcan affect the properties of the granules formed

slide32
The granulating solution, the type and length of mixing and the method and rate of wet and dry screening can change the density and particle size of the granules, which can have a major effect on fill weight and compaction qualities
slide33
Type and rate of drying

can lead not only to critical changes in equilibrium MC but also to unblending as soluble active ingredients migrate to the surfaces of the drying granules

More unit processes are incorporated in production, the chances of batch-to-batch variation are compounded

slide34
Prime particle dissociation

Each primary drug particle is liberated from the tablet mass and is available for dissolution

Disintegrate rapidly to the primary particle state

slide35
Uniformity of particle size

Greater stability of tablet on aging

Color

Dissolution rate

Fewer chemical stability problems would be encountered as compared to those made by the wet granulation process

slide36
Concerns

Excipient available from only one supplier and often cost more than filler used in granulation

Procedure conservation

Machine investments

Lack of material knowledge

slide37
Physical limitation of drug

No compressibility

No flowability

Physical characteristics of materials (both drug and excipient)

Size and size distribution

Moisture

Shape and surface

Flowability

Density

slide38
Lot to lot variability

Dusting problem

Coloring

direct compression fillers
Direct compression fillers

Common materials that have been modified in the chemical manufacturing process to improve fluidity and compressibility

soluble fillers
Soluble fillers

Lactose

Spray dried lactose

Lactose is placed in aqueous solution, removed impurities and spray dried

Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals

Good flowability but less compressibility

Poor dilution potential

slide41
Loss compressibility upon initial compaction

Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the presence of basic amine drugs and catalyzed by tartrate, citrate and acetate ions

slide42
Fast-Flo lactose (early 1970s)

Spherical aggregates of microcrystals lactose monohydrate

Held together by a higher concentration of glass (amorphous lactose)

Much more compressible

Highly fluid

Non hygroscopic

slide43
Tablets are three to four times harder than regular spray dried

Tabletose: aggromerate form of lactose

More compressible than spray dried but less compressible than Fast Flo lactose

slide44
Anhydrous lactose: free flowing crystalline lactose

Produced by crystallization above 93C which produces the beta form

Pass through steam heated rollers

Good flow property, contained high amount of fines, its fluidity is less than optimal

Can be reworked

slide45
At high RH anhydrous lactose will pick up moisture forming the hydrated compound  increase in the size of tablets if the excipient makes up a large portion of the total tablet weight

Excellent dissolution property

slide46
Sucrose

Di-Pac: cocrystallization of 97% sucrose and 3% modified dextrin

Small sucrose crystals glued together by dextrin

Good flow properties and needs a glidant only when atmospheric moisture levels are high (>50%RH)

Excellent color stability on aging

slide47
Concentration of moisture is extremely critical in terms of product compressibility

compressibility increases rapidly in a moisture range of 0.3-0.4%, plateaus at a level of 0.4-0.5% and rises again rapidly up to 0.8% when the product begins to cake and lose fluidity

slide48
Dilution potential 20-35%

Tablets tend to harden slightly during the first hours after compression or when aged at high humidities and then dried (this is typical of most direct compression sucroses or dextroses)

slide49
Nutab: 95.8% sucrose, 4% convert sugar (equimolecular mixture of levulose and dextrose) and 0.1 to 0.2% each of cornstarch and magnesium strarate

Large particle size distribution and good fluidity

Poor color stability

slide50
Dextrose

Emdex: spray crystallized

90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides

Available both anhydrous and a hydrate product

Excellent compressibility

Largest particle size, blending problem may occur

slide51
Sorbitol

Exists in a number of polymorphic crystalline forms and amorphous form

Widely used in sugar-free mints and as a vehicle in chewable tablets

Cool taste and good mouth feel

Forms a hard compact

slide52
Hygroscopic and will clump in the feed frame and stick to the surfaces of the die table when tableted at humidities > 50%

Lubricant requirements increase when the MC of the sorbitol drops below 0.5% or exceeds 2%

slide53
Mannitol

Exists in a number of polymorphic forms

Not make as hard a tablet as sorbitol

Less sensitive to humidity

Widely used where rapid and complete solubility is required

Use as a filler in chewable tablets

Cool mouth feel but expensive

slide54
Maltodextrin

Maltrin

Highly compressible

Completely soluble

Very low hygroscopic

insoluble fillers
Insoluble fillers

Starch

Starch 1500: intact starch grains and ruptured starch grains that have been partially hydrolyzed and subsequently aggromerated

Extremely high MC (12-13%)

Does not form hard compacts

Dilution potential is minimal

slide56
Not generally used as filler-binder but as filler disintegrant

Retains the disintegrant properties of starch without increasing the fluidity and compressibility of the total formulation

Deforms elastically when a compression force is applied, it imparts little strength to compacts

Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500

slide57
Spray dried starch

Era-Tab: spray-dried rice starch

Good fluidity

MC 10-13%

Compressibility depend on moisture

Reworkability

Low bulk density

slide58
Celulose

Microcrystalline cellulose (Avicel)

The most important tablet excipient developed in modern times

Derived from a special grade of purified alpha wood cellulose by severe acid hydrolysis to remove the amorphous cellulose portions, yielding particles consisting of bundles of needlelike microcrystals

slide59
PH101 powder

PH102 more agglomerated, larger particle size, slightly better fluidity but not significant decrease in compressibility

Most compressible

Highest dilution potential

slide60
A strong compact is formed due to the extremely large number of clean surfaces brought in contact during the plastic deformation and the strength of the hydrogen bonds formed

Extremely low coefficient of friction, no lubricant requirement

When >20% of drugs or other excipients are added, lubrication is necessary

slide61
Not used as the only filler because of its cost and density

Usually used in the conc of 10-25% as a filler-binder-disintegrant, rapid passage of water into the compact and the instantaneous rupture of hydrogen bonds

slide62
Fluidity is poor because of its relatively small particle size, small amount of glidant are recommended in the formulations containing high conc of MCC

Tablets are soften on exposure to high humidities

This softening is reversible when tablets are removed from the humid environment

>80% MCC may slow the dissolution rates of AI having low water solubility

slide63
Small particles get physically trapped between the deformed MCC particles, which delays wetting and dissolution

This phenomenon can be overcome by adding portions of water soluble excipient

slide64
Inorganic calcium salts

Dicalcium phosphate (Emcompress or DiTab)

Free flowing aggregates of small microcrystals that shatter upon compaction

Inexpensive and possesses a high degree of physical and chemical stability

Nonhygroscopic at a RH of up to 80%

Good fluidity

slide65
Slightly alkaline with a pH of 7.0 to 7.3

Precludes its use with AI that are sensitive to even minimal amounts of alkalinity

Tricalcium phosphate (TriTab) is less compressible and less soluble, higher ratio of calcium ions

references
References

1. ยาเม็ด (ม.มหิดล)

2. Pharmaceutics. The science of dosage forms design. (M.E.Aulton)

3. The theory and practice of industrial pharmacy.

4. Pharmaceutical dosage forms: Tablets. Volume 2.

5. Pharmaceutical dosage forms and drug delivery systems.