รศ.ดร.จอมใจ พีรพัฒนา คณะเภสัชศาสตร์ มหาวิทยาลัยขอนแก่น T a b l e t s ยาเม็ด รศ.ดร.จอมใจ พีรพัฒนา คณะเภสัชศาสตร์ มหาวิทยาลัยขอนแก่น

ยาเม็ด บทนำ ข้อดี-ข้อเสีย ชนิดของยาเม็ด Tablet compression machines แบ่งตามการบริหารยา แบ่งตามกระบวนการผลิตและการใช้ Tablet compression machines Single punch Multi-station rotary presses

กระบวนการผลิตยาเม็ด - Direct compression - Wet granulation Dry methods - Dry granulation Wet method - Wet granulation

1843 Tomas Brockedon จดลิขสิทธิ์ยาเม็ด และยาอม บทนำ 1843 Tomas Brockedon จดลิขสิทธิ์ยาเม็ด และยาอม 1874 เครื่องตอก rotary และ eccentric 1885 glyceryl trinitrate tablets ใน BP 1980 มี 300 monographs ในเภสัชตำรับ

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

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

Absorption of drug form tablets

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

Lubricants Glidants Antiadherants 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

Dissolution (enhancers and retardants) Wetting agents Antioxidants Preservatives Coloring agents Flavoring agents

คุณสมบัติของยาเม็ดที่ดี ขนาดของยาถูกต้อง แข็งแรงเพียงพอ ต่อกระบวนการผลิต การขนส่ง นำส่งยาไปบริเวณที่ออกฤทธิ์ ในปริมาณถูกต้อง ขนาดเม็ด, รูปร่างลักษณะเป็นที่ยอมรับ คงตัวทั้งทางเคมีและกายภาพ

- Route of administration ชนิดของยาเม็ด - Route of administration Oral tablets Sublingual or buccal tablets Vaginal tablets - กระบวนการผลิตและการใช้ Compressed tablets

Multiple compressed tablets table within a tablet : core, shell multilayer tablet Sugar-coated tablets ปกป้องยาเม็ดจากอากาศ ความชื้น กลบกลิ่น รส ลักษณะน่าใช้ สวยงาม เคลือบด้วยชั้นฟิล์มบางๆ

Film-coated tablets Chewable tablets Effervescent tablets ฟิล์มโพลิเมอร์ที่ละลายหรือไม่ละลายในน้ำ แตกตัวได้เร็ว เคี้ยวก่อนกลืน Chewable tablets ยาเด็ก, ยาลดกรด และขับลม ออกฤทธิ์เร็ว Effervescent tablets ใส่ในน้ำ รับประทานขณะฟองกำลังฟู่

กระบวนการผลิตยาเม็ด

กระบวนการผลิตยาเม็ด Tableting procedure คุณสมบัติสำคัญของอนุภาค Flowability Compressibility ไม่มีอนุภาคใดๆ ที่มีคุณสมบัติครบถ้วน Tableting procedure Filling Compression Ejection

Tablet compression machines ส่วนประกอบพื้นฐาน Hopper บรรจุแกรนูลป้อนเข้า die Dies พิมพ์กำหนดรูปร่าง ขนาด Punches ตอกอัดยาเม็ดภายใน die Cam tracks รางควบคุมการเคลื่อนที่ Feeding mechanisms

Single Punch Machine (Tablets) Upper and Lower Collar Collar locker

1. Single punch, single stroke, eccentric press - Die 1 อัน, punches 1 คู่ - Punch บนเคลื่อนลงไปใน die เกิดการตอกอัด - อนุภาคเกาะกลุ่มกันเป็นยาเม็ด - Punch บนเคลื่อนที่ขึ้น punch ล่างเลื่อนขึ้น - ยาเม็ดถูกผลักออก

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)

upper punch raising cam (H) cam (I) ejector knob เพิ่มอัตราการผลิต (production rate) จำนวน station สำหรับตอก

Production rate ถูกควบคุมโดย จำนวนชุดของเครื่องมือ (tooling sets) จำนวน compression stations ความเร็วรอบของการตอก ยาเม็ดหลายชั้น ยาเม็ดตอกเคลือบ (coated tablets) มีส่วนให้ความเย็น ตอกสาร MP ต่ำ เช่น waxes

การเตรียมยาเม็ด การเตรียมยาเม็ด แบ่งได้เป็น 2 วิธีใหญ่ๆ คือ 1. Dry method 1.1 Direct compression 1.2 Dry granulation 2. Wet method 2.1 Wet granulation

Direct compression method

Advantages Economy Machine: fewer manufacturing steps and pieces of equipment Labor: reduce labor costs Less process validation Lower consumption of power 29

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

Elimination of variabilities in wet granulation processing 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 kneading can affect the properties of the granules formed

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

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

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

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

Concerns Excipient available from only one supplier and often cost more than filler used in granulation Procedure conservation Machine investments Lack of material knowledge

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

Lot to lot variability Dusting problem Coloring

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

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

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

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

Tabletose: aggromerate form of lactose 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

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

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

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

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

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)

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

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

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

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%

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

Maltodextrin Maltrin Highly compressible Completely soluble Very low hygroscopic

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

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

Spray dried starch Era-Tab: spray-dried rice starch Good fluidity MC 10-13% Compressibility depend on moisture Reworkability Low bulk density

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

PH101 powder PH102 more agglomerated, larger particle size, slightly better fluidity but not significant decrease in compressibility Most compressible Highest dilution potential

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

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

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

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

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

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 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.