Metode Pembuatan Tablet

      METODE PEMBUATAN TABLET

      WET GRANULATION

Ø  Terbentuknya granul àmemperbaiki sifat alir dan kompresibilitas, proses kompaksasi lebih mudah karena pecahnya granul membentuk permukaan baru yang lebih aktif

Ø  Obat-obat dosis tinggi yg mempunyai sifat alir dan kompresibilitas jelek àhanya perlu sedikit bahan pengikat

Ø  Untuk bahan dengan dosis rendah dengan pewarna, maka distribusi lebih baik dan menjamin keseragaman isi zat aktif

Ø  mencegah segregasi komponen-komponen campuran yang sudah homogen

Ø  Memperbaiki dissolusi obat yang bersifat hidrofob

      DISADVANTAGES OF WET GRANULATION

-          Proses lebih panjang à lebih mahal

-          Peralatan  lebih banyak àpersonnel yang diperlukan >>

-          ≠ obat-obat yang sensitif thd kelembaban dan pemanasan

-          tablet berwarna dapat terjadi migrasi dan ketidak homogenan à tablet berbintik-bintik

-          Incompabilitas antar komponen di dalam formulasi akan diperbesar, terutama untuk obat-obat campuran (multivitamin, dll)

      Proses-proses dlm Granulasi Basah

Ø  Pengayakan dan Pencampuran serbuk

Ø  Proses Granulasi àPenambahan larutan bahan pengikat ke campuran serbuk untuk membentuk massa dengan ukuran yang cukup basah (plastis)

Ø  Pengayakan dengan ukuran granul yang sesuai

Ø  Pengeringan

Ø  Pengayakan kering

Ø  Penambahan bahan pelicin, bahan penghancur atau bahan tambahan lain

Ø  Pengempaan/pentabletan

Proses pembentukan granul

Prinsip: Granul dibentuk dgn jalan mengikat serbuk dgn suatu pengikat (dlm bentuk larutan atau “bubur” yg mengandung pengikat)

 Pengikat bisa juga dicampurkan kering, baru diberi larutan

Yang perlu diperhatikan: Massa yg terbentuk hanya berupa massa lembab (tdk boleh terlalu basah)

Lama proses tergantung sifat pembasahan dari campuran serbuk dan cairan pengikat, serta alat yg digunakan

Low Shear Granulation

      This is the traditional means of granulation employing low speed planetary or trough mixers in which the drug and intragranular excipients are granulated with a binder solution, the resulting wet mass is screened to form discrete granules which are typically dried in a tray drier.

      The dried granules are rescreened or milled to the required size, blended with extragranular excipients, lubricated and compressed.

      The main disadvantages of this process are the open nature of the equipment and the manual transfer of the materials being processed, the long drying times, potential for migration of soluble components during tray drying (2) and the general lack of instrumentation for in-process control

      4 MACAM MESIN YANG DIGUNAKAN: Ribbon nlender, Planetary  mixer, Sigma Blade Granulator, Orbiting Screw Granulator

HIGH SHEAR MIXER

      High shear mixer granulators are characterised by their use of two mixing blades.

      An impeller that rotates in the base of the mixer and a high speed “chopper” that continually breaks up the wet mass as granulation proceeds.

      This combination provides for very effective mixing of components and usage of small amounts of water compared to low shear granulation. The entire process of mixing and granulation Can be completed in a few minutes and the systems can be fitted with a variety of devices to monitor and determine the end point of granulation.

      A high shear mixer granulator is a closed vessel, and the granules produced are generally able to be

      transferred to a fluid bed drier in a closed system thus minimising the extent of handling necessary.

      A key advantage of high shear granulation is its wide applicability to almost any formulation.

      However, the intensity of the mixing process can rapidly lead to overgranulation with adverse effects on

      granule tabletability (3). In general any process factor that increases the extent of granulation (increasing

      water, massing time or impeller speed) tends to increase granule density and reduce tabletability (4). It

      may be possible to counteract the effect of overgranulation to some extent by milling the dried granules

      (5). Our general advice, based on published studies and work in our own laboratories, is to make a light

      granulation but one that is consistent with good flow. Such a granulation is achieved by carefully

      controlling the relative proportions of diluents, the amount of granulating water and the duration of wet

      massing.

DRY GRANULATION

Merupakan metode yang biasa digunakan untuk bahan obat yang tidak tahan pemanasan dan kelembaban

Prinsip Granulasi Kering
Prinsip granulasi kering adalah menciptakan ikatan antara partikel-partikel dengan pemberatan secara mekanik. Ikatan yang mungkin timbul antar partikel-partikel tergantung dari sifat serbuk serta campuran. Sifat ikatan bermacam-macam, yaitu :
1. Ikatan yang timbul karena jeratan, karena dalam campuran ada serat-serat, misalnya selulosa.
2. Ikatan yang terjadi karena gaya molekular.
3. Gaya pengikat dari pengikat kering.
4. Melalui pancairan yang kemudian membeku kembali.

Keuntungan pembuatan tablet dengan metode granulasi kering adalah :

1. Memerlukan tahap proses yang lebih sedikit sehingga mengurangi kebutuhan akan proses validasi.

2. Waktu.Tidak memerlukan pengeringan sehingga tidak terlalu lama pengerjaan-- hancur lebih cepat karena tidak diperlukannya larutan pengikatnya.

4. Dapat digunakan untuk zat aktif dosis besar yang peka terhadap panas dan lembab.

Kerugian pembuatan tablet dengan metode granulasi kering adalah :
1. Perlu mesin khusus untuk pembuat slug.
2. Tidak dapat mendistribusikan warna dengan homogen.
3. Tidak dapat digunakan untuk zat aktif yang tidak larut.
4. Kemungkinan terjadinya kontaminasi silang lebih cepat.
5. Keseragaman kandungan lebih sulit dicapai

6. Cenderung menghasilkan fines

      TAHAPAN GRANULASI KERING

PENGHALUSAN, PENCAMPURAN, SLUGGING, PENGAYAKAN, PENAMBAHAN BAHAN LAIN, PENCETAKAN

      ALAT-ALAT DRY GRANULATION

1. Mesin Slug
   Massa serbuk ditekan pada tekanan tinggi sehingga menjadi tablet besar yang tidak berbentuk, kemudian digiling dan diayak hingga diperoleh granul dengan ukuran partikel yang diinginkan.
2.  Mesin Rol
   Massa serbuk diletakkan diantara mesin rol yang dijalankan secara hidrolik untuk menghasilkan massa rata yang tipis, lalu diayak atau digiling hingga diperoleh granul dengan ukuran yang diinginkan.

 Metode Cetak Langsung

Pada pembuatan tablet dengan metode cetak langsung, campuran obat dan semua bahan tambahan (pengisi, penghancur, pelincir) dicampur kemudian dicetak

Syarat agar campuran tersebut dapat dicetak, antara lain : mempunyai sifat alir yang baik, kompressibilitas tinggi dan mempunyai efek lubricant yang baik.

Keuntungan metode Cetak Langsung :

      Lebih ekonomis dibanding kedua metode yang lain

      Tidak terpengaruh oleh panas dan kelembaban

      Stabilitas produk terjamin

      Ukuran partikel seragam

      Metode Cetak Langsung

Kerugian :

      Perbedaan ukuran partikel dan kerapatan bulk antara obat dengan pengisi dapat menimbulkan stratifikasi di antara granul àtdk homogen isi obat dalam tablet

      obat dosis besarà+ bahan pengisi àtablet  besar

      pengisi yang bisa dicetak langsungà harganya mahal

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

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

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

v  Good flowability but less compressibility

v  Poor dilution potential

v  Loss compressibility upon initial compaction

v  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)

v  Spherical aggregates of microcrystals lactose monohydrate

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

v  Much more compressible

v  Highly fluid

v  Non hygroscopic

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

–        Tabletose: aggromerate form of lactose

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

–        Anhydrous lactose: free flowing crystalline lactose

v  Produced by crystallization above 93C which produces the beta form

v  Pass through steam heated rollers

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

v  Can be reworked

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

v  Excellent dissolution property

      Sucrose

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

v  Small sucrose crystals glued together by dextrin

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

v  Excellent color stability on aging

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

v   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

v  Dilution potential 20-35%

v  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

v  Large particle size distribution and good fluidity

v  Poor color stability

      Dextrose

–        Emdex: spray crystallized

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

v  Available both anhydrous and a hydrate product

v  Excellent compressibility

v  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

v  Highly compressible

v  Completely soluble

v  Very low hygroscopic

Insoluble fillers

      Starch

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

v  Extremely high MC (12-13%)

v  Does not form hard compacts

v  Dilution potential is minimal

v  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

v  Era-Tab: spray-dried rice starch

Ø  Good fluidity

Ø  MC 10-13%

Ø  Compressibility depend on moisture

Ø  Reworkability

Ø  Low bulk density

      Celulose

–        Microcrystalline cellulose (Avicel)

v  The most important tablet excipient developed in modern times

v  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

v   PH101 powder

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

v  Most compressible

v  Highest dilution potential

v  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

v  Extremely low coefficient of friction, no lubricant requirement

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

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

v  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

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

v  Tablets are soften on exposure to high humidities

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

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

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

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

      Inorganic calcium salts

–        Dicalcium phosphate (Emcompress or DiTab)

v  Free flowing aggregates of small microcrystals that shatter upon compaction

v  Inexpensive and possesses a high degree of physical and chemical stability

v  Nonhygroscopic at a RH of up to 80%

v  Good fluidity

v  Slightly alkaline with a pH of 7.0 to 7.3

v  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

PROSES TABLETASI

Tablet dibuat dengan jalan mengempa bahan atau campuran bahan obat pada mesin cetak yang diisebut dengan pencetak/penekan (press)

Komponen-komponen dasar mesin cetak :

      Hopper, yaitu untuk tempat menyimpan granul yang akan dikempa

      Die yang menentukan ukuran dan bentuk tablet

      Punch untuk mengempa granulat yang terdapat di dalam die

      Jalur Cam, untuk mengatur gerakan punch

Pencetak tablet dibagi dua,

-          pencetak tunggal (single punch)

-           pencetak ganda berputar (rotary multi punch)

Tableting procedure

      Filling , Compression, Ejection

Tablet compression machines

      Hopper for holding and feeding granulation to be compressed

      Dies that define the size and shape of the tablet

      Punches for compressing the granulation within the dies

      Cam tracks for guiding the movement of the punches

      Feeding mechanisms for moving  granulation from the hopper into the dies

Single punch machine

      The compression is applied by the upper punch

      Stamping press

Multi-station rotary presses

      The head of the tablet machine that holds the upper punches, dies and lower punches in place rotates

      As the head rotates, the punches are guided up and down by fixed cam tracks, which control the sequence of filling, compression and ejection.

      The portions of the head that hold the upper and lower punches are called the upper an lower turrets

      The portion holding the dies is called the die table

      The pull down cam (C) guides the lower punches to the bottom, allowing the dies to overfill

      The punches then pass over a weight-control cam (E), which reduces the fill in the dies to the desired amount

      A swipe off blade (D) at the end of the feed frame removes the excess granulation and directs it around the turret and back into the front of the feed frame

      The lower punches travel over the lower compression roll (F) while simultaneously the upper punches ride beneath the upper compression roll (G)

      The upper punches enter a fixed distance into the dies, while the lower punches are raised to squeeze and compact the granulation within the dies

      After the moment of compression, the upper punches are withdrawn as they follow the upper punch raising cam (H)

      The lower punches ride up the cam (I) which brings the tablets flush with or slightly above the surface of the dies

      The tablets strike a sweep off blade affixed to the front of the feed frame (A) and slide down a chute into a receptacle

      At the same time, the lower punches re-enter the pull down cam (C) and the cycle is repeated

      Although tablet compressing machinery has undergone numerous mechanical modifications over the years, the compaction of materials between a pair of moving punches within a stationary die has remained unchanged

      The principle modification from earlier equipment has been an increase in production rate which is regulated by

–        Number of tooling sets

–        Number of compression stations

–        Rotational speed of the press   

      Special adaptations of tablet machines allow for the compression of layered tablets and coated tablets

      A device that chills the compression components to allow for the compression of low-melting point substances such as waxes i.e. suppositories

EVALUASI TABLET

 Pemeriksaan Sebelum tabletting

      Kualitas formulasi bahan yang dipakai

      Homogenitas campuran obat dengan bahan tambahan setelah proses pencampuran

      Kualitas granul : fluiditas, moisture content (MC), distribusi ukuran partikel dan kompressibilitas

Pemeriksaan Selama dan setelah Tabletting

      Penampilan umum (organoleptis)

      Keseragaman kadar zat aktif (content uniformity)

      Keragaman bobot (weight variation)

      Kekerasan (hardness)

      Kerapuhan (friability)

      Waktu hancur (disintegration time)

      Kecepatan Pelarutan (dissolution)

Problema Pencetakan Tablet

1.Binding

      Keadaan dimana bahan yang ditablet sebagian melekat pada die atau matris, sehingga sukar didorong keluar

      Penyebab :

- Kurang lubricant atau lubricant kurang efektif

- Granul terlalu dingin atau terlalu panas atau kurang kering

- Die/matris sudah usang/perlu pemolesan

2.Sticking

      Keadaan di mana sebagian massa tablet melekat pada punch

      Penyebab:

- Granul terlalu basah (kurang kering) atau pemanasan kurang sempurna

- Tekanan pengempaan mesin tablet kurang

- Punch sudah usang/aus atau perlu pemolesan

- RH ruangan pencetakan terlalu tinggi

3. Capping

      Keadaan dimana lapisan atas atau bawah tablet terbelah sebagian atau seluruhnya. Hal ini dapat terjadi SEGERA setelah keluar dari cetakan atau setelah BEBERAPA WAKTU kemudian

      Penyebab :

-          Adanya udara yang ikut terkempa sehingga setelah tablet keluar dari cetakan, udara bereaksi mendesak keluar

-          Terlalu banyak fines

-          Pengeringan granul kurang sempurna atau granul terlalu kering

-          Lubricant terlalu banyak atau terlalu sedikit

4. Mottling

      Keadaan dimana terjadi warna yang tidak merata pada permukaan tablet

      Penyebab :

•       Obat atau hasil uraiannya mempunyai warna yang berbeda dengan bahan tambahan dan tidak tercampur homogen

•       Terjadi migrasi warna selama proses pengeringan granul

•       Bahan tambahan yg berupa larutan berwarna tidak terbagi merata, hal ini disebabkan karena larutan panas dicampur dengan serbuk dingin

5. Variasi Berat

      Tablet yang dihasilkan tidak memenuhi syarat keragaman bobot

      Penyebab :

1.Distribusi granul tidak rata

2.Granul tidak free flowing

3.Lubricant atau glidant tidak tercampur merata