METODE PEMBUATAN TABLET

SUTRIYO

METHODS OF PREPARATION

MOLDING

DIRECT COMPRESSION

DRY GRANULATION

WET GRANULATION

SELECTION OF METHODS

STABILITY CHARACTERISTICS OF THE DRUG

HUMIDITY TEMPERATURE

STABLE UNSTABLE

DIRECT COMPRESSION

DRY GRANULATION

WET GRANULATION

WET GRANULATION

DIRECT COMPRESSION

DRY GRANULATION

Dose of Drug

High Dose

(> 250 mg)

Most of the tablet will

be drug

a. compressibility

b. flowability

Low Dose

(< 25 mg)

Most of the tablet will be

excipients

Content uniformity problem

PROPERTIES OF BULK

BULK PROPERTIES

DIRECT COMPRESSION

DRY GRANULATION

WET GRANULATION

COMPRESSIBILITY GOOD GOOD NONE

FLOWABILITY GOOD NONE NONE

DIRECT COMPRESSION

the process by which tablets are compressed directly from powder blends of the active ingredient and suitable excipients (including fillers, disintegrants, and lubricants), which will flow uniformly into a die cavity and form into a firm compact.

No pretreatment of the powder blends by wet or dry granulation procedures

Advantages 1. More economical :

– reduced processing time – reduced labor costs – fewer manufacturing steps – Fewer pieces of equipment, – less process validation – lower consumption of power

2. without the need for moisture and heat which is inherent in most wet granulation procedures and the avoidance of high compaction pressures involved in producing tablets by slugging or roll compaction

3. optimization of tablet disintegration (disintegrant is able to perform optimally)

4. fewer chemical stability problems would be encountered in tablets prepared by direct compression

5. Useful for crystalline drugs, large dose drugs, or drugs that are moisture sensitive

6. Limited number of excipients - optimal bioavailability

Disadvantages

Requires materials that can be directly compressed

Drugs/Excipients must have good flow properties

Can get non-uniform tablets

PROCESS

MILLING OF DRUGS AND EXCIPIENTS

MIXING OF INGREDIENTS

TABLET COMPRESSION

Direct Compression

drug, filler, internal

disintegrant

bulk

milling mixing

compression tablet evaluation

ballmill V-Blend

GRANULATION

• proses aglomerasi atau pembesaran ukuran partikel dari partikel kecil menjadi aglomerat yang secara fisik lebih besar dan lebih kuat sedangkan partikel asal masih dapat diidentifikasi

• Proses granulasi adalah setiap proses dimana partikel kecil berkumpul menjadi lebih besar, dengan massa yang permanen, dimana partikel asal masih dapat diidentifikasi. (Perry’s Chemical Engineer’s Handbook)

• ….. terbentuknya suatu kelompok (clusters) dari serbuk atau campuran serbuk dan pengikat untuk menghasilkan material yang kohesif dan bebas mengalir yang selanjutnya dapat diproses dengan kompresi atau enkapsulasi.

TUJUAN GRANULASI

1. meningkatkan ukuran partikel

2. meningkatkan sifat aliran (flowability)

3. meningkatkan kompresibilitas (compressibility)

4. mengecilkan volume (densification)

5. menghasilkan partikel yang lebih sferis dan seragam

6. menghasilkan permukaan yang hidrofilik

7. mendistribusikan bahan aktif

PROSES DAN METODE

Proses Metode

Granulasi basah Wet massing

Fluid Bed Granulation

Spray Drying

Pan Granulation

Extrusion and Pelletizing

Granulasi Kering Roller Compaction

Slugging

DRY GRANULATION

• Dry granulation or Slugging - process of preparing a tablet mixture without a wet binder or moisture.

• A slug is formed and then compressed

• Advantages

– Useful for water and heat sensitive drugs

– Fewer steps

• Disadvantages

– Requires drugs or excipients with cohesive properties

DRY GRANULATION

MILLING OF DRUGS AND EXCIPIENTS

MIXING OF MILLED POWDER

COMPRESSION INTO LARGE, HARD TABLETS (SLUGS)

SCREENING OF SLUGS ..... GRANULE

MIXING WITH LUBRICANT AND EXTERNAL DISINTEGRANT

TABLET COMPRESSION

drug, filler,

internal

disintegrant

bulk

milling mixing slugging crushing

compression tablet evaluation mixing sifting

ballmill V-Blend

chilsonator

V-Blend

Lubricant &

External disintegrat

SLUGING/COMPACTOR

DRY GRANULATOR

V-BLEND

Oscilating granulator

Double cone mixer V-Blend

WET GRANULATION

a. wet massing of a tablet powder mixture with liquid adhesives followed by wet screening or granulation

b. Advantages

Most reliable

Highest probability of meeting the requirements for making a successful tablet

c. Disadvantages

– Need to prepare a uniform granulation

– Labor Intensive

– Time Consuming

– Can not use for water and heat sensitive drugs

WET GRANULATION

1. Milling of Drugs And Excipients

2. Mixing of Milled Powder

3. Preparation of Binder Solution

4. Mixing Binder Solution With Powder Mixture to Form Wet Mass (Kneading)

5. Coarse Screening of Wet Mass using 6-12 Mesh

6. Drying Moist Granules (Indikator : MC = 2,5 – 5 %)

7. Screening Dry Granules using 14-20 Mesh

8. Mixing Screened Granules with Lubricant and External Disintegrant

9. Tablet Compression

Stages involved in granulation (Newitt , Conway-Jones dan Barlow )

compression tablet evaluasi Final mixing Sifting 2

Lubricant &

External disintegrat

drying

Fluid Bed

Dryer

drug, filler,

internal

disintegrant

bulk milling premixing

Sifting 1 wetmixing

Binder solution

ballmill V-Blend Planetary

Mixer

SCREENING DRY GRANULES

Diameter Tablet

(inchi)

Diameter Tablet

(mm)

Ayakan (mesh)

6/32 5 20

7/32 – 9/32 5,5 – 7

16

10/32 – 13/32

8 – 10 14

≥ 14/32 ≥ 11 12

METODE PEMBUATAN DIRECT

COMPRESSION DRY GRANULATION WET GRANULATION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF INGREDIENTS

3. TABLET COMPRESSION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF MILLED POWDER

3. COMPRESSION INTO LARGE, HARD TABLETS (SLUGS)

4. SCREENING OF SLUGS

5. MIXING WITH LUBRICANT AND EXTERNAL DISINTEGRATOR

6. TABLET COMPRESSION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF MILLED POWDER

3. PREPARATION OF BINDER SOLUTION

4. MIXING BINDER SOLUTION WITH POWDER MIXTURE TO FORM WET MASS (KNEADING)

5. COARSE SCREENING OF WET MASS USING 6-12 MESH

6. DRYING MOIST GRANULES (indikator : MC = 2,5 – 5 %)

7. SCREENING DRY GRANULES USING 14-20 MESH

8. MIXING SCREENED GRANULES WITH LUBRICANT AND EXTERNAL DISINTEGRATOR

9. TABLET COMPRESSION

HIGH SHEAR GRANULATOR

PLANETARY MIXER

LOW SHEAR GRANULATOR

RIBBON BLENDER

ORBITING SCREW MIXER TWIN-SHELL BLENDER

ZIG-ZAG MIXER AGGLOMERATOR

BATCH FLUID BED GRANULATOR

Pencampuran kering (dry blend)

Mekanisme utama dry blending

• diffusion (difusi)

• convection (konveksi)

• shear (mencukur)

Diffusion

redistribusi partikel dengan gerakan acak dari partikel satu ke partikel yang lain.

convection gerakan dari kelompok partikel yang berdekatan dari

satu tempat ke tempat yang lain dalam campuran.

Shear perubahan dalam konfigurasi bahan melalui

pembentukan bidang yang menggelincir (slip) dalam campuran

Pencampuran padat (solid mixing)

Pencampuran Cair-Padat (Liquid-Solid Mixing): kneading

• Agglomerasi (agglomeration)

• Pemecahan agglomerasi (agglomeration breakdown)

• Agglomerasi kembali (Re-agglomeration)

• Pembentukan Pasta (Paste Formation)

Agglomerasi (agglomeration)

• Tetesan pelarut seperti air atau alkohol atau larutan pengikat, berkontak dan melekat pada partikel serbuk yang bergerak, dan membuat lingkaran di sekelilingnya.

• Partikel serbuk terbasahi oleh cairan, cairan bermigrasi melalui aksi kapiler (pendular dan/atau funicular) menjadi celah partikel-partikel dan membentuk agglomerat serbuk–cair yang besar.

• Melekatnya partikel ke partikel lain membentuk suatu agglomerat dengan ukuran diameter 1 – 5 cm atau lebih besar.

Pemecahan agglomerasi (agglomeration breakdown)

• Setelah fase awal pembentukan agglomerat yang besar, forsa shear dan forsa pencampuran mulai memecah agglomerat.

• Dalam fase ini, cairan dibawa melalui campuran, melewati agglomerat yang lebih kecil yang terus menerus mengurangi ukuran.

• Berkurangnya cairan pada permukaan partikel menyebabkan terjadinya pemecahan aglomerat

Agglomerasi kembali (Re-agglomeration)

• Partikel saling berkontak membentuk jembatan akibat adanya larutan pengikat atau bahan yang terlarut

Pembentukan Pasta (Paste Formation)

• Jika pencampuran dilanjutkan setelah titik akhir granulasi yang normal tercapai (yang berbeda untuk tiap formula), suatu massa basah yang kental yang menyerupai pasta mulai terbentuk sebagai hasil dari solubilisasi, solvasi dan sebagainya.

• Pasta ini, akan sulit untuk dikeringkan dan jika kering menjadi granul yang sangat keras yang sulit untuk digiling (milling) dan dalam banyak kasus menunjukkan compaction yang jelek dalam mesin tablet

DIRECT COMPRESSION

DRY GRANULATION WET GRANULATION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF INGREDIENTS

3. TABLET COMPRESSION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF MILLED POWDER

3. COMPRESSION INTO LARGE, HARD TABLETS (SLUGS)

4. SCREENING OF SLUGS

5. MIXING WITH LUBRICANT AND EXTERNAL DISINTEGRATOR

6. TABLET COMPRESSION

1. MILLING OF DRUGS AND EXCIPIENTS

2. MIXING OF MILLED POWDER

3. PREPARATION OF BINDER SOLUTION

4. MIXING BINDER SOLUTION WITH POWDER MIXTURE TO FORM WET MASS (KNEADING)

5. COARSE SCREENING OF WET MASS USING 6-12 MESH

6. DRYING MOIST GRANULES (indikator : MC = 2,5 – 5 %)

7. SCREENING DRY GRANULES USING 14-20 MESH

8. MIXING SCREENED GRANULES WITH LUBRICANT AND EXTERNAL DISINTEGRATOR

9. TABLET COMPRESSION