TEKNOLOGI SEDIAAN PADAT PMSF 602445

SUTRIYO

REFERENCE

Lieberman, Pharmaceutical Dosage Forms : Tablet Vol. 1 Lachman, L., Theory and Practice of Industrial Pharmacy. Rowe, Handbook of Pharmaceutical Excipients Pharmaceutical Granulation technology Gibson, M, Pharmaceutical Preformulation. Drug Formulation Ansel,H.C., Intoduction to Pharmaceutical Dosage Form

KOMPETENSI MATA AJAR

1. Kompetensi (Sasaran Pemelajaran) • Sasaran pemelajaran terminal • Setelah selesai mengikuti perkuliahan mata ajar ini, mahasiswa

diharapkan mampu: – Menjelaskan teori dasar bentuk-bentuk sediaan padat ( granul, tablet, kapsul

dan supositoria) serta prinsip-prinsip cara pembuatan obat yang baik. (C2 Komprehensif)

– Memilih dan menentukan metoda pembuatan sediaan padat yang paling sesuai. (C4 Analisa)

– Mengidentifikasi dan menganalisa permasalahan-permasalahan yang timbul pada proses pembuatan (C4 Analisa)

– Mendisain formula sediaan padat yang baik. (C5 Sintesis) – Menyusun (menulis) prosedur pembuatan sediaan padat yang baik. (C5

Sintesis) – Mendisain formula larutan penyalut lapis tipis dan penyalut gula. (C5 Sintesis) – Menginterpretasi data evaluasi sediaan padat. (C6 Evaluasi) – Menjelaskan dan menilai formula sediaan padat yang baik. (C6 Evaluasi) – Menjelaskan jenis dan mekanisme pelepasan obat dari sediaan padat – Menganalisa sistem pelepasan dan penghantaran obat dari sediaan padat

• Subkompetensi (Sasaran Pemelajaran Penunjang) – Mahasiswa mampu menjelaskan karakteristik sediaan padat yang baik. – Mahasiswa mampu menjelaskan sifat-sifat fisikokimia obat. – Mahasiswa mampu menjelaskan komponen formulasi sediaan padat – Mahasiswa mampu menjelaskan karakteristik bahan eksipien dalam sediaan

padat. – Mahasiswa mampu menjelaskan metoda-metoda pembuatan tablet – Mahasiswa mampu menganalisis permasalahan yang terjadi dalam

pencetakan – Mahasiswa mampu menjelaskan jenis, prosedur, alat dan persyaratan evaluasi

sediaan padat – Mahasiswa mampu menganalisis hasil evaluasi sediaan padat. – Mahasiswa mampu menjelaskan pengaruh faktor fisikokimia obat, formulasi

dan metoda pembuatan terhadap mutu sediaan tablet yang baik. – Mahasiswa mampu menjelaskan formula larutan penyalut, proses dan

permasalahan yang timbul dalam proses penyalutan tablet dengan salut gula,

– Mahasiswa mampu menjelaskan formula larutan penyalut, proses dan permasalahan yang timbul dalam proses penyalutan tablet dengan salut lapis tipis

– Mahasiswa mampu menganalisis permasalahan yang terjadi dalam penyalutan tablet

– Mahasiswa mampu menjelaskan formulasi sediaan granul effervescent. – Mahasiswa mampu menjelaskan formulasi sediaan kapsul keras dan kapsul

lunak – Mahasiswa mampu menjelaskan, formulasi dan evaluasi sediaan supositoria – Mahasiswa mampu menjelaskan jenis pelepasan obat berdasarkan bentuk

fisik, rute pemberian dan mekanisme pelapasan dari sediaan padat. – Mahasiswa mampu menjelaskan mekanisme pelepasan obat dari tablet

konvensional dan tablet lepas cepat – Mahasiswa mampu menjelaskan mekanisme pelepasan obat dari tablet lepas

lambat – Mahasiswa mampu menjelaskan mekanisme pelepasan obat dari tablet dan

transdermal lepas terkendali – Mahasiswa mampu menjelaskan mekanisme pelepasan obat dari tablet lepas

tunda – Mahasiswa mampu menjelaskan konsep penghantaran targeting

DESKRIPSI

Mata ajaran ini bertujuan agar mahasiswa : a. mengetahui, memahami dan mampu menjelaskan teori

dasar sediaan solid (padat) meliputi sediaan granul, kapsul dan supositoria,

b. memahami karakteristik sediaan padat yang baik,

c. mampu merancang formula,

d. mengidentifikasi permasalahan-permasalahan yang timbul dalam proses pembuatan,

e. menganalisis faktor-faktor penyebabnya, (baik faktor formulasi, fisikokimia maupun proses pembuatannya).

f. dapat melakukan proses pembuatan dan evaluasi terhadap berbagai bentuk sediaan padat.

POKOK BAHASAN

DEFINISI DAN JENIS SEDIAAN TABLET

STUDI PRA FORMULASI

FORMULASI SEDIAAN TABLET

METODE PEMBUATAN SEDIAAN TABLET

PERMASALAHAN SEDIAAN TABLET

EVALUASI SEDIAAN TABLET

PHARMACEUTICAL DOSAGE FORM

is a drug delivery system which is formed by technological processing (drug

formulation)

WHY ???

Why ????

SEDIAAN PADAT

DEFINITION

• Various shapes: round, triangular, square, rectangular, etc...

• Thick or thin, flat or convex,

• Carry a symbol used for indentification, may be colored

DEFINISI

• Farmakope Indonesia III : sediaan padat kompak, dibuat secara kempa/cetak, dalam bentuk tabung pipih atau sirkuler, kedua permukaannya rata atau cembung, mengandung satu jenis obat atau lebih dengan atau tanpa zat tambahan.

• Tablet (Menurut FI IV) adalah sediaan padat mengandung bahan obat dengan atau tanpa bahan pengisi, dibuat terutama dengan cara kompresi. Sejumlah tertentu dari tablet dibuat dengan mencetak

Conventional tablets

• Multiple compressed tablets • Sugar-coated tablets • Film-coated tablets • Enteric coated tablets • Buccal & Sublingual tablets • Chewable tablets • Effervescent tablets

• Triturates Tablets • Hypodermic tablets

TYPES OF TABLETS

COMPRESSED TABLET MOLDED TABLET

Advantages and Disadvantages of

tablets

•Problems with bioavailability •Some drugs resist compression into tablet. •Difficulty in swallowing in some patients; pediatrics

and geriatrics.

Most stable of all oral preparations Unit dose Simple to identify

Properties of Tablet

must be sufficiently Strong and resistant to abrasion (Hardness and Friability Test)

must be Uniform in weight and drug content (uniformity test)

the drug content of the tablet must be bioavailable (disintegration, Dissolution, BA-BE Test)

must be elegant in appearance (Organoleptik)

Must be retain stability and efficacy (stability)

GRANULES OR AGGREGATES

FINES PARTICLE

DRUG IN SOLUTION

DRUG IN BLOOD AND OTHER

BIOLOGICAL FLUIDS AND TISSUES

DRUG PROFILE

Multiple compressed tablets

– more than one compression step is involved. – results in a multiple-layered tablet within a tablet (shell and core). – each layer is usually colored with a different color.

Advantage: medicinal agents are separated to prevent incompatibility, or

each layer provides drug release at a different stage or for coating purposes.

Disadvantage:

expensive process requires accurate and precise machinery

Sugar-coated tablets

coating is sugar-based, water soluble

and quickly dissolves after swallowing.

coating may be colorless or colored. Advantages: 1. protects drugs from the effects of

air and humidity. 2. masks unpleasant odor and taste. 3. enhances the appearance of

compressed tablets. Disadvantage: 1. time and expertise required for

the process. 2. increase in the size and weight of

the tablet (50% increase).

Film-coated tablets: covered by a film of water-insoluble polymer that

ruptures in the GI tract. Enteric coated tablets:

1. coating resist dissolution or disruption in the stomach but not the intestines

2. protects drugs that are destroyed in acid medium

3. protects the stomach from drugs that cause irritation to the gastric mucosa.

4. used when by-pass of the stomach greatly enhances drug absorption

FILM AND ENTERIC COATED TABLETS

FILM & ENTERIC COATED TABLET

Buccal or sublingual tablets

a. sublingual tablets are the one that dissolves when held beneath the tongue, permitting direct absorption of the active ingredient by the oral mucosa

b. Generally flat, oval tablets intended to disslove in the buccal pouch or beneath the tongue for absorption through the oral mucosa.

c. Tablets intended for buccal administration are formulated to dissolve slowly (progesterone tablets) whereas those for sublingual adminstration dissolve to give rapid drug effects.

d. used for drugs that are destroyed by gastric juice and/or are poorly absorbed from the GI tract

Sub Lingual & Buccal Tablet

Advantages

• Rapid absorption

• Rapid onset of action

• Increased bioavailability

• Effective dose is less

• No first pass metabolism

Disadvantages :

• High dose can not be administered

• Surface area for absorption is limited

• Highly ionic drugs can not be formulated

• Drugs which are irritating and undesirable taste cannot be used

• Noncompliance to patient

• Patient should avoid eating, drinking, chewing, smoking and possible talking in order to keep the tablet in place

Choice Of Drug

• The drug should have following characteristics:

• Undergo passive diffusion

• Optimum partition coefficient

• Aqueous solubility

• Optimum pKa value

• Dose of the drug should be low (10mg – 15mg)

• The drug should not be highly ionic or at least capable of being buffered in tablet form

Structure of Oral mucosa

Sublingual tablets

Chewable tablets

• Have a smooth rapid disintegration when chewed to dissolve in the mouth.

• Formulated in mannitol.

• Used mainly for children’s multivitamin tablets and for the administration of antacids and anti-flatulents.

Effervescent tablets

• Prepared by compression of granular effervescent salts that release gas when in contact with water.

• Fast disintegration and dissolution of drug for rapid action

Reaction

Citric Acid 3 NaHCO3 + C6H8O7H2O ---> 4H2O + 3CO2 + Na3 C6H5O7

3 mol 1 mol

1 gram of citric acid reacts with 1.2 g sodium bicarbonate.

Tartaric Acid 2 NaHCO3 + C4H6O6 ---> 2 H2O + 2 CO2 + Na2 C4H4O6

2 mol 1 mol : (2 x 84 1 mol

1 grams of tartaric acid reacts with 1.12 g of sodium bicarbonate

EFFERVESCENT MIX Acid Sources

1. Food Acids

» Citric Acid

» Tartaric Acid

» Ascorbic Acid

» Fumaric Acid

» Malic Acid

» Adipic And Succinic Acids

» Acetyl SalicYLIC ACID

2. Acid Anhydrides

• Citric anhydride

• succinic anhydride

3. Acid Salts

• Sodium Dihydrogen Phospate (Monosodium Phospate)

• Disodium Dihydrogen Pyrophospate (Sodium Acid Pyrophospate)

• Acid Citrate Salts

• Amino Acid Hydrochlorides

• Sodium Acid Sulphite

Carbonate Sources

• Sodium Bicarbonate

• Sodium Carbonate

• Potassium Bicarbonate And Potassium Carbonate

• Sodium Sesquicarbonate

• Sodium Glycine Carbonate

• L-lysine Carbonate

• Arginine Carbonate

• Amorphous Calcium Carbonate

• Calcium Carbonate

Hypodermic tablets

• Tablet triturates originally intended to be dissolved by a physician

• in a suitable vehicle and parenteral administration

Tablet triturates • Small, usually cylindrical molded or compressed

tablets containing small amounts of usually potent drugs.

• Diluent is usually sucrose and lactose, water-insoluble materials are avoided in the formulation

• tablet triturates must be readily soluble in water.

Uses:

• oral or sublingual adminstration of drugs (e,g Nitroglycerin).

• insert directly one or more of these in a capsule for accurate dosing.

• to fortify liquid preparations.

STUDI PRA FORMULASI

Definition

Goal

Physicochemical characteristics

Preformulation

• Development stage where physical and chemical properties of a drug material are characterized for the purpose of making a stable, effective and safe dosage form.

• focuses mainly on investigation to obtain basic and general information on how to make an effective and stable preparation

Goals of Preformulation

(1). To establish necessary physicochemical

parameters of drug substance;

(2). To determine its kinetic rate profiles;

(3). To establish its physicochemcal characteristics;

(4). To establish its mechanical characteristics

(4). To establish its compatibility with common

excipients.

PHYSICOCHEMICAL PROPERTIES

PHYSICOCHEMICAL PROPERTIES

Ionization constant

Partition coefficient

solubility

stability polymorphism

hygroscopicity

compatibility

pKa Determinations

• Many potential candidate drugs are weak acids or bases.

• the ionization of weak acids or bases is dependent on pH

pH-pKa Relationship with proportion unionized.

HA

A

U

IpKpH a loglog

HB

B

I

UpKpH a loglog

For weak acidic drugs:

For weak basic drugs:

Gastrointestinal (GI) Physiology

Organs pH

Buccal approx 6

Oesophagus 5-6

Stomach 1.7-3.5

Duodenum 5 - 7

Small Intestine 6 – 7.5

Large intestine 6.8 - 7

Fluid pH

Aqueous humour 7.2

Blood 7.4

Colon 5-8

Duodenum (fasting) 4.4-6.6

Duodenum (fed) 5.2-6.2

Saliva 6.4

Small intestine 6.5

Stomach (fasting) 1.4-2.1

Stomach (fed) 3-7

Sweat 5.4

Urine 5.5-7.0

http://library.thinkquest.org/C004535/media/cell_membrane.gif

PARTITION COEFFICIENT

• The lipophilicity of an organic compound is usually described in terms of a partition coefficient, log P,

• The partition coefficient can be defined as the ratio of the concentration of the unionized compound, at equilibrium, between organic and aqueous phases

• log P = 0 means that the compound is equally soluble in water and in the partitioning solvent.

• log P = 5, then the compound is 100,000 times more soluble in the partitioning solvent.

• log P = –2 means that the compound is 100 times more soluble in water, it is quite hydrophilic.

SOLUBILITY • The solubility of a candidate drug may be the critical

factor determining its usefulness, since aqueous solubility dictates the amount of compound that will dissolve and, therefore, the amount available for absorption.

solubility

Particle size

(milling)

Cristallinity

(solid dispersion)

Prodrugs

(salt,complex,

ester, etc)

Polymorphism

(stable, meta stable, unstable

form)

Solvate/

hydrate

Description Parts of solvent required

for one part of solute

Very soluble < 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble 1000 - 10,000 Insoluble > 10,000

TERM OF SOLUBILITY

Noyes-Whitney equation

s t

dC DSC C

dt h

• where dC/dt is the rate of dissolution

• D is the diffusion coefficient of the drug in solution in g.i. fluid

• S is the effective surface area of drug particle in contact with the g.i. fluid,

• Cs is the saturation solubility of the drug in the diffusion layer and

• Ct is the concentration of drug in solution in the bulk medium (g.i. fluid).

STABILITY

stability

hydrolysis

racemerization Epimerization

Hydrolysis

• Degradation by hydrolysis is affected by a number of factors, of which

– solution pH,

– Buffer salts and

– ionic strength

Hydrolysis

CLASS EXAMPLE

ESTER ASPIRIN

THIOL ESTER SPIROLACTONE

AMIDE CHLORAMPHENICOL

SULPHONAMIDE SULPHAPYRAZINE

IMIDE PHENOBARBITONE

LACTAM METHICILLIN

LACTONE SPIRONOLACTONE

HALOGENATED ALIPHATIC CHLORAMBUCIL

Hydrolysis of cefotaxime sodium

Oxidation of Vitamine C

Isomerization (racemization) of epinephrine

Epimerization of tetracycline

Polymorphism

• Capacity of a compound existing in more than one crystalline form.

• Different packing of molecules in crystal • Polymorphism occurs only to drug materials with crystalline

properties. • Polymorphism is just a physical phenomenon, the

chemistry remains identical • May have different melting points, IR, Xray density,

solubility • Enantiotropic : forms can change reversibly from one form

to another with the change in temperatures or pressure • Monotropic : the change between the two forms is

irreversible

Effect of Crystalline/polymorphic form on dissolution rate of Chloramphenicol palmitate

PARTICLE SIZE

• The particle size of pharmaceuticals is important since it can affect the formulation characteristics and bioavailability of a compound (Chaumeil 1998).

• Size also plays a role in the homogeneity of the final tablet

• When large differences in size exist between the active components and excipients,mutual sieving (demixing) effects can occur making thorough mixing difficult

• Size can also be a factor in stability; fine materials are relatively more open to attack from atmospheric oxygen, heat, light, humidity, and interacting exipients than coar-se materials

PARTICLE SIZE

CRYSTALLINITY

• Habit : The external shape of a crystal

• Crystal morphology or habit is important, since it can influence many properties of the compound. – powder flow properties,

– compaction and

– stability

• Ex. tolbutamide B (plate like) caused powder bridging in the hopper and a capping problem when tableted.

Crystal Habits

Habit Description Habit Description

Acicular Elongated prism, needlelike

Irregular Lacking any symmetry

Angular Sharp edged, roughly polyhedral

Nodular Rounded irregular shape

Bladed Flattened acicular Flaky/Platy Plate or saltlike

Crystalline Geometric shape fully developed in fluid

Prismatic Columnar prism

Dendritic Branched crystalline Spherical Global shape

Fibrous Regular or irregular threadlike

Tabular

Rectangular with a pair of parallel faces

Granular Equidimensional irregular shape

CRYSTALLINITY

Hygroscopicity

• Hygroscopicity is the rate and extent of moisture adsorbed/absorbed by a solid substance

• important to study the moisture absorption behavior of drugs to choose the processing and storage conditions for the drug

HYGROSCOPICITY

Degree Of Hygroscopicity

*) Callaghan et al. (1982) Equilibrium moisture content of pharmaceutical excipients., in Drug Dev. Ind. Pharm., Vol. 8, pp. 355–369. Marcel Dekker, Inc.

No Class Increase in mass

1 Non-hygroscopic Essentially no moisture increases occur at relative humidities below 90%.

2 Slightly hygroscopic Essentially no moisture increases occur at relative humidities below 80%.

3 Moderately hygroscopic Moisture content does not increase more than 5% after storage for 1 week at relative humidities below 60%.

4 Very hygroscopic Moisture content increase may occur at relative humidities as low as 40 to 50%.

DRUG-EXCIPIENT COMPATIBILITY STUDY

DRUG

EXCIPIENT

50 % Mixture

No Interaction

Interaction

Recomended Excipient

Significant Breakdown

Alternative Excipient

DSC

Difractogram DSC

Particle, Powder, and Compact Characterization

• Particle size and distributions

• Crystalinity

• shape

• Density (true, bulk, tapped)

• Flowability

• Deformation (elastic, plastic , brittle fracture/ductile)

• Compressibility

• Compactibility

DENSITY

• The true density of a substance is the average mass of the particles divided by the solid volume, exclusive of all the voids

• Bulk density is the mass per unit volume of a loose powder bed. Bulk Density (g/mL) = (M/Vo) where M mass in grams and Vo untapped apparent volume in

milliliters. • Tapped density of a powder is the ratio of the mass of the powder

to the volume occupied by the powder after it has been tapped for a defined period of time

Tapped Density(g/mL) = (M/Vf) where M mass in grams, and Vf the tapped volume in milliliters. • Tapped density values are generally higher for more regularly

shaped particles (i.e., spheres), as compared to irregularly shaped particles such as needles

• The formulation should have sufficient flowability to ensure that the appropriate quantity of powder flows into the dies of the tablet machine on a consistent basis

ANGEL OF REPOSE

𝜶 = 𝐭𝐚𝐧−𝟏𝒉

𝒓

r

h

Fixed Funnel Method

Angle of Repose () is the maximum angle between the surface of a pile of powder and horizontal plane

BULK-TAPPED DENSITY

𝑩𝒖𝒍𝒌 𝑫𝒆𝒏𝒔𝒊𝒕𝒚 𝝆𝒐 = 𝒎

𝑽𝟎 𝑻𝒂𝒑𝒑𝒆𝒅 𝑫𝒆𝒏𝒔𝒊𝒕𝒚 𝝆𝒕 =

𝒎

𝑽𝒇

Carr’s Index dan Hausner Ratio

𝑪𝒐𝒎𝒑𝒓𝒆𝒔𝒔𝒊𝒃𝒊𝒍𝒊𝒕𝒚 𝑪𝒂𝒓𝒓′𝒔 𝑰𝒏𝒅𝒆𝒙 % =𝝆𝒕𝒂𝒑𝒑𝒆𝒅−𝝆𝒃𝒖𝒍𝒌

𝝆𝒕𝒂𝒑𝒑𝒆𝒅 x 100

𝑯𝒂𝒖𝒔𝒏𝒆𝒓 𝑹𝒂𝒕𝒊𝒐𝒏 = 𝑻𝒂𝒑𝒑𝒆𝒅 𝒅𝒆𝒏𝒔𝒊𝒕𝒚

𝑩𝒖𝒍𝒌 𝒅𝒆𝒏𝒔𝒊𝒕𝒚

Flow Character Angle of

Repose ()

Compressibility

Index (%)

Hausner

Ratio

Excellent 25-30 10 1.00-1.11

Good 31-35 11-15 1.12-1.18

Fair 36-40 16-20 1.19-1.25

Passable 41-45 21-25 1.26-1.34

Poor 46-55 26-31 1.35-1.45

Very Poor 56-65 32-37 1.46-1.59

Very Very Poor >66 > 38 >1.60

Ref. Powder Flow" in USP 29–NF 24 (US Pharmacopeial

Convention, Rockville, MD), p. 3017

Scale of Flowability

Classification of Powder by Fineness

Classification of Powder d50 sieve opening (µm)

Very Coarse 1000

Coarse 355 - 1000

Moderately Fine 180 - 355

Fine 125 - 180

Very Fine 90 - 125

Deformation (elastic, plastic , brittle fracture/ductile)

• Elactic deformation : A change in shape caused by the applied stress is completely reversible, and the specimen will return to its original shape on release of the applied stress

• Plastic deformation is the permanent change in shape of a specimen due to applied stress

• brittle fracture or ductile fracture; fracture being the separation of a body into two or more parts.

• Ductile fracture is characterized by extensive plastic deformation followed by fracture. Ductile failure is not typically seen with compacts of pharmaceutical materials.

COMPACTION

• There are two principal types of compaction studies used to characterise material:

– pressure/volume relationships and

– pressure/strength relationships.

• the pressure/volume relationships provide the information about the compaction properties of a material that allows an appropriate formulation to be developed

• Compressibility and compactibility

Compressibility

• compressibility of a powder as the ability to decrease in volume under pressure. and

• Compressibility of powders is characterized from the density-compression pressure relationship according to the Heckel plot

• 𝑙𝑛1

1−𝐷𝑟= 𝑘𝑃 + 𝐴

– 𝐷𝑟: relative density; P is the compressional pressure; k and A are constants

compactibility

• Compactibility : as the ability of the powdered material to be compressed into a tablet of specified tensile strength (Lueuenberger and Rohera)

• The compactibillty of pharmaceutical powders can be characterized by studying tensile strength and indentation hardness

• Hiestand and Smith used tensile strength and indentation hardness to determine three dimensionless parameters Strain index, bonding index, and brittle fracture index-to characterize tableting performance of individual components and mixtures

Compression

• Compression is the process of applying pressure to a material.

• In pharmaceutical tableting an appropriate volume of granules in a die cavity is compressed between an upper and a lower punch to consolidate the material into a single solid matrix, which is subsequently ejected from the die cavity as an intact tablet.

Compression

• The subsequent events that occur in the process of compression are

a. transitional repacking,

b. deformation at points of contact,

c. fragmentation and/or deformation,

d. bonding,

e. deformation of the solid body,

f. decompression, and

g. ejection.

Preformulation Study

1. Background

2. Organoleptic properties

3. Microscopic examination

4. Physical characteristics

5. Solution properties

6. Stability (solid)

7. Drug-excipient compatibility studies

8. Solution stability

9. Recommendations

Background

1. Compound:

2. Chemical name:

3. Chemical structure

4. Lot numbers

5. Solvents of recrystallization

6. Purity

7. Therapeutic category

8. Anticipated dose

Physical characteristics

1. Density

2. Particle size

3. Surface area

4. Static charge

5. Flow properties

6. Compressibility

7. Hygroscopicity

8. Polymorphism

Solution properties

1. pH of 1% Suspension

2. pKa

3. Solubility

4. Effect of solUbilizing agents

5. Partition coefficient

6. Dissolution rates

TABLET COMPOSITION

Lain-lain

Excipients

• To increase bulk in order to produce a tablet of practical weight for compression

Filler/diluent/bulking agent

• To facilitate rapid breakup and disintegration after administration.

Disintegrant

• To impart cohesive properties to the powders by the formulation of granules

Binder

• To reduce interparticulate friction and to facilitate tablet ejection from the die (lubricants),

• To prevent sticking/adhesion of powder to the surfaces of punches and dies (anti adherent),

• to improve flow characteristics of the granulation (glidant)

Lubricant

EXCIPIENTS

1. MUST BE PHYSIOLOGICALLY INERT

2. MUST BE ACCEPTABLE TO REGULATORY AGENCIES

3. MUST BE PHYSICALLY AND CHEMICALLY STABLE

4. MUST BE FREE OF ANY BACTERIA PATHOGENIC

5. MUST BE INTERFERE WITH THE BIOAVAILABILITY OF THE

DRUG

6. MUST BE COMMERCIALLY AVAILABLE AND PURITY

7. COST MUST BE RELATIVELY INEXPENSIVE

8. MUST BE CONFORM TO ALL CURRENT REGULATORY

REQUIREMENTS

BAHAN PENGISI (DILUENT/FILLER/BULKING AGENT)

Water insoluble

• Starch

• Powdered cellulose

• Microcrystalline cellulose

• Calcium carbonate

• Dicalcium phosphate

• Calcium triphosphate

• Magnesium carbonate

Water soluble

• Lactose

• Sucrose

• Mannitol

• Modified starch

• Sorbitol, etc.

Selection of diluent

compressibility, solubility, flowability,

disintegration qualities, hygroscopicity, lubricity ,

stability, etc

Filler Characteristics

A = compressibility B = flowability C = solubility D = disintegration E = Higroscopisity F = Lubricity G = Stability

0 = tidak ada 1 = jelek/ rendah 5 = baik/ tinggi

Filler Characteristics

A B C D E F G Dextrose 3 2 4 2 1 2 3

Spray-dried Lactose 3 5 4 3 1 2 4

Fast-Flo Lactose 4 4 4 4 1 2 4

Anhydrous Lactose 2 3 4 4 5 2 4

Emdex 5 4 5 3 1 2 3

Sucrose 4 3 5 4 4 1 4

Starch 2 1 0 4 3 3 3

Sta-Rx 1500 3 2 2 4 3 2 4

Dicalcium phosphate 3 4 1 2 1 2 5

Emcompress 3 4 0 4 1 1 3

Avicel 5 1 0 2 2 4 3

Filler Characteristics

A = availability B = flowability C = solubility D = absorbansi E = asam (a)/ basa (b) F = friability G = lubricity

0 = tidak ada 1 = jelek/ rendah 5 = baik/ tinggi

Filler Characteristics

A B C D E F G

Calcium carbonate 2 4 0 3 b 2 1

Dicalcium phosphate 2 2 0 4 b 2 0

Calcium triphosphate 3 2 0 5 b 2 0

Magnesium carbonate 2 2 0 4 b 1 1

Sodium chloride 5 5 5 2 a 3 2

TRADE NAME DESCRIPTION Fast Flo lactose® It is spray processed lactose which is a mixture of crystalline α-lactose monohydrate

and amorphous lactose.

Microcellac® 75% lactose and 25% MCC (MicroCrystalline Cellulose)

Ludipress® 93% α-lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone.

Nu-Tab® Sucrose 95-97%, invert sugar 3-4% and magnesium stearate 0.5%

Di-Pac® Sucrose 97% and modified dextrins 3%

Sugartab® Sucrose 90-93% and invert sugar 7-10%.

Emdex® Dextrose 93-99% and maltose 1-7%

Cal-Tab® Calcium sulfate 93% and vegetable gum 7%

Cal-Carb® Calcium carbonate 95% and maltodextrins 5%

Calcium 90® Calcium carbonate (minimum) 90% and Starch, NF (maximum) 9%

EMCOMPRESS Dibasic Calcium Phosphate USP (Special Size Praction)

STA-RX 1500 Pregelatinized (Compressible)

EMCOCEL Microcrystallin Cellulose NF

AVICEL 101, 102 Microcrystallin Cellulose NF

TRITAB Tricalcium Phosphat Anhydrous (DC)

VITACEL Coprocessed Product Containing 30 % Calcium Carbonate And 70 % Microcrystalline Cellulose)

BINDERS To impart cohesive properties to the powders by

the formulation of granules

SUGAR NATURAL BINDERS SYNTHETIC/SEMISYNTHETIC POLYMER

Sucrose : 50-75 %

Acacia : 10-25 % Cellulose derivate (HPMC, HPC, NaCMC, EC,MC) : 5-10 %

Liquid glucose: 25-50 %

Tragacanth : 3-10% Polyvinyl Pyrrolidone (PVP) : 3-15 %

Sorbitol : 10-25 %

Gelatine : 10-20 % Polyvinyl Alcohol (PVA)

Starch Paste : 5-10% Polyethylene Glycol (PEG)

Pregelatinezed Starch : 1-5 % Polymethacrylates : 5-15 %

Alginic acid : 5-10 %

Cellulose

Sodium Alginate 3-5 %

DC BINDER CLASS

Avicel (PH 101) MCC

SMCC (50) SMCC (Silicified MCC)

UNI-PURE(DW) Partially PGS (Pregelatinized Starch)

UNI-PURE (LD) Low density starch

DC Lactose DC lactose anhydrous

DI TAB DC-DCPD (Dibasic Calcium Phosphate Dihydrate)

DIRECT COMPRESSION BINDER

Flow Behavior DI TAB > SMCC(50) > DC Lactose , UNI PURE(DW) > Avicel (PH 101) > UNI PURE(LD)

Compressibility UNI PURE(LD) > SMCC(50) , Avicel (PH 101) > UNI PURE(DW) , DC Lactose > DI TAB

Crushing Strength UNI PURE(LD) > SMCC(50) > UNI PURE(DW) > Avicel(PH 101) > DC Lactose &gt DITAB

LUBRICANT Oil to the system

To reduce interparticulate friction and to facilitate tablet ejection from the die (lubricants),

To prevent sticking/adhesion of powder to the surfaces of punches and dies (anti adherent),

to improve flow characteristics of the granulation (glidant), Too much can cause waterproofing

LUBRICANT

CONCENTRATION (%)

GLYDANT PROPERTIES

ANTI-ADHERENT PROPERTIES

LUBRICANT PROPERTIES

METALLIC (Ca/Mg) STEARATES

1 OR LESS NONE GOOD EXCELLENT

TALC 1 – 5 GOOD EXCELLENT POOR

STEARIC ACID 1 - 5 NONE POOR GOOD

CAB-O-SIL 1 OR LESS EXCELLENT GOOD NONE

CORN STARCH 5 - 10 EXCELLENT EXCELLENT POOR

WATER SOLUBLE LUBRICANT

WATER SOLUBLE LUBRICANT

CONCENTRATION (%)

BORIC ACID 1

SODIUM CHLORIDE 5

SODIUM BENZOIC 5

SODIUM ACETATE 5

PEG 4000 1-4

PEG 6000 1-4

DL-LEUCIN 1-5

Na LAURYL SULPHATE 1-5

Mg LAURYL SULPHATE 1-2

DISINTEGRANTS

To facilitate rapid breakup and disintegration

after administration.

Will be added during (internal/intragranular) and

after granulation (external/extragranular)

Mechanism of tablet disintegrants

1. By capillary action 2. By swelling 3. Because of heat of wetting (AIR EXPANSION) 4. Due to disintegrating particle/particle

repulsive forces 5. Due to deformation 6. Due to release of gases 7. By enzymatic action

DISINTEGRANTS CONCENTRATION IN

GRANULES (%W/W) SPECIAL COMMENTS

Starch USP 5-20 Higher amount is required, poorly

compressible

Starch 1500 5-15 -

Avicel®(PH 101, PH

102)

10-20 Lubricant properties and directly

compressible

Solka floc® 5-15 Purified wood cellulose

Alginic acid 1-5 Acts by swelling

Na alginate 2.5-10 Acts by swelling

Explotab® 2-8 Sodium starch glycolate, superdisintegrant.

Polyplasdone®(XL) 0.5-5 Crosslinked PVP

Amberlite® (IPR 88) 0.5-5 Ion exchange resin

Methyl cellulose, Na

CMC, HPMC

5-10 -

AC-Di-Sol® 1-3 Direct compression