Studi Pra Formulasi Dan Formulasi Teknologi Sediaan Solid
Studi Pra Formulasi Dan Formulasi Teknologi Sediaan Solid
PMSF 602445
SUTRIYO
REFERENCE
WHY ???
Why
????
SEDIAAN PADAT
DEFINITION
DRUG IN
SOLUTION
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 AND ENTERIC COATED TABLETS
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 & 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
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
Ionization
constant
PHYSICOCHEMICAL solubility
hygroscopicity PROPERTIES
polymorphism
stability
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.
For weak acidic drugs:
pH pK a log
I
log
A
U HA
For weak basic drugs:
pH pK a log
U
log
B
I HB
Gastrointestinal (GI) Physiology
Organs pH Fluid pH
Buccal approx 6 Aqueous humour 7.2
Oesophagus 5-6 Blood 7.4
Stomach 1.7-3.5
Colon 5-8
Duodenum 5-7 Duodenum (fasting) 4.4-6.6
6 – 7.5 Duodenum (fed) 5.2-6.2
Small Intestine
Saliva 6.4
Large intestine 6.8 - 7
Small intestine 6.5
Stomach (fasting) 1.4-2.1
Stomach (fed) 3-7
Sweat 5.4
Urine 5.5-7.0
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.
Particle size
(milling)
Cristallinity
Solvate/
hydrate (solid
dispersion)
solubility
Polymorphism Prodrugs
(stable, meta (salt,complex,
stable, unstable
form) ester, etc)
TERM OF SOLUBILITY
stability
Epimerization
racemerization
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, Irregular Lacking any symmetry
needlelike
Angular Sharp edged, roughly Nodular Rounded irregular shape
polyhedral
Bladed Flattened acicular Flaky/Platy Plate or saltlike
Crystalline Geometric shape fully Prismatic Columnar prism
developed in fluid
Dendritic Branched crystalline Spherical Global shape
Fibrous Regular or irregular Tabular Rectangular with a pair of
threadlike 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
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 No Interaction
Alternative Significant
Excipient Breakdown
Difractogram DSC
Particle, Powder, and Compact
Characterization
h
r
Fixed Funnel Method
𝒎 𝒎
𝑻𝒂𝒑𝒑𝒆𝒅 𝑫𝒆𝒏𝒔𝒊𝒕𝒚 𝝆𝒕 = 𝑩𝒖𝒍𝒌 𝑫𝒆𝒏𝒔𝒊𝒕𝒚 𝝆𝒐 =
𝑽𝒇 𝑽𝟎
Carr’s Index dan Hausner Ratio
𝝆𝒕𝒂𝒑𝒑𝒆𝒅 −𝝆𝒃𝒖𝒍𝒌
𝑪𝒐𝒎𝒑𝒓𝒆𝒔𝒔𝒊𝒃𝒊𝒍𝒊𝒕𝒚 𝑪𝒂𝒓𝒓′ 𝒔 𝑰𝒏𝒅𝒆𝒙 % = x 100
𝝆𝒕𝒂𝒑𝒑𝒆𝒅
𝑻𝒂𝒑𝒑𝒆𝒅 𝒅𝒆𝒏𝒔𝒊𝒕𝒚
𝑯𝒂𝒖𝒔𝒏𝒆𝒓 𝑹𝒂𝒕𝒊𝒐𝒏 =
𝑩𝒖𝒍𝒌 𝒅𝒆𝒏𝒔𝒊𝒕𝒚
Scale of Flowability
Angle of Compressibility Hausner
Flow Character
Repose () Index (%) Ratio
Lain-lain
Excipients
Filler/diluent/bulking agent
• To increase bulk in order to produce a tablet of practical weight for
compression
Disintegrant
• To facilitate rapid breakup and disintegration after administration.
Binder
• To impart cohesive properties to the powders by the formulation of granules
Lubricant
• 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)
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 Water soluble
• Starch
• Powdered cellulose
• Lactose
• Microcrystalline cellulose • Sucrose
• Calcium carbonate
• Dicalcium phosphate • Mannitol
• Calcium triphosphate • Modified starch
• Magnesium carbonate
• Sorbitol, etc.
Selection of diluent
compressibility,
solubility, flowability,
disintegration qualities,
hygroscopicity, lubricity ,
stability, etc
Filler Characteristics
Characteristics
Filler 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
Nu-Tab® Sucrose 95-97%, invert sugar 3-4% and magnesium stearate 0.5%
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 > 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
CONCENTRATION GLYDANT ANTI-ADHERENT LUBRICANT
LUBRICANT (%) PROPERTIES PROPERTIES PROPERTIES
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
CONCENTRATION IN
DISINTEGRANTS SPECIAL COMMENTS
GRANULES (%W/W)