tablets - first lec
TRANSCRIPT
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• Pharmaceutics is the science of dosage form
design.
• It deals with the formulation of a pure drug
substance into a dosage form.
• They are means by which drug molecules are
delivered to sites of action within the body.
Pharmaceutics and Dosage form Safe and
convenient
deliveryProtection of
API from
atmosphere
Protection
of API from
GIT
Delivery of
insoluble or
unstable API
Mask bitter taste or
obnoxious odour
Extend
drug action
Optimal
drug action
from topical
sites
Placement Placement
of drugs
with in the
body Ease of drug
identification
Ideal properties of a dosage form
Effective
Safe
Reliable
Stable
Pharmaceutically elegant
Convenient
TABLETS
What are tablets?????
Tablet is defined as a compressed solid unit dosage form containing
medicaments with or without excipients
As per IP:Tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drug or a mixture of drugs, with or without diluents
Advantages
Dose precision
Low cost
Compact
Easiest to package and ship
Easy to swallow
(least hang up)
Can sustain drug effect
Bitterness and bad
odour can be masked
Easy of large scale production
Greatest stability
Easy to identify product
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Disadvantages
Difficult for children Difficult for
unconscious patients
Not for a variety of
drugs
AmorphousPoorly
compactable Poorly wetable
Sensitive to
atmospheric
conditions
Poorly solublePoorly
bioavailable
Which drugs ????? General properties of tablets
1. Elegance
Free of defects like chips, cracks, discoloration, and contamination.
2. Strength
Withstand mechanical shock during its production packaging, shipping and dispensing.
3. Release the
drug
Release the medicinal agents in a predictable and reproducible manner.
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4. Physically stable
Stable to maintain its physical attributes over time
5. Chemically stable
Chemical stability over time so as not to allow degradation of the medicinal agents.
TYPES OF TABLETS Tablets
Ingested orally
Used in oral cavity
Administered by other route
Used to prepare a solution
Compressed tablets
Multiple compressed tablets
Modified release tablets
Coated tablets
Chewable tablets
Targeted tablets
Tab
lets
ing
est
ed
ora
lly Buccal tablets
Sublingual tablets
Troches or
lozenges
Dental conesTab
lets
to
be
use
d i
n o
ral
cav
ity
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Implantable tablets
Vaginal tablets
Tab
lets
ad
min
iste
red
by
oth
er
rou
tes
Effervescent tablets
Dispersible tablets
Hypodermic tablets
Tablet triturates
Tab
lets
use
d t
o p
rep
are
a
solu
tio
n
Preformulation
Definition:
� It is a stage of formulation development where
physical and chemical properties of drugs alone and
when combined with excipients are studied
Objective:
� To generate information useful to formulator in
developing stable and bioavailable dosage forms
Sta
ge
s in
fo
rmu
lati
on
de
ve
lop
me
nt
Preformulation
Bulk characterisation
Description
Crystallinity
Polymorphism
Particle size
Bulk density
Powder flow properties
Hygroscopicity Hygroscopicity
Solubility characterisation
pKa
pH solubility profile
Common ion effect
Thermal effect
Partition coefficient
Dissolution
Stability characterisation
Solid state stability
Solution stability
Bulk stability
Compatibility
pH rate profile
Stability in formulation
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BULK
CHARACTERISATION
Description
• The colour, odour, and taste of the drug is recorded
Molecular structure
Chemical structure
External HabitOverall appearance of
the compound
Internal
Amorphous
Crystalline
Single entity
Molecular adduct
(pseudopolymorphism)
Salt forms
Solvates/ hydrates
Internal structure
• Amorphous form: Highest energy state –
greatest solubility
• Crystalline form – polymorphism
– ENANTROPIC – polymorphs can be reversibly
changed into another stable form by changing the
temperature or pressure. RARE
– MONOTROPIC – one polymorph is stable at all
temperatures and pressures and others will
eventually convert to the stable form. COMMON
Higher energy state – High solubility, Less
stability
Solubility:
AMORPHOUS > METASTABLE > STABLE
FORMULATORS PREFER THE METASTABLE FORM.
� Chloramphenicol palmitate: 3 polymorphic forms A, B and C
B – metastable form, best BA
A – most stable, biologically inactive
Polymorphs have different physical properties like
1. Melting point
2. Density
3. Compaction behaviour
4. Vapour pressure
5. Solubilities
6. Flow properties
7. X-ray diffraction patterns
8. Crystal and optical behaviour
9. Different stabilities
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Distinguishing amorphous and
crystalline forms
Powder X~raydiffraction patterns of amorphous and crystalline trihydrate forms of epicillin
Pseudopolymorphim
• Crystalline form of drug can exist as a molecular
adduct.
• If water molecules are incorporated into the drug
molecules – hydrate and water is know as water of
crystallisation
• If any other solvent – solvates and solvent of
crystallisation
• Anhydrous form > hydrate form
eg. Ampicillin has more solubility than
ampicillin trihydrate
• Solvates > non-solvates
eg. Chloroform solvate of griseofulvin is more
soluble than griseofulvin
Distinction between solvate and true
polymorph
Observing melting behavior of substances
Hot stage micrometer
– Drug dispersed in silicone oil using hot stage
microscopy
– Hydrates and solvates evolve a gas causing
bubbling of oil
» The temperature of bubbling is close to
boiling point of solvent
– True polymorphs melt without gas evolution
Salt form of the drug
� Most drugs exist as weak acids or weak bases, thus making
salt forms improves solubility
� Acidic drugs – ppt in stomach eg. Pentobarbital, hexobarbital
– sodium or potassium salts � Pentobarbital sodium, Warfarin sodium
� Basic drugs – ppt in intestine eg. Codeine, theophylline
– hydrochloride or sulphate salts� Codeine hydrochloride, Ranitidine hydrochloride
Crystal habit
1. cubic system is one where all sides
equal one another and where all
angles are 90°.
2. orthorhombic system all angles are
90° but the side lengths are
unequal.
3. monoclinic system is one where all
sides are different, where two of the
angles are 90° but one is not
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Crystal characteristic and stability
• For drugs prone to degradation in solid state, physical form of drug
influences rate of degradation
• Eg: Aztreonam, a monobactam antibiotic exists in needle like α and dense
spherical β-crystalline forms
• In presence of high humidity (37°C/75% RH),
– α form undergoes β -lactam hydrolysis more readily
• Half life of 6 months
– β form under identical conditions is stable for several
years
• Polymorphic transformations can occur during grinding,
granulating, drying, and compressing operations.
• Eg: Digoxin, spironolactone, and estradiol undergo
polymorphic transformations during comminution process
• During granulation use of a solvent can lead to a solvate
formation
• Drying may cause transformation to an amorphous form
Crystal characteristics and tableting
behavior
Eg: different polymorphs of sulfathiazole,
barbitone. and asprin differ significantly in
their compression characteristics
• Crystalline indomethacin yields tablets with
better hardness than amorphous form
How to study Purity?
� Generally determined by the analytical department
1. Thermal analysis – DTA, DSC and TGA
2. Spectroscopy – UV and FTIR
3. Chromatography – TLC and HPLC
4. Melting point
Differential thermal analysis (DTA)
• Material under study and an inert reference are made
to undergo identical thermal cycles, and temperature
difference between them are recorded.
• Differential temperature is plotted against time.
• Changes in sample, either exothermic or endothermic,
can be detected relative to inert reference.
Differential scanning calorimetry (DSC)
• Measures amount of
energy required to
keep the sample at
the same
temperature as the
reference. i.e.
measures the
enthalpy of transition
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Thermo-gravimentric Analysis (TGA)
Ca Oxalate Thermogram
Change in weight with change in temperature is monitored
UV-Vis spectroscopy
UV spectrum of theophylline
FTIR spectroscopy
FTIR spectra of cinnarizine
Chromatography
TLC
• Paper chromatography
• Thin layer of silica, alumina, cellulose etc on glass plates
HPLC
• Normal phase
• Polar stationary phase
• Non polar mobile phase
• Reverse phase
• Non - Polar stationary phase
• polar mobile phase
Melting point
• Requires minute amount of substance
• Information regarding
1. Thermal properties of substance
2. Stability of the compound
Hygroscopicity
• Tendency to absorb moisture from atmosphere
-Delinquescent
• Chemical stability, flowability and compatibility are
affected if moisture is absorbed
• Mechanical processing of solids such as grinding,
milling, micronization, compaction, etc., can induce
changes in their reactivity toward water vapor
• Preformulation study should be conducted with the
form of material to be used in the final formulation
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• TEST
• Powder is exposed to a range of controlled
humidity environment and moisture uptake is
recorded
• Any compound that takes up more that 5%
moisture should be stored at low humidity
Particle size
• Fine particle characterization
• Various methods like:
– Coulter counter method
– SEM
Density
• Absolute and bulk densities of the drug substance decides size
of the final dosage form.
• Very critical for
– Drugs of low potency - constitute the bulk of final
granulation of tablet
– High- dose capsule formulation
– Filling of tablet dies
• Density of solids affects their flow properties
• Significant difference in the absolute densities of components
leads to segregation
Measurement of bulk densities
Flowability
• Flow properties of powders are critical for efficient tableting
operation
– to assure efficient mixing and acceptable weight
uniformity
• Bad flow is improved by selecting appropriate excipients i.e.
glidants
• Measured by angle of repose, flow through an orifice or
compressibility index
• When a heap of powder is
allowed to stand with only
gravitational force acting on
it, the angle between free
surface of the static heap of
horizontal plane achieves a
certain maximum value for a
given powder and is known as
static angle of repose
Angle of repose
θ
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Angle of repose as an indication of
flow properties
Angle of repose Type of flow
<20 Excellent
20-30 Good
30-34 Passable*
>40 Very poor
* May be improved by adding glidant; Eg:0.2% Aerosil
Compactibility/ Compressibility
• "Compressibility" of a powder is the ability to decrease
in volume under pressure. (Carr’s ratio)
• "Compactibility” is the ability of the powdered material
to be compressed into a tablet of specified tensile
strength.
• Hausner’s ratio is related to Carr’s ratio by the formula
−×=
T
BC
ρ
ρ1100
−×=
CH
11100
Carr’s index
• Is an indication of the compressibility of a powder
• Frequently used as an indication of flowability of powder
• A Carr’s index >33 (equivalent to 1.5 of Hausner’s ratio)
indicates poor flow,
• Carr’s ratio <20 (equivalent to 1.25 of Hausner’s ratio)
indicates good flow
Carr’s ratio Type of flow
5-15 Excellent
12-16 Good
18-21 Fair to passable*
23-25 Poor*
33-38 Very poor
>40 Extremely poor
May be improved by glidant Eg: 0.2% Aerosil
SOLUBILITY
CHARACTERISATION
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Solubility
• Solid drugs administered orally for systemic activity must
dissolve in GI fluids prior to absorption
• Dissolution of drugs in gastrointestinal fluids influences the
rate and extent of their absorption
• Compounds with an aqueous solubility of greater than 1% w/v do not present dissolution-related absorption problems
Intrinsic Solubility C0
• Definition: Fundamental solubility of any substance when it
is completely unionized
• ie the solubility of an acid in acid and the solubility of a
base in base
• If solubility of a substance increases in aqueous basic
solution in comparison to water is known as a weak acid
• Similarly increase in solubility in alkaline solutions suggests
weakly acidic drug