TABLETS

Definition: Tablets are solid preparations consisting of one or

more active ingredient obtained by compressing uniform volumes
of particles into various shapes and sizes.
 official tablets are defined as circular discs with either flat or convex faces

 intended for oral administration

 used mainly for systemic drug delivery but also local action
 active ingredients + excipients
 some tablets are ----- swallowed whole
after being chewed
dissolved or dispersed in water
retained in the mouth where drug is liberated.
 ADVANTAGES
 Production aspects
1. Large scale production at lowest cost
2. Easiest and cheapest to package and ship
3. High stability (chemical, mechanical & biological)
4. Lightest and most compact
 Formulation aspects
1. Greatest dose precision with least content variability
2. Lend to give special release profile products e.g. enteric or delayed
release tablets
3. Product identification is cheap – embossing or monogrammed punch face
 Patient aspects
1. Ease of handling
2. Coating can mark unpleasant tastes & improve patient acceptability
 DISAVDANTAGES
 Some drugs resist compression into dense compacts

 Drugs with poor wetting, slow dissolution,

intermediate to large dosages may be difficult or
impossible to formulate and manufacture as a tablet
that provides adequate or full drug bioavailability

 Bitter taste drugs, drugs with an objectionable odor,

or sensitive to oxygen or moisture may require
encapsulation or entrapment prior to compression or
the tablets may require coating
Preformulation Aspects
 Tablets are one of the most challenging of all pharmaceutical products to
design and manufacture.
 Poor wetting or slow dissolution or good cohesive compacts of amorphous
or flocculent drugs may result in low bioavailability.
 The focus is to see that action taken to improve one objective should not
cause another objective to degrade
For eg. Tablets should have smooth surface, good appearance, surface gloss
and also be cohesive and compact so as not to undergo friability,
powdering or chipping during handling.
Therefore, steps taken to achieve the first set of objectives (using binder or
adhesive, ↑ing compression pressure or punch dwell time or using
precompression must not have negative impact on other set of objectives
(disintegration time, drug dissolution rate & bioavailability)
 A satisfactory compromise between competing set of objectives may be
simple or extremely complex.
 Statistical optimization can be carried out.
Step 1. Complete preformulation data regarding the physicochemical
characteristics of the drug like

a. Stability (solid state): light, temperature, humidity

b. Stability (solution): drug-excipient stability (DSC or accelerated ss)
c. Physicomechanical studies: particle size, bulk and tap density,
compressibility, MP, taste, color, appearance and odor
d. Physicochemical properties: solubility and pH profile of
solution/dispersion (water, solvents)
e. In vitro dissolution: pure drug, pure drug pellet, dialysis of drug,
absorbability, effect of excipients and surfactants

Step 2. Tablet production design requires 2 major activities.

i. Identifying the excipients most suited for a prototype formulation of
drug (checking drug – excipients compatibility)
ii. Optimizing the levels of those excipients
Medical
 Desired release profile
 Dissolution is the rate limiting step
 Targeting drug delivery
Marketing
Appearance: colour, texture, shape, size, coating and
embossing
Economics
 Cost of excipients
 Type of process (labor, energy and time)

Experimental approach
 Analysis of variance (ANOVA)
 Statistical screening design

Plackett Burman (levels)

Extreme vertices
Bioavailability studies
Stability data
Validation data

Pg 77- 88; pharmaceutical dosage forms volume 1

Preformulation involves the application of biopharmaceutical
principles to the physicochemical parameters of drug substance
are characterized with the goal of designing optimum drug
delivery system.
Before beginning the formal preformulation programs the
preformulation scientist must consider the following factors

• The amount of drug available.

• The physicochemical properties of the drug already known.
• Therapeutic category and anticipated dose of compound.
• The nature of information, a formulation should have or would
like to have.
 Preformulation drug characterization in a structured
program
Test Method/ function Characterization
Fundamental  
1) UV spectroscopy Simple assay
2) Solubility Phase solubility/ purity
  a) Aqueous Intrinsic & pH effect
  b) pKa solubility control , salt formation  
  c) Salt Solubility, hygroscopicity & stability
  d)Solvents Vehicles & Extraction
  e) ko/ w Lipophillicity, structure activity
  f) Dissolution Biopharmacy
3) Melting point DSC-polymorphism hydrate & solvent
4) Assay development UV, HPLC, TLC
5) Stability  
    In Solution Thermal, hydrolysis, pH
    In solid state Oxidation, proteolysis metal ion
Derived  
6) Microscopy Particle size and morphology
7) Bulk density Tablet and capsule formation
8) Flow properties Tablet and capsule formation
9) Compression properties Acid / excipient choice
10) Excipient compatibility Preliminary screen by DSC, Conformation by TLC
1. UV Spectroscopy
The first requirement of any preformulation study is the development of
a simple analytical method for quantitative estimation in subsequent
steps.
Most of drugs have aromatic rings and/or double bonds as part
of their structure and absorb light in UV range, UV spectroscopy being
a fairly accurate and simple method is a performed estimation
technique at early preformulation stages.
The absorption Co-efficient of the drug can be determined by the formula:-
E =    AF / X 
Where ,          A = Absorbance
F= dilution factor
                        X = weight of drug (mg)
It is now possible to determine concentration of drug in any solution by
measuring absorbance.
C =      AF / E mg/ ml
Characterization of drug molecules is very important step at the
preformulation
phase of product development. Following studies are conducted as basic
preformulation studies, special studies are conducted depending on the type of
dosage form and the type of drug molecules.

1)         Solubility determination

2)         pKa determination
3)         Partition co-efficient
4)         Crystal properties and polymorphism
5)         Practical size, shape and surface area.
6)         Chemical stability profile.
1. Solubility Determination
 The solubility of drug is an important physicochemical parameter because it effects the
bioavailability of the drug, the rate of drug release into dissolution medium and
consequently, the therapeutic efficiency of the pharmaceutical product is affected by
solubility.
 The solubility of a new drug must be determined as a function of pH over the physiological
pH range of 1 to 8.
 Solubility is also determined in variety of commonly used solvents and some oils if the
molecule is lipophillic.  
 The solubility of material is usually determined by the equilibrium solubility method,
which employs a saturated solution of the material, obtained by stirring small incremental
amounts of solute to a fixed amount of solvent and examining visually for any undissolved
solute particles till equilibrium is achieved i.e when some solute remains undissolved, the
total amount added up to that point serves as a good and rapid estimate of solubility.
 Commonly used solvents include: Water, polyethylene glycols, propylene glycol, glycerin,
sorbitol, ethyl alcohol, methanol, benzyl alcohol, isopropyl alcohol, tweens, polysorbates,
castor oil, peanut oil, sesame oil, buffer at various pHs
2. pKa determination

 Many drugs are weakly acidic or basic compounds and in solution depending on
the pH values exist as ionized or un-ionized species.
 The un-ionized species are more lipid soluble and hence more readily absorbed.
 The GI absorption of weakly acidic or basic drugs, thus is related to the fraction of
drug in solution that is un-ionized.
 Conditions that suppress ionization favor absorption.
 The important factors are pH at the site of action, ionization constant and lipid
solubility of un-ionized species (pH partition theory).
 The Henderson – Hasselebalch  equation provides an estimate of the ionized and un
ionized drug concentration at a particular pH.

pH = pKa + log  (un-ionized form]) / [ionized form]) for bases

pH = pKa + log  (ionized form]) / [un-ionized form]) for acids

3. Partition Coefficient

 Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an

indication of its ability to cross cell membranes. It is defined as the ratio of
unionized drug distributed between the organic and aqueous phases at equilibrium.
P o/w = (C oil / C water) equilibrium.
 For series of compounds, the partition coefficient can provide an empiric
knowledge in handling and in screening for some biologic properties. For drug
delivery, the lipophilic/ hydrophilic balance has been shown to be a contributing
factor for the rate and extent of drug absorption.
 Although partition coefficient data alone does not provide understanding of in vivo
absorption, it does provide a means of characterizing the lipophilic/ hydrophilic
nature of the drug.
 Since biological membranes are lipoidal in nature. The rate of drug transfer for
passively absorbed drugs is directly related to the lipophilicity of the molecule. The
partition coefficient is commonly determined using an oil phase of octanol or
chloroform and water.
 Drugs having P vales much greater than 1 are classified as lipophilic, whereas those
with partition coefficient much less than 1 are indicative of a hydrophilic drug.
 Although it appears that the partition coefficient may be the best predictor of
absorption rate, the effect of dissolution rate, pKa and solubility on absorption must
not be neglected.
4. Dissolution
It is important to realize that usually drugs are absorbed if they are in solution form. Hence a solid
dosage form has to undergo dissolution before absorption.

When dissolution is the significantly slower of the two processes the absorption is described as
dissolution rate-limited.
Since dissolution precedes absorption, any change in the process of dissolution would influence
the absorption.
4a. Intrinsic dissolution
The dissolution rate of a solid in its own solution is described by Noyes-Nernst
equation:
dc = AD (Cs – C )
dt hV
Where,
dc/dt = dissolution rate
A = surface area of dissolving solid
D = diffusion co-efficient
h = diffusion layer thickness
V = volume of the dissolution medium
Cs = solute conc. in the diffusion layer
During early phase of disso, Cs >> C and is equal to saturation solubility S and if A and
V are constant, at constant temp and agitation above equation reduces to
dc = KS (intrinsic dissolution rate)
dt
where K = AD/hV = constant
5. Crystal properties and polymorphism
 Many drug substance can exit in more than one crystalline from with different
space lattice arrangements. This property is known as polymorphism.
 The different crystal forms are called polymorphs.
 Occasionally, a solid crystallizes, entrapping solvent molecule in a specific lattice
position and fixed stoichiometry, resulting in a solvate or pseudopolymorph.
 Polymorphs generally have different dissolution, true density, crystal shape, solid
state stability, melting points, x-ray diffraction patterns and  solubility even though
they are  chemically identical.
 Differences in the dissolution rates and solubilities of different polymorphs of a
given drug are very commonly observed. When the absorption of a drug is
dissolution rate limited, a more soluble and faster-dissolving polymorph may be
utilized to improve the rate and extent of bioavailability.
 For drugs prone to degradation in the solid state, physical form of the drug
influences degradation. Therefore, a polymorph that is chemically more stable in a
solution is preferred.
 Different polymorph also lead to different morphology, tensile
strength and density of power bed which all contribute of
compression characteristics of materials.
 Some investigation of polymorphism and crystal habit of a drug
substance which relates in pharmaceutical processing is desirable
during preformulation evaluation especially, when the active
ingredient is expected to constitute the bulk of the tablet mass.
 Although a drug substance may exist in two or more polymorphic
forms, only one form is thermodynamically stable at a given
temperature and pressure. The other forms would convert to the
stable form with time.
 In general, the stable polymorph exhibits the highest melting point ,
the solubility, and the maximum chemical stability.
 Various techniques are available for the investigation of the solid 
state. These include microscopy (including hot stage microcopy),
infrared spectrophotometry, single-crystal x-ray and x-ray power
diffraction, differential thermal analysis, differential scanning
colorimetry and dilalometry.
6. Particle Size, Shape and Surface Area

 Bulk flow, formulation homogeneity, and surface-area control processes

such as dissolution and surface morphology of the drug particles.
 In general, each new drug candidate should be tested during
preformulation with the smallest particle size as is practical to facilitate
preparation of homogeneous samples and maximize the drug’ s surface
area for interactions.
 Chemical, physical properties and biopharmaceutical behavior of drug
substances are affected by their particle size distribution and shapes.
 For e.g. phenacetin & griseofulvin
 Poorly soluble drugs showing a dissolution- rate limiting step in the
absorption process will be more readily bioavailable when administered in
a finely subdivided state rather than as a coarse material.
 In case of tablets, size and shape influence the flow and the mixing
efficiency of powders and granules. Size can also be a factor in stability:
fine materials are relatively more open to attack from atmospheric oxygen,
humidity, and interacting excipients than coarse materials.
6a. Particle size determination

 Microscopy: is the simplest technique of estimating particle size ranges and

shapes. Material is suspended in a non dissolving fluid and polarizing lens is
used to observe and determine the particle size. Estimating size range includes
particles above 1µm and upwards. But as it requires counting of a large number
of particles for quantitative estimation, it is not suited for rapid, quantitative size
determination.
 Sieve analysis: particle size range upwards from above 50 µm.
 But most pharmaceutical powders range in size from 1 to 120 µm.
 Therefore instruments based on laser (Malvern), light scattering (Royco), light
blockage (HIAC) and blockage of electrical conductivity path (Coulter counter)
are used.
6b. Surface Area Determination

 Surface area is most commonly determined based on Brunauer-Emette-Teller (BET) theory of

adsorption.
 Most substances adsorb a monomolecular layer of gas under certain conditions of partial
pressure of gas and temperature.
 Knowing the monolayer capacity of adsorbent and the area of absorbable molecule, the
surface area can be calculated
 The adsorption process is carried out at liquid nitrogen temperatures -195˚C
 The partial pressure of nitrogen is attainable when it is in a 30% mixture with an inert gas
(helium).
 Then adsorption takes onto most solids by virtue of Vander wall’s forces.
 The BET equation is
__1__
____1____ = C-1 P +
λmC P0 λmC
λ (P /P – 1)
0

Where, λ = gms of absorbate per gram of absorbent

λm = value of that ratio for monolayer
P = partial pressure of the absorbate gas
P0 = vapour pressure of the pure absorbate gas
C = a constant
7. Chemical stability profile
 Preformulation stability studies are usually the first quantitative 
assessment of chemical stability of a new drug. These studies include both
solution and solid state experiments under condition typical for the
handing, formulation, storage, and administration of a drug candidate as
well as stability in presence of other excipients.
 Factors effecting chemical stability which are critical in rational dosage
form design include temperature, pH and dosage form diluents.
 The method of sterilization of potential product will be largely dependent
on the temperature stability of the drug.
 Drugs having decreased stability at elevated temperatures cannot be
sterilized by autoclaving but must be sterilized by another means, e.g.,
filtration.
 The effect of pH on drug stability is important in the development of both
oral and liquid dosage forms. - Solid state stability
7a. Solid state stability
 Chemical instability normally results from either of the following reactions
hydrolysis, oxidation, photolysis and pyrolysis.
 Chemical structure of the drug is the determination of drug to either of
these attacks.
 Esters and lactase and to lesser extent, amides are prone to solvolysis .
 In saturation or electron rich centre in the structure make the molecule
vulnerable for free radical mediated or photo-catalyzed oxidation.
 Amorphous materials are less stable than their crystalline forms.
 Denser materials are more stable to ambient stress.
7b. Elevated temperature studies
 The elevated temperatures commonly used are 40, 50, and 60 degree
centigrade with ambient humidity.
 The samples stored at highest temperature are observed weekly for
physical and  chemical changes and compared to an appropriate control.
 If a substantial change is seen, samples stored at lower temperature are
examined.
 If no change is seen after 30 days at 60 degree centigrade, the stability
prognosis is excellent .
7c. Stability under high humidity conditions
 Solid drug samples can be exposed to different relative humidity
conditions by keeping them in laboratory desiccators containing saturated
solutions of various salts.
 The closed desiccators in turn are kept in oven to provide constant
temperature.
 The preformulation data of this nature are useful in determining if the
material should be protected and stored in controlled low humidity
environment or if non aqueous solvent be used during formulation.
7d. Photolytic stability
 Many drugs fade or darken on exposure to light.
 Though the extent of degradations may be small and limited to the exposed
surface area, it presents aesthetic problems.
 Exposure of drug 400 and 900 footcandles (fc) of illumination for 4 and 2
week periods, respectively is adequate to provide some idea of
photosensitivity.
 Resulting data may be useful in determining if amber glass or opaque
containers can be used or if dye can be incorporated in the product to mask
the discoloration.
7e. Stability to Oxidation
 Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of
high oxygen tension.
 Usually a 40% oxygen atmosphere allows for rapid evaluation.
 A shallow layer of drug exposed to a sufficient headspace volume ensures that the
system is not oxygen limited.
 Samples are kept in desiccators equipped with three-way stop cocks, which are
alternatively evacuated and flooded with desired atmosphere.
 The process is repeated 3 or 4 times to ensure 100% desired atmosphere.
 Results may be useful in predicting if an antioxidant is required in the formulation
or if the final product should be packaged under inert atmospheric conditions.
7f. Compatibility studies
 The knowledge of drug excipients interaction is useful for the formulation to select
appropriate excipients.
 The described preformulation screening of drug excipients interaction requires only
5mg of drug in a 50% mixture with the excipients to maximize the likelihood of
obscuring an interaction .
 Mixtures should be examined under nitrogen to limit oxidation and paralytic effect
at a standard heating rate on DSC, over a temperature range, which will encompass
any thermal changes due to both the drug and excipient
 Appearance or disappearance of one or more peaks in themograms of drug
excipient mixtures are considered as indication of interaction.
7g. Solution phase stability
 As compared with the dry form, the degradation is much rapid in solution
form.
 It is important ascertain that the drug doesn’t degrade when exposed to GI
fluid.
 The pH based stability study, using different stimulator GI condition can
be designed.
 A poor solution stability of drug may urge the formulator to choose a less
soluble salt form, provided the bioavailability is not compromised
7h. Absorption behavior
 It is essential to test the in vivo behavior of the new drug for successful
formulation of a dosage from good bioavailability.
 Partial in vivo and in vitro test are designed to study pharmacokinetic
profile of the drug.