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7/12/2012 1 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 delivery Protection 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

Tablets - First Lec

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Page 1: Tablets - First Lec

7/12/2012

1

• 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