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Pharmaceutics and Dosage form

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.

Safe and convenient delivery

Protection of API from atmosphere

Extend drug action

Protection of API from GIT

Optimal drug action from topical sites

Delivery of insoluble or unstable API

Placement of drugs with in the body

Mask bitter taste or obnoxious odour Ease of drug identification

Ideal properties of a dosage form

Effective

TABLETS

Convenient

Safe

Pharmaceutically elegant

Reliable

Stable

What are tablets?????

Dose precision Easy to identify product Low cost

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

Greatest stability

Compact

Advantages
Easy of large scale production Easiest to package and ship

Bitterness and bad odour can be masked

Can sustain drug effect

Easy to swallow (least hang up)

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Not for a variety of drugs

Difficult for children

Difficult for unconscious patients

Disadvantages

Which drugs ?????

Poorly compactable Sensitive to atmospheric conditions

General properties of tablets

Amorphous

Poorly wetable

Poorly soluble

Poorly bioavailable

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.

Ingested orally Used in oral cavity Tablets Administered by other route Used to prepare a solution

TYPES OF TABLETS

Tablets to be used in oral cavity

Compressed tablets

Tablets ingested orally

Buccal tablets Sublingual tablets Troches or lozenges Dental cones

Multiple compressed tablets Modified release tablets Coated tablets Chewable tablets Targeted tablets

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Implantable tablets Vaginal tablets

Tablets used to prepare a solution

Tablets administered by other routes

Effervescent tablets Dispersible tablets Hypodermic tablets Tablet triturates

Definition: It is a stage of formulation development where physical and chemical properties of drugs alone and when combined with excipients are studied

Preformulation
Objective: To generate information useful to formulator in developing stable and bioavailable dosage forms

Preformulation

Stages in formulation development

Bulk characterisation

Solubility characterisation

Stability characterisation

Description

pKa

Solid state stability Solution stability

Crystallinity

pH solubility profile Common ion effect

Polymorphism

Bulk stability

Particle size

Thermal effect

Compatibility

Bulk density

Partition coefficient

pH rate profile

Powder flow properties

Dissolution

Stability in formulation

Hygroscopicity

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Description
The colour, odour, and taste of the drug is recorded

BULK CHARACTERISATION

Molecular structure

Internal structure
Higher energy state High solubility, Less stability 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

External Chemical structure Internal

Habit

Overall appearance of the compound

Amorphous

Single entity Molecular adduct (pseudopoly morphism) Salt forms Solvates/ hydrates

Crystalline

Polymorphs have different physical properties like

1. Melting point

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

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~ray diffraction 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

Distinction between solvate and true polymorph

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
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

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

Basic drugs ppt in intestine eg. Codeine, theophylline hydrochloride or sulphate salts
Codeine hydrochloride, Ranitidine hydrochloride

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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 and dense spherical -crystalline forms In presence of high humidity (37C/75% RH),

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

form undergoes -lactam hydrolysis more readily

Half life of 6 months

form under identical conditions is stable for several years

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
1. 2. 3. 4.

How to study Purity?

Generally determined by the analytical department
Thermal analysis DTA, DSC and TGA Spectroscopy UV and FTIR Chromatography TLC and HPLC 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)

UV-Vis spectroscopy

Ca Oxalate Thermogram Change in weight with change in temperature is monitored

UV spectrum of theophylline

FTIR spectroscopy
TLC

Chromatography
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

FTIR spectra of cinnarizine

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

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Angle of repose as an indication of flow properties

Angle of repose <20 20-30 30-34 >40 Type of flow Excellent Good Passable* Very poor

Compactibility/ Compressibility
"Compressibility" of a powder is the ability to decrease in volume under pressure. (Carrs ratio) "Compactibility is the ability of the powdered material to be compressed into a tablet of specified tensile strength.
C = 100 1 B T

* May be improved by adding glidant; Eg:0.2% Aerosil

Hausners ratio is related to Carrs ratio by the formula

1 H = 100 1 C

Carrs index
Is an indication of the compressibility of a powder Frequently used as an indication of flowability of powder A Carrs index >33 (equivalent to 1.5 of Hausners ratio) indicates poor flow, Carrs ratio <20 (equivalent to 1.25 of Hausners ratio) indicates good flow

Carrs ratio 5-15 12-16 18-21 23-25 33-38 >40

Type of flow Excellent Good Fair to passable* Poor* Very poor Extremely poor

SOLUBILITY CHARACTERISATION

May be improved by glidant Eg: 0.2% Aerosil

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Solubility
Solid drugs administered orally for systemic activity must dissolve in GI fluids prior to absorption

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

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

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