DOSAGE FORM CONSIDERATION:

PREFORMULATION

By: LOUJESSA D. ARCELO

DOSAGE FORM CONSIDERATION

The need for dosage forms

General considerations in dosage
form design
Preformulation Studies
Drug and Drug Product Stability
Pharmaceutical ingredients and
excipients

Dosage Form Design

PHARMACEUTICS
study on the: formulation, manufacture, stability, and
effectiveness of pharmaceutical dosage forms

Pharmaceutical ingredients or
excipients
solubilize thicken stabilize
suspend dilute
preserve
suspend emulsify color

flavor
efficacious
appealing closure forms.

Requirements of a proper design &

formulation of dosage form

compatible with one

another - stable,
efficacious,
attractive, easy to
administer & safe

*manufactured
under appropriate
measures of quality
control & packaged
in containers to
make product stable

Consideration
of drug
substances:

*labeled to promote
correct use & stored
under conditions to
maximize shell life

THE NEED FOR DOSAGE

FORMS

THE NEED FOR DOSAGE FORMS

Mechanism for safe
and convenient
delivery of
accurate dosage
Provide liquid
preparations of
insoluble drugs

Conceal bitter,
salty, or
offensive taste
or odor

Protection of
drug from
atmosphere (CT)

Protection of
drug from
gastric acid
(EC)

THE NEED FOR DOSAGE FORMS

Provide clear
liquid dosage
forms
Provide for
inhalation
therapy

Provide ratecontrolled drug

action

Provide for
placement into
bloodstream

Provide topical
drug action
Provide for
insertion into
body cavity

GENERAL CONSIDERATIONS
IN DOSAGE FORM DESIGN

General Considerations in Dosage

Form Design
Determine desired product type
framework for product development.

Develop and examine initial formulations of

the product:
desired features: drug release profile, bioavailability,
clinical effectiveness
pilot plant studies and production scale-up.

MASTER FORMULA
- formulation that best meets the goals of the product

General Considerations in Dosage

Form Design
Factors to consider before formulation
of a medicinal agent in one or more
dosage forms
Therapeutic matters (nature of the illness)
manner it is treated (locally or through
systemic action)
age and anticipated condition of the
patient.

Reliability

Stability
Pharmaceutical
elegance

Safety

Effectiveness

Design
of Drug
Products

Convenience

PREFORMULATION

PREFORMULATION
Is branch of Pharmaceutical science that utilizes
biopharmaceutical principles in the determination of
physicochemical properties of the drug substance.

PREFORMULATION
Safe handling
of ingredients
and
equipments

Proper
sequence of
addition of
ingredients

Optimum
environmental
conditions

Precautions to
be observed

Expected
interaction

Need for
overages

Preformulation Studies
1. Physical Description
Liquid drugs
are used to a
much lesser
extent than
solid drug

Ability to get to
site of action and
elicit a response

Structure,
form,
reactivity

Solids,
liquids,
gases

Chemical
Properties

Biological
Properties

Physical
Properties
Description, particle
size, crystalline
structure, melting
point, solubility

Preformulation Studies
1. Physical Description: ORGANOLEPTIC PROPERTIES
COLOR

ODOUR

TASTE

OFF-WHITE

PUNGENT

ACIDIC

CREAM-YELLOW SULFUROUS

BITTER

SHINY

FRUITY

SWEET

AROMATIC

TASTELESS

ODOURLESS

TASTELESS

Preformulation Studies
2. Microscopic Examination

Particle size
Particle
shape

Particle size
range

Crystal
structure

Preformulation Studies
3. Heat of Vaporization

Vapor pressure

Personnel
exposure

Volatile drugs
can migrate
within a solid
dosage form

Preformulation Studies
4. Melting point depression

Purity
determination

Identity

Preformulation Studies
5. Phase Rule

Phase diagrams constructed determines:

existence & extent of the presence of solid and liquid

phases in binary, ternary & other mixtures

Preformulation Studies
6. Particle Size

affects : physicalchemical properties of drug

substances:
*dissolution rate
stability
flow properties

bioavailability
taste
absorption

content uniformity
texture
sedimentation rate

Preformulation Studies
7. Polymorphism
substances can exist
in more than one
crystalline form

Polymorphic forms
diff. physical-chemical
properties (melting pt.
& solubility)

POLYMORPHS

Crystalline and
Amorphous

Evaluation of:
*crystal structure
(microscopy, IR
spectroscopy, thermal
analysis, x-ray diffraction)

Preformulation Studies
8. Solubility

If solubility is
<1mg/ml

Solubility:
4C and 37C.

Preformulation Studies
8. Solubility
Description

Parts of solvent required for

one part of solute

Very soluble
Freely soluble
Soluble
Sparingly soluble
Slightly soluble

<1
1 - 10
10 - 30
30 - 100
100 - 1000

Very slightly soluble

1000 - 10,000

Insoluble

> 10,000

Preformulation Studies
8. Solubility
Chemical
nature and
type of drug;
chemical
modification
Some aqueous
solubility
required for
therapeutic
efficacy

SOLUBILITY
and PARTICLE
SIZE

SOLUBILITY
and pH

SOLUBILITY

Preformulation Studies
8. Solubility: SALTS

Points to consider:

Salts prepared from strong acids or

bases
Salts prepared from weaker acid or
base
Injections should ideally lie in the pH
range 3-9
Oral syrups should not be too acidic

Preformulation Studies
8. Solubility: SURFACTANT

SURFACTANT
low
concentration?

Very high
concentration?

Preformulation Studies
8. Solubility: EFFECT OF TEMPERATURE

Endothermic
reaction

Exothermic
reaction

Preformulation Studies
8. Solubility: PARTICLE SIZE

Coarse
(#20)

Very coarse
(#8)

Moderately
coarse
(#40)
Fine (#60)

PARTICLE
SIZE

Very fine
(#80)

Preformulation Studies
8. Solubility: PARTICLE SIZE

Dissolution
rate

Suspendability

Penetrability

Uniform
distribution

Lack of
grittiness

Preformulation Studies
8. Solubility and pH
adjustment of
pH of solvent
where drug is
dissolved to
adjust
solubility

Weak acidic
or basic drugs

pH on
solubility and
stability

cosolvents ,
complexation,
micronization,
or solid
dispersion

Preformulation Studies
8. Solubility: INCREASE SOLUBILITY

Addition of
co-solvent

pH change
method

Reduction of
particle size

Temperature
change
method

Addition of
Surfactant

Complexation

Preformulation Studies
8. Solubility: INCREASE SOLUBILITY
CO-SOLVENT

PG, ehtanol,
glycerin, sorbitol,
PEG, Glyceryl
formal, glycofurol,
ethyl carbamate,
ethyl lactate and
dimethyl
acetamide.

pH CHANGE METHOD

For weak acidic

drug?
For weak base
drug?

Preformulation Studies
8. Solubility: CO-SOLVENT

It must be nontoxic. Nonirritating.

It should be
able to cross
the
membrane.

It should be
able to
solubilize the
drug in given
solvent.

Preformulation Studies
8. Solubility: INCREASE SOLUBILITY

ENDOTHERMIC
REACTION?
EXOTHERMIC
REACTION?

Preformulation Studies
8. Solubility: INCREASE SOLUBILITY

Cationic

IONIC

Anionic

NON-IONIC

Zwitterionic

SURFACTANT

Preformulation Studies
8. Solubility: INCREASE SOLUBILITY
CATIONIC
Cetyl Trimethyl
Ammonium
Bromide (CTAB)
Hexadecyl
Trimethyl
Ammonium
Bromide, and
other
Alkyltrimethyl
Ammonium
Salts,
Cetylpyridinium
Chloride (cpc)

ANIONIC

Sodium Dodecyl
Sulphate (SDS),
Ammonium
Lauryl Sulphate
and other alkyl
sulfate salts,
Sodium
Laureth
Sulphate, also
known as
Sodium Lauryl
Ether Sulphate
(SLES).

ZWITTERIONIC

Dodecly
Betamine
and Dodecly
Dimethylam
ine Oxide

Preformulation Studies
8. Solubility: SURFACTANT (HLB SCALE)
0

Most antifoaming agents

W/O Emulsifying agents

sorbitan
ester

Wetting and Spreading agents

TWEEN
12

O/W Emulsifying agents

15

Detergents and Solubilizing agents

18

(polyoxyethylen
ederivative of
span)

Preformulation Studies
9. Dissolution Rate

Time for the drug to dissolve in the fluids at

the absorption site
(rate-limiting step in absorption)
Can affect onset, intensity, and duration of response and
control overall bioavailability of the drug from the dosage
form

Increasing dissolution rate:

decreasing the particle size.
use a highly water soluble salt of the parent substance.

Preformulation Studies
9. Dissolution Rate

Ficks law
(law of
diffusion)
NoyesWhitney
Equation

1st law: relates to a steady state

flow
2nd law: relates to a change in conc.
of drug with time, at any distance,
or a nonsteady state of flow

Describes the relationship between

particle size, diffusion layer
coefficient, and drug saturated
solubility (Dissolution)

Preformulation Studies
10. Membrane Permealibility

drug molecule
must cross a
biologic
membrane

early assessment
of passage of
drug molecules
across biologic
membranes

The biologic
membrane (lipid
barrier)

Membrane
Permeability

pKa, solubility, and

dissolution rate
data can provide an
indication of
absorption.

EVERTED
INTESTINAL
SAC

Preformulation Studies
11. Partition Coefficient

octanolwater
partition
coefficient

Preformulation Studies
12. pKa / Dissociation Constants

Extent of
dissociation or
ionization

Can affect
absorption,
distribution,
and
elimination

Dependent
on pH of
medium

Preformulation Studies
12. pKa / Dissociation Constants
Can be calculated by Henderson Hasselbach
equationFor acidic drugs.pH= pKa+ log [ionized drug]
[unionized drug]

For basic drugs.pH= pKa+ log[unionized drug]

[ionized drug]

DRUG AND DRUG PRODUCT STABILITY

Stability is the extent to which a product retains within specified
limits and throughout its period of storage and use (i.e., its shelf
life) the same properties and characteristics that it possessed at the
time of its manufacture.

Substantial
changes in
physical
appearance of
the dosage form
Undesired
change in
performance

Cause product
failures

INSTABILITY

Drug Stability: Mechanisms

of Degradation
Hydrolysis
(solvolysis
process)

Oxidation

(drug) molecules
interact with water
molecule to yield
breakdown product.

loss of electrons
from an atom or
molecule; involves
free radicals

esters, substituted
amides, lactones,
and lactams

aldehydes, alcohols,
phenols, sugars,
alkaloids &
unsaturated fats &
oils

Photolysis
decomposition
by light
1. suitable packing in
amber-coloured
bottles
2. cardboard outers
3. aluminium foil over
wraps

Drug and Drug Product Stability:

A. Kinetics and Shelf Life
CHEMICAL STABILITY

active ingredient retains chemical integrity

and labeled potency within the specified
limits.

PHYSICAL STABILITY

original physical properties, appearance,

palatability, uniformity, dissolution and
suspendability are retained.

MICROBIOLOGICAL
STABILITY

sterility/resistance to microbial growth

THERAPEUTIC
STABILITY

therapeutic effect remains unchanged

TOXICOLOGIC
STABILIY

no significant increase in toxicity occurs.

Drug and Drug Product Stability:

B. Rate Reactions

description of the drug

concentration with respect to time
ZERO ORDER
FIRST ORDER
KINETICS
KINETICS
(LINEAR
(NONLINEAR
PHARMACOKINETICS) PHARMACOKINETICS)

Drug and Drug Product Stability:

C. Q10 METHOD
estimate the shelf
life of a product that
has been stored or
to be stored under a
different set of
conditions.

the rate constant

increases for a
100C temp.
increase

Accelerated
Stability
Studies

Q10
METHOD

ENHANCING DRUG
STABILITY

ENHANCING STABILITY
HYDROLYSIS

OXIDATION

ENHANCING STABILITY
Tablet:
waterproof
protective
coating
pH: pH 5 & 6

Reduction or
elimination of
water

Buffering
agent
HYDROLYSIS

ENHANCING STABILITY

Tightly closed
containers

liquid
formulation:
water replaced
by substitute
liquids.

unstable antibiotic
drugs (aq. prepn
desired)
HYDROLYSIS

injectable
products:
anhydrous
vegetable oils
may be used as
solvent

ENHANCING STABILITY
packaged in
sealed
containers with
air replaced by
inert gas

prepared in
dry state

add
antioxidants

OXIDATION

ENHANCING STABILITY
AQUEOUS PREPARATION

Na2SO3, NaHSO3,
Na2S2O5, ascorbic
acid

OLEAGINOUS/UNCTOUS
PREPNS:

alpha tocopherol,
butylhydroxy
anisole &
ascorbyl
parmitate

ENHANCING STABILITY
purification of
source of
contaminant

TRACE METALS
complexing or
binding metal
(chelating agents)

OXIDATION

LIGHT

light-resistant or
opaque
containers

TEMPERATURE

Cool place

pH

Buffering agent

Ca disod edetate
& EDTA)

STORAGE TEMPERATURE
Conditions

Temperature

Freezer

-20C (-10C)

Refrigerator

2C - 8C

Cold

Not exceeding 8C

Cool

8C 15C

Warm

30C 40C

Excessive Heat

Above 40C

NOTE: Article for storage in cool place stored in refrigerator.

Article for storage in a controlled room temperature may be stored
in a cool place.

Other destructive process in

pharmaceutical preparations
POLYMERIZATION

Reaction between
two or more
identical molecules
with resultant
formation of new &
generally larger
molecule
(formaldhyde)

OTHER PROCESSES

Decarboxylation

decomposition of
RCOOH & release of
CO2

Deamination
removal

of nitrogen
containing group from
organic amine (ex.
Insulin)

ASSIGNMENT.
Enumerate 3 The instability possibilities in
different formulations: (1 whole yellow paper)
1.
Oral Solutions
2.
Parenteral Preparations
3.
Suspension
4.
Emulsion
5.
Semi-solid Preparations
6.
Capsule and Tablets

STABILITY TESTING

Requisite data to demonstrate and

document the products stability

Before approval for marketing, a products stability must

be assessed with regard to its formulation;
the influence of its pharmaceutical ingredients;
the influence of the container and closure;
the manufacturing and processing conditions (e.g., heat);
packaging components;
conditions of storage;
anticipated conditions of shipping, temperature, light, and
humidity;
and anticipated duration and conditions of pharmacy shelf
life and patient use

STABILITY TESTING

Expiration Date
The date placed on the immediate container
label of a drug product that designates the
date through which the product is expected
to remain within specifications

STABILITY TESTING
Duration
Long Term

12 mos.

Storage
Condition
25C2

Humidity

Intermediate

6 mos.

30C2

605% RH

Short Term

6 mos.

40C2

75% RH

605% RH

Scientific data pertaining to the stability

of a formulation

leads to:
*prediction of the expected shelf-life of the
proposed product
*redesign of the drug (to more stable salt or
ester form)
*reformulation of the dosage form.

PHARMACEUTICAL INGREDIENTS
(EXCIPIENTS)

PHARMACEUTICAL INGREDIENTS &

EXCIPIENTS
FOR SOLUTIONS

Stabilizers (antioxidants and

chelating agents) prevent
decomposition

FOR TABLETS

Solvents used to dissolve the

drug substance
Flavors and Sweeteners make
product more palatable
Colorants enhance appeal
Preservatives prevent
microbial growth

Diluents or fillers to increase

bulk of the formulation
Binders adhesion of the
powdered drug and
pharmaceutical substances

Antiadherents or lubricants
assist smooth tablet formation
Disintegrating agents
promote tablet breakup after
administration

PHARMACEUTICAL INGREDIENTS &

EXCIPIENTS

HARMONIZATION OF STANDARDS
United

States Pharmacopeia National

Formulary (USP-NF)
British Pharmacopeia
European Pharmacopeia
Japanese Pharmacopeia

Appearance and Palatability

Flavoring

Pharmaceuticals

Color,

odor, texture, and taste must coincide/balance

In general, LMW salts are salty while HMW salts are bitter.
In organic chemistry, the more hydroxyl group present,
increase sweetness.
Different types of flavors: Natural, Artificial, Spice
Delaney Clause
Flavor

Type of Drug

Cocoa

Bitter drugs

Fruit or citrus

Sour and acid-tasting drugs

Cinnamon, Orange, Raspberry &

others

Salty drugs

Delaney Clause
"No additive shall be deemed to be
safe if it is found to induce cancer
when ingested by man or laboratory
animals or if it is found, after tests
which are appropriate for the
evaluation of the safety of food
additives, to induce cancer in man or
animals."

Flavor Selection Guide

Salty
Bitter

Acrid/Sour

Oily

Sweet
Acid

Butterscotch/Maple
Wild Cherry/Licorice
Chocolate Mint
Raspberry/Fruit
Berry/Acacia Syrup
Peppermint/Anise
Wintergreen
Fruit/Berry/Vanilla
Citrus

Sweetening Pharmaceuticals
Dextrose

Sucrose

Sorbitol

Mannitol

Saccharin

Sweetening Pharmaceuticals

Aspartame
- 1st artificial sweetener (1958 amendment)

w/ requirement for pre-marketing proof of safety.

- Aspartame breaks down in the body into three basic components:
phenylalanine, aspartic acid, and methanol.
-

Acesulfame potassium (nonnutritive sweetener)

- structurally similar to saccharin (USP approved)

-180 200 times as sweet as sucrose, excreted unchanged in

the urine;
- more stable than aspartame
-

Stevia (Stevia rebaudiana bertoni)

new sweetening agent: natural, nontoxic, safe,
30x sweeter than cane sugar/sucrose

Sweetening Pharmaceuticals

Saccharin & cyclamate - used in foods

-generally recognized as safe (before the
amendments passage)
- use on rats: developed incidence of bladder
tumors (cancer)
- continued availability but warning labels be used
-cyclamates (banned) - possible carcinogenicity,
genetic damage, testicular atrophy

Coloring Pharmaceuticals
Coloring

Pharmaceuticals
Used in pharmaceutical preparations for esthetics
Certain agents that are not pharmaceutical
colorants
Sulfur (Yellow)
Riboflavin (Yellow)
Cupric sulfate (Blue)
Ferrous sulfate (Bluish green)
Cyanocobalamin (Red)
Red Mercuric iodide (Vivid Red)
Aniline dyes

Coloring Pharmaceuticals
Coal tar (pix carbonis)
- thick black viscid liquid
- by product of destructive distillation of coal.
- source of synthetic coloring agents in pharm.
products in the middle of the 19th century
Dyes added to pharmaceutical preps. in the
form of diluted solutions
Lakes - commonly used in the form of fine
dispersions or suspensions.

Coloring Pharmaceuticals

90% of the dyes used in the products - synthesized from

derivative of benzene (aniline)

FDA - regulates use color additives in foods, drugs, and

cosmetics (Federal Food, Drug, and Cosmetic Act of 1938)
- FD&C color additives - foods, drugs, and cosmetics

- D&C color additives - drugs, some in cosmetics &

medical devices

- external D&C color additives - restricted to external parts

of the body (not including the lips and other parts that
are covered by mucous membrane)

Factors in selecting dyes

Solubility of
prospective dye

Dyes must be
photostable

pH & pH stability
of the preparation
to be colored

PRESERVATIVES

liquid and semisolid preparations

- must be preserved against microbial
contamination.

Sterilization and Preservation

some types of pharmaceutical products

(ex. Ophthalmic and injectable
preparations)
- sterilized by physical methods :
*autoclaving (20min at 15 lb. press. &
121C, dry heat at 180C for 1 hr)
*bacterial filtration.

Sterilization and Preservation

Preparations that provide excellent growth

media for microbes
- aqueous preparations: syrups, emulsions,

suspensions
- semi solid preparations particularly creams.
- hydro-alcoholic & most alcoholic preparation
*may not require addition of chemical
preservative

Sterilization and Preservation

prevent microbial growth:

*15% alcohol in acid media
*18% alcohol in alkaline media.
Alcohol-containing pharmaceuticals (elixirs, spirits,
and tinctures) - self sterilizing and do not require
additional preservation.

Preservative Selection

Considerations in selecting preservative in

pharmaceutical preparations:
1.

2.

3.

Prevents the growth of the type of

microorganisms ( contaminants of the
preparations)
Soluble enough in water to achieve adequate
concentrations in aqueous phase with two or more
phase systems
Proportion of preservative remaining
undissociated at the pH of preparation (can
penetrate the microorganism & destroy its
integrity).

Preservative Selection
4.

5.

6.

7.

Concentration of the preservative does not

affect the safety/comfort of the patient
With adequate stability and not reduced in
concentration by chemical decomposition/
volatilization
Compatible with all other formulative
ingredients and does not interfere with them
Does not adversely affect the preparations
container or closure.

Preservative Selection

Dosage form

Route of
administration

Compatibility
with
excipients

Container and
closure
compatibility

General Preservative Considerations

Range of
activity

Concentration
required

pH
requirements

Compatibility

Mode of action: Mechanisms preservative interfere

with microbial growth, multiplications, and metabolism:
1. Modifications of cell membrane
permeability & leakage of cell constituents
(partial lysis)

2. Lysis and cytoplasmic leakage

3. Irreversible coagulation of cytoplasmic
constituents
4. Inhibition of cellular metabolism by
interfering with enzyme systems/inhibition of
cell wall synthesis
5. Oxidation of cellular constituents and
Hydrolysis

PRESERVATIVES
Benzoic acid/sodium benzoate
Alcohol
Phenylmercuric nitrate/acetate
Phenol
Cresol
Chlorobutanol
Benzalkonium chloride
Methylparaben/propylparaben
Others

PRESERVATIVES
PRESERVATIVE

PROBABLE MODE OF ACTION

Benzoic acid, Boric acid, phydroxybenzoates

Denaturation of proteins

Phenols and chlorinated phenolic

compounds

Lytic & denaturation action on cytoplasmic

membranes and for chlorinated preservatives,
also by oxidation of enzymes

Alcohols

Lytic & denaturation action on membranes

Quaternary compounds

Lytic action on mebranes

Mercurials

Denaturation of enzymes by combining with

thiol (-SH groups)