FORMULASI

dan
TEKNOLOGI
LIKUIDA
Dr. Rendra Pranadipa Tofani, Apt.
2017
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Biasakan Baca Referensi dari BUKU ASLInya
(JANGAN terjemahan)

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 OUTLINE
1. Introduction to Dosage Forms & Liquids
2. Pharmaceutical Solutions:
1. Aqueous
2. Non-Aqueous & Viscid
3. Disperse Systems:
1. Suspension
2. Emulsion
3. Colloidal

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FORMULASI dan TEKNOLOGI LIKUIDA

Kuliah 1A:

INTRODUCTION to
DOSAGE FORMS
Dr. Rendra Pranadipa Tofani, Apt.
2017
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 Objectives of the Lecture
Pada akhir kuliah, anda akan bisa menjelaskan:
• Why drugs are not used as such?
• What are excipients?
• What are dosage forms (bentuk sediaan)?
• Why formulation is necessary?
• Pharmaceutical Dosage Form vs. Pharmaceutical
Preparation (Bentuk Sediaan vs. Sediaan Jadi)
• Types of dosage forms available
• Consideration factors before formulating

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 Active Pharmaceutical Ingredients (API) / Drug
Active drug substance (active pharmaceutical
ingredient - API)
• chemical compound with pharmacological (or
other direct effect ) intended for used in
diagnosis, treatment or prevention of diseases
• International nonproprietary names (INN,
„generic“ names)

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 Why needs DOSAGE FORMs ?
1. safe and convenient delivery of accurate dosage
Examples: Tablets, Capsules, syrups

2. protection from oxygen or moisture. Examples:

coated tablets, sealed ampules

3. Protection from gastric acid after oral

administration. Example: enteric coated tablets

4. Conceal bitter taste, salty obnoxious or odor of a

drug substance. Examples: Capsules, coated tablets,
flavored syrups
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5. Most APIs are administered in very small amounts

Examples Of Drugs with Low Usual doses:

Ferrous sulfate 300 mg Hematinic
Cimetidine 300 mg Antiulcer
Amoxicillin 250 mg Antibacterial
Propoxyphene HCl 65 mg Analgesic
Phenobarbital 30 mg Sedative
Diphenhydramine HCl 25 mg Antihistamine
Morphine sulfate 10 mg Narcotic Analgesic
Cochicine 0.5 mg Gout suppressant
Nitroglycerin 0.4 mg Antianginal
Digoxin 0.25 mg Cardiotonic
Ethinyl Estradiol 0.05 mg Estrogen
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6. Provide liquid preparations of substances that are either
insoluble or unstable in the desired vehicle. Example:
suspension

7. Provide liquid dosage forms of substances soluble in

desired vehicle. Example: solution

8. Provide extended drug action (controlled release).

Examples: controlled release tablets, capsules, suspensions

9. Various administration routes. Examples: ointments,

creams, ophthalmic, ear and nasal preparations, rectal &
vaginal suppositories, inhalants, implants

10. Ease of visual identification: color, shape, & other

markings 10
 From API to Pharmaceutical Preparation
1. Active drug substance (active pharmaceutical ingredient - API)

2. Excipients (inactive pharmaceutical ingredients)

• Technological, biopharmaceutical and/or stability reasons
• Diluents/fillers, binders, lubricants, desintegrants, coatings, preservants
and stabilizers, colorants and flavouring

3. Pharmaceutical dosage form

• is a drug delivery system which is formed by technological processing (drug
formulation)
• determines the physical form of the final pharmaceutical preparation

4. Pharmaceutical preparation (PP)

• particular pharmaceutical product containing active and inactive
pharmaceutical ingredients formulated into the particular dosage form.
• Packed and labelled appropriately
• Two major types of PP according the origin:
o Manufactured in large scales by pharmaceutical industry (original and generic
preparations)
o Compounded individually in compounding pharmacies
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 TYPES of Dosage Forms

Administration Route: Physical Form:

Oral: Intraoral, Solid
intragastric, intracolon Semisolid
Topical & Transdermal Liquid
Parenteral
Inhalation & Intranasal Gas
Buccal & Sublingual
Ophthalmic
Otic
Rectal
Vaginal
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 General Considerations in Dosage Form Design
• Drug Considerations
– Physicochemical properties of the API
– Stability of API and of the Formulation
– Preservation
– Appearance and Palatability

• Therapeutic Considerations
– Nature of the disease
– Age of Patients, or other limitations of administration

• Biopharmaceutics Considerations
– Biopharmaceutics
– Bioavailability
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Any Questions ??

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 FORMULASI dan TEKNOLOGI LIKUIDA

Kuliah 1B: Liquid Dosage Forms

Overview of
SOLUTION / LARUTAN
Dr. Rendra Pranadipa Tofani, Apt.
2017
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 TYPES of LIQUID Dosage Forms
Active/s DISSOLVED in
a vehicle: CLEAR, Preparation with 2 or
HOMOGENOUS more PHASES

Monophasic (Solutions) Polyphasic

SOLID Active/s
Active/s dissolved in SUSPENDED in Liquid
AQUEOUS vehicle
Suspensions

Fine PARTICLES
SUSPENDED in Liquid
Aqueous Solutions Colloids
Active/s dissolved in
NON-AQUEOUS LIQUID Active/s or
Solvent/s system/s DISPERSED
in Liquid
Non-Aqueous Solutions Emulsion

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 Definition of SOLUTION (LARUTAN)
• Homogenous
• One-Phase
• Transparent
• Consists of 2 or more components

– Do NOT SEPARATE on storage

– Do NOT SEPARATE when Filtrated

• Prepared by DISSOLVING active/s in a solvent

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 SOLUBILITY (KELARUTAN)
MAX amount of a Solute (weight) that can be
dissolved in an amount of Solvent (volume), under
specific Temperature and Pressure.

• A solute will easily be dissolved in a solvent with:

SIMILAR POLARITY
• Solute particles are surrounded by solvent 
dissolved  SOLVATION process

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 Factors affecting Solubility
• Electrostatic forces between water and solid
ion/molecules
• Pressure (in gases)
• Size of solute: molecule / particle / agregates
– Molecular size: larger particle generally LESS soluble.
– “branching” organic compounds ↑ solubility 
reduce size of the molecule  easier for solvation
– Solubility of a substance is CONSTANT, BUT the RATE
of solution depends on size.
• External physical forces: agitation
• Temperature: heat provides energy to break
bonds in the solid (generally)
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• pH of solution: Many important organic medicinal
agents are either weak bases or weak acids and their
solubility depends on the pH of the solvent. These
drugs react either with strong acids or strong bases
to form water-soluble salts.
• Weak bases NOT very soluble in water, BUT soluble in
dilute solutions of acids.
– Alkaloids (atropine), local anesthetics (cocaine, procaine),
etc.
• Weak acids form water-soluble salts in basic solution.
– Barbiturates (phenobarbital), sulfonamides (sulfadiazine),
etc.
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 WHY Liquid Dosage Forms ??
• Route of administration for patients UNABLE to
swallow solid DF

• Children

• Elderly

• Weak conditions / after surgery

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 Advantages of Solution
1. Easy to swallow: children, elderly, unconscious,
etc
2. Quicker absoprtion
3. Homogenous  uniform dose (compared to
suspension or emulsion)
4. Can be designed for various routes of
administration
5. Flexible dosing
6. Dilute irritant action of some drugs (aspirin, KI,
KBr)  ↓ adverse effect in GIT
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 Disadvantages of Solutions
1. Bulky
2. Difficult to mask unpleasant taste & odour
3. Precise dosing are difficult  accurate spoon &
human technical capability
4. Poorly soluble drugs  difficult to formulate
5. LESS STABLE than solid DF:
1. Colour change
2. Precipitation
3. Microbial growth
4. Gas formation
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Classification of Solutions: Based on VEHICLE

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Classification of Solutions: Based on ROUTEs of ADM

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 Methods of Preparations

1. Simple Solution (Larutan Sederhana)

2. Solution by Chemical Reaction

3. Solution by Extraction

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 1. SIMPLE SOLUTION
• Dissolving solute/s in a suitable solvent:
By Stirring and/or Heating
• Examples: Calcium hydroxide solution USP (lime
water)

• Solvent may contain other ingredients, to:

– Stabilise
– Solubilise / increase solubility
• Examples: Lugol’s solutions
– Solubility of Iodine in water = 1:2950
– Addition of KI dissolves iodine  form poly-iodides
(KI.I2 , KI.2I2 , KI.3I3 , KI.4I4 )
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 2. Solution by Chemical Reaction
• By REACTING two or more solutes in a suitable
solvent

• Ex: Calcium lactate mixture:

– By reacting calcium carbonate + lactic acid

• Ex: Magnesium citrate:

– By reacting magnesium carbonate + citric acid

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 3. Solution by Extraction

• Usually for plant / animal sourced products  by

extraction

• Interchangeably classified as: EXTRACT

(will be discussed separately)

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 EXCIPIENTS in Solutions
1. Preservatives
2. Antioxidants
3. Sweetening Agents
4. Bufferss
5. Isotonicity modifiers
6. Viscosity enhancers
7. Flavours or fragrances

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 Excipients: 1. PRESERVATIVES
Contamination may be resulted from:
• Raw materials are excellent growth media for
bacteria  gums, dispersing agents, sugars, flavours.
• During manufacture: personnel, instruments,
environment
• Incorrect usage of the product by consumers.

Preservatives of choice should be:

1. Wide spectrum of microorganisms
2. Stable during desired shelf life
3. Non-toxic & non-sensitizing
4. Compatible with other excipients & API
5. Taste-less and odour-less
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 Excipients: 1. PRESERVATIVES
Alcohols
• Also functions as organic solvent
• Works as preservative at high concentration
• Ethanol: as preservative > 10%
• Propylene Glycol: as preservative 15 – 30 %

Acids: Benzoic Acid & Sorbic Acid

• Usage: 0.1 – 0.5 %
• Effective as NON-IONIZED form  pH below 4.5

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Esters of p-hydroxybenzoic acid (parabens)
• R: methyl, ethyl, propyl, butyl
• Usage: =< 0.2%
• Effective at pH 4 – 8

Quarternary Ammonium Compounds

• Benzalkonium Chloride
• Usage: 0.002 – 0.02 %
• Effective pH: 4 – 10
• Cationic  incompatible with anionic surfactants
etc
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 Excipients: 2. ANTIOXIDANTS
• Vitamins, essential oils, fats, oils  easily oxidized
• Initiation of Oxidation Rx:
– Light  light-proof container
– Heat  storage at a certain temperature
– Heavy Metals (e.g. Fe, Cu)  use Citric Acid or EDTA
as sequestering agent

• Examples of antioxidants:
– Propyl & octyl esters of gallic acid
– Ascorbic acid (vitamin C)
– Sodium sulfite, sodium metabisulfite
– Oil-soluble: Tocopherols (vitamin E), BHT
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 Excipients: 3. SWEETENING AGENTS
• Most widely used: SUCROSE
Colourless, highly water-soluble, increase viscosity,
Stable in wide pH (4-8), masks salty & bitter taste,
Soothing sensation on throat.

• Polyhidric alcohols:
– Sorbitol, mannitol, glycerol
– Lower Glycemic Index  for diabetic preparations

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 Excipients: 4. BUFFERS

• To maintain pH value of the final product

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 Excipients: 5. ISOTONICITY MODIFIERS

• To achieve similar osmotic pressure

– Solutions for Injection  Ringer Solution 0,9% NaCl
– Application to mucous membrane
– Large-volume ophthalmic application

• Commonly used: Dextrose and NaCl

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 Excipients: 6. VISCOSITY ENHANCEMENT
• Commonly used in TOPICAL solution formulations
• Low viscosity of aqueous-based solution  very
short CONTACT TIME with the skin
• Need to SLIGHTLY increase Viscosity
• Examples: Acacia Gum, Xanthan Gum, Na-CMC,
Bentonite, etc.

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 Excipients: 7. FLAVOURs and FRAGRANCEs
• To mask unpleasant taste and odour

• Natural source: fruit juices, aromatic oil

(pepermint, lemon, etc.)
– Thermolabile
– Some may be oxidised easily

• Artificial fragrances:
– Cheaper
– Better stability
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 STABILITY of Solutions
• PHYSICAL stability:
– Clarity
– Viscosity

• CHEMICAL stability:
– Colour
– Odour
– Taste
– Active content

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Any Questions ??

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