BTF1623

Liqu id & Cr e a m
Pr odu c t ion Sys t e m
Dr Nadiya binti Hj Abd Halim
 List of Topics
1. Introduction
2. Advantages & Disadvantages
3. Classification of Liquid Dosage Forms
4. Manufacturing of Liquid Dosage Forms:
a) Raw Materials
b) Equipment:
- High shear mixer
- Filling machine
c) Packaging
5. Critical process parameters
 INTRODUCTION
Dosage forms are the means by which drug molecules/APIs are
delivered to sites of action within the body to produce optimum
desired effects and minimum adverse effect.
 NEED OF DOSAGE FORMS
 Provide safe and convenient delivery of accurate dosage.
Example – Tablets, capsules, syrups
 Protection of a drug substances from atmospheric oxygen or moisture.
Example – Coated capsules, sealed ampules
 Protection of a drug substances from gastric acid after oral administration.
Example – Enteric coated tablets
 Conceal bitter taste, or odor of drug substances.
Example – Capsules, coated tablets, flavored syrups
 Provide liquid preparation of drug that insoluble or unstable in the desired
vehicle. Example – Suspension
 Provide liquid dosage forms of substances soluble in desired vehicle.
Example – Solution.
 NEED OF DOSAGE FORMS
 Provide optional drug action from topical administration sites. Example –
Ointment, cream, ear and nasal preparations.
 Provide for insertion of a drug into one of the body’s orifices. Example –
Rectal and vaginal suppositories.
 Provide extended drug action through controlled release mechanisms.
Example – Controlled release tablets, capsules, suspensions.
 Provide for the placement of drugs within body tissues.
Example – Implants.
 Provide for the optimal drug action through inhalation therapy. Example –
Inhalants.
 INTRODUCTION
What is liquid dosage form (LDF)?
“A solution is a liquid-preparation that contains one or more
soluble chemical substances dissolved in a specified solvent.”

Liquid dosage form mainly divided into:

 Solution

 Syrup

 Suspension

 Emulsion
 Adva n t a ge s
● Immediately available for absorption.
● Administration convenient, particularly for infants, psychotic
patients.
● Easy to color, flavor & sweeten.
● Liquids are easier to swallow than solids and are therefore
particularly acceptable for pediatric patient.
● A solution is a homogeneous system and therefore the drug will
be uniformly distributed throughout the preparation.
● Some drugs like aspirin, KCl can irritate gastric mucosa if used
orally as a solid dosage forms. But this effect can be reduced by
solution system.
 Dis a dva n t a ge s
● Bulky than tablets or capsule, so difficult to carry transport.
● Less stable in aqueous system. Incompatibility is faster in solution
than solid dosage form.
● Patients have no accurate measuring device.
● Accident breakage of container results in complete loss.
● Solution often provide suitable media for the growth of micro-
organisms.
● The taste of a drug, which is often unpleasant, is always more
pronounced when in solution than in a solid form.
CLASSIFICATIONS OF LIDUIDS
 Mon oph a s ic Liqu id Dos a ge For m s :
● Monophasic liquid dosage forms are represented by true or
colloidal solution.
● The component of the solution which is present in a large quantity
is known as “SOLVENT” whereas the component present in small
quantity is termed as “SOLUTE”.
● A solution is homogenous because the solute is an ionic or
molecular forms of subdivision.
● In case of colloidal solutions, the solutes are present as
aggregates although they cannot be seen by necked eye or
ordinary microscope.
● It is sub classified as – I) Internal Use, II) External use
 CLASSIFICATION OF LIQUIDS

Monophasic Liquid Dosage Forms

Liquid forExternal
Liquid forInternal
administration
administration

Liquidsused Liquid Liquidsinstilled - Syrups

applied to into Body
in Mouth - Mixtures
the skin Cavities
- Elixirs
- EyeDrops - Linctuses
- Gargles - Lotions
- Ear Drops
- Mouthwashes - Liniments
- Nasal Drops
- Throat paints - Collodions - Douches
- Paints - Enemas
 Biph a s ic Liqu id Dos a ge For m s :

● The liquid which consist of two phases are known as a

biphasic liquid dosage forms.
● They are sub categorized into two different forms namely
as –
I) Emulsion
II) Suspension
● In emulsion both phases are available in liquid whereas in
suspension, finely divided solid particles are suspended in
liquid medium.
 Biphasic Liquid DosageForms

Solids inLiquid Liquid inLiquid

Oral Parenteral External Oral External

SUSPENSION LOTION EMULSION LINIMENTS

 Wh a t is Se m is olid Dos a ge For m ?

● Semisolid is NOT POURABLE and DOES NOT FLOW at low

shear stress or conform to its container at room
temperature.
 SEMI-SOLID DOSAGE FORMS

Cream

Paste SEMI-SOLID Gel

Ointment
 Type of Liqu id Dos a ge For m
● Oral liquids are formulated as solutions, suspensions and emulsion
depending on the nature of the active ingredients, particularly their
solubility and stability.

Types of LDF Description

• consist of soluble material or material (solute) dissolved

in a liquid (solvent) Oral Dosage Topical
Solutions
• clear dosage
• homogenous
Syrup Colloidal
• consists of two immiscible liquids, either oil in water or
Elixir Tinctures
Emulsions water in oil
• an emulsion that settles is called a temporary emulsion Oral Antibacterial
Suspensions
• consists of non-soluble solid particles dispersed in liquid
phase Mouthwash Liniment
Suspensions
• heterogeneous
• not clear
 LIQUID DOSAGE FORMS

1 – ORAL SOLUTION
 Oral solutions are clear Liquid preparations for oral use containing one or
more active ingredients dissolved in a suitable vehicle.

2 – ORAL EMULSION
 Oral emulsions are stabilized oil-in-water dispersions, either or both phases of which
may contain dissolved solids either oil is dispersed in finely divided form in water or
vice versa.

3 – ORAL SUSPENSION
 Biphasic liquid preparations for oral use containing one or more active ingredients
suspended in a suitable vehicle. It sediment which is readily dispersed on shaking to
give a uniform suspension which remains sufficiently stable to enable the correct
dose to be delivered.
4 – SYRUP
 It is a concentrated aqueous solution of a sugar, usually sucrose towhich
medicaments are added.

 Flavored syrups are a convenient form of masking disagreeabletastes.

5 – ELIXIR
 It is pleasantly flavored clear liquid oral preparation of potent or nauseousdrugs.
 The vehicle may contain a high proportion of ethanol or sucrose togetherwith
antimicrobial preservatives which confers the stability of the preparation.

6 – MOUTHWASHES
 These are similar to gargles but are used for oral hygiene and to treat infections
of the mouth.
7 – LINCTUSES
 It is viscous, liquid oral preparations that are usually prescribed for the relief of
cough. It contain high proportion of syrup and glycerol which have a demulcent
effect on the membranes of the throat.

 The dose volume is small (5ml) and, to prolong the demulcent action, they
should be taken undiluted.

8 – ORAL DROPS
 Oral drops are liquid preparations for oral use that are intended to be
administered in small volumes with the aid of a suitable measuringdevice.

 They may be solutions, suspensions or emulsions.

9 – GARGLES
 They are prepared in a concentrated solution with directions for thepatient
to dilute with warm water before use.

 They are aqueous solutions used in the prevention or treatment of throatinfections.

10 – LOTIONS
 It is mono-phasic liquid preparations (aqueous) for external application without
friction either dabbed on the skin or applied on a suitable dressing and covered
with a water proof dressing to reduce evaporation.

11 – NASAL DROPS &SPRAYS

 Drugs in aqueous solution may be instilled into the nose from a dropper or froma
plastic squeeze bottle.
 Used for local effect, e.g. antihistamine, decongestant.
11 – COLLODION
 Collodion is a solution of nitro cellulose in ether or acetone, some timeswith
the addition of alcohols.

 As the solvent evaporates, it dries to a celluloid-likefilm.

 It is highly flammable.
 Compound Wart Remover consists of acetic acid and salicylic acid inan
acetone collodion base used in treatment of warts by Keratolysis.

12 – PAINTS
 Paints are mono-phasic liquids for application to the skin or mucous membranes.
 Skin paints contain volatile solvent that evaporates quickly to leave a dry
resinous
film of medicament.
 Throat paints are more viscous due to a high content of glycerol that designed
to prolong contact of the medicament with the affectedsite.
 PARENTERAL DOSAGE FORMS
An injection is an infusion method of putting liquid into the body, usuallywith a
hollow needle and a syringe which is pierced through the skin.

Intravenous Injection
• It is a liquid administered directly into the bloodstream via avein.
• It is advantages when a rapid onset of action isneeded.

Intramuscular Injection
• It is the injection of aAPIs directly into a muscle.
• Intramuscular injections are often given in the deltoid,vastus
lateralis, ventrogluteal and dorsoglutealmuscles.

Subcutaneous Injection
• It is injecting into the subcutis, the layer of skin directly below
the dermis and epidermis.
• It is highly effective in administering vaccines and insulin.
 SEMI-SOLID DOSAGE FORMS

1 – OINTMENTS

 Ointments are semi-solid, greasy preparations for application to the skin, rectumor
nasal mucosa.
 Base is usually anhydrous and immiscible with skinsecretions.
 Ointments may be used as emollients or dissolved medicaments to theskin.

2 – GELS
 In gel a liquid phase is constrained with in a 3-D polymeric matrix (consistingof natural
or synthetic gum) having a high degree of physical or chemical cross- linking.

 It is used for medication, lubrication and some miscellaneous applicationslike

carrier for spermicidal agents to be used intra vaginally.
 3 – CREAMS
Oil-in-water (O/W)
• It composed of small dropletsof
oil dispersed in a continuous
aqueous phase.
• Less greasy and more easily
washed off using water.
Water-in-oil (W/O)
• It composed of small droplets of
water dispersed in a continuous
oily phase.
• More difficult to handle butused
for hydrophobic drugpreparation.
• Reduces water loss fromthe
stratum corneum maintain
moisture of skin.
 4 – PASTES

 Pastes are basically ointments into which a high percentage of

insoluble solid has been added.

 The extra ordinary amount of particulate matter stiffens the system.

 It provide less heating and penetration than ointment.
 It make good protective barrier when placed on the skin, the solid
they contain
can absorb and thereby neutralize certain noxious chemicals before
they ever
reach the skin.
 ADDITIVES USED IN LIQUID DOSAGE FORMS

1. Vehicles
2. Buffers
3. Density modifiers
4. Stabilizer
5. Isotonicity modifiers
6. Viscosity enhancement
7. Preservatives
8. Sweetening agents
9. Reducing agents and antioxidants
10. Flavors and perfumes
11. Colors
MANUFACTURING OF LIQUID DOSAGE FORMS
Process Flow in the LDFs

1st Addition of raw material 3st Filtration

Active ingredient + Filter press or cartridge
excipient as per formula filter

2st Mixing 4st Filling

Agitated, jacketed vessel Automatic filling machine

Source: Good Design Practices for GMP Pharmaceutical Facilities

 MANUFACTURING OF LIQUID DOSAGE FORMS

1. Raw material

● The raw material used for the manufacturing of pharmaceutical are as per the
standard specification.
● These specifications should assure identity, purity, uniformity and freedom
from excessive microbial contamination.
● Incoming raw material should be thoroughly tested before they are released
for manufacturing.
● Additional processing may be necessary to obtained a desirable property,
such as particle size or microbial contamination.
 MANUFACTURING OF LIQUID DOSAGE FORMS

● Aside from the active ingredient, water is usually the most important
constituent in a liquid products.
● It should meet the USP requirement for purified water and obtained by ion
exchange or distillation.
● To prevent microbial growth, various techniques employed include reverse
osmosis purification, U.V. sterilization, membrane filtration and constant
circulation in piping systems that have no dead ends where microorganism
grow.
MANUFACTURING OF LIQUID DOSAGE FORMS
2. Equipment
● The type of equipment used in the manufacture of oral solutions consists of mixing
tanks equipped with a means of agitation, measuring devices for large and small
amounts of solids and liquids, and a filtration system for the final polishing and or
sterilization of the solution.
● All equipment must be thoroughly cleaned and sanitized before use.
● Appropriate disinfectants, include dilute solutions of hydrogen peroxide, phenol
derivatives and peracetic acid.
● Equipment and lines can be sterilized by such methods as alcohol, boiling water,
autoclaving, steam or dry heat.
● Tanks are usually constructed of polished stainless steel and are usually jacketed to
allow for heating or cooling of the contents.
● They can be obtained in a number of different sizes. If tanks are use for the
compounding of the bulk liquid, they have a built-in agitation system.
MANUFACTURING OF LIQUID DOSAGE FORMS
● Water condensate that forms on the lid of mixing tanks and during heating and
chilling steps may provide a source of microbial contamination that is often
overlooked.
● The liquid is then clarified by cycling through a filtration system and the polished
solution is stored in an adjacent tank until released by the Q.C. dept.
● The liquid may then be transported to the filling line, either manually by filling into
portable transport tanks or by pumping through suitable liquid delivery system.
● The distance should be less to prevent microbial growth.
● A major source of microbial contamination is often the processing operators.
● Head covering should be worn all times while gloves and face mask should be worn as
necessary.
 MANUFACTURING OF LIQUID DOSAGE FORMS
High Shear Mixer

• High shear mixers: also known as high shear

reactors (HSRs), rotor-stator mixers, and high
shear homogenizers.
• Function: to emulsify, homogenize, disperse,
grind and/or dissolve immiscible mixtures with
components of the same or different phases.
• Characteristics: high rotor tip speeds, high
shear rates, localized energy dissipation rates,
and higher power consumption than ordinary
mixers.
● Shearing forces mixing the components are generated by the relative
motion of the rotating and stationary parts of the mixer.
● The rotating parts may be one or a set of impellers, paddles, or screws.
● The stationary parts, on the other hand, are the walls of the tank or
chamber, and in some designs, baffles, and vanes.
● High shear mixers generally have two main parts: the rotor and the stator.
● Available in batch (vertical) or inline (horizontal)
configurations, high shear mixers are comprised of a
rotor that turns at high speed within a stationary stator.
● As the blades rotate, materials are continuously drawn
into one end of the mixing head and expelled at high
velocity through the openings of the stator.
● The hydraulic shear generated promotes fast mixing,
breaks down agglomerates and reduces the size of
droplets. Rotor tip speeds between 3,000 to 4,000 ft/min
are typical.
Ope r a t in g Pr in c iple of High Sh e a r Mix e r
Emulsion Homogenization

• This requires liquid droplets to be uniform in size,

completely distributed to create a mixture with one
continuous phase.
• The liquid in the form of droplets are in the
dispersed phase, while the liquid where the droplets
are suspended is the continuous phase. In an
emulsion, natural separation happens between the
dispersed and continuous phases.
• The objective of the high shear mixer is to
continuously break down these droplets before
natural separation happens.
Ope r a t in g Pr in c iple of High Sh e a r Mix e r
Suspension Homogenization

● A suspension mixture has solid particles that are

large enough to settle down which cannot be
dissolved completely in the mixture. The
objective is to break down the large solid particles
into smaller ones while evenly dispersing it into
the medium.
● One problem in this process is the difficulty in
wetting the solid particles. These solid particles
tend to form on the surface of the solvent. This is
due to the surface tension of the liquid and the
hydrophobic property of the particles.
Ope r a t in g Pr in c iple of High Sh e a r Mix e r
Suspension Homogenization

● A suspension mixture has solid particles that are

large enough to settle down which cannot be
dissolved completely in the mixture. The
objective is to break down the large solid particles
into smaller ones while evenly dispersing it into
the medium.
● One problem in this process is the difficulty in
wetting the solid particles. These solid particles
tend to form on the surface of the solvent. This is
due to the surface tension of the liquid and the
hydrophobic property of the particles.
 Type of High Sh e a r Mix e r
Batch High Shear Mixer In-line High Shear Mixer
MANUFACTURING OF LIQUID DOSAGE FORMS
4. Filling and Packaging

● The specific method used for filling a pharmaceutical liquid varies greatly
depending on the characteristics of liquid, the type of package into which
the liquid is placed and the required production output.
● Three basic filling methods for most liquid filling operations :
 Gravimetric (specific weight)
 Volumetric (specific volume)
 constant level
MANUFACTURING OF LIQUID DOSAGE FORMS
Gravimetric filling

● Gravimetric filling works on the principle of gravitational force but

rarely used.
● In this, a particular weight of liquid is filled into the container. This
type of filling is rare in use because it can be used only for highly
viscous liquid or to fill large size containers.
MANUFACTURING OF LIQUID DOSAGE FORMS
Volumetric filling

● Volumetric filling is usually accomplished by positive displacement piston

action.
● Each filling station is equipped with a measuring piston and cylinder
● The fill accuracy is controlled by the close tolerances to which the pistons
and cylinders are manufactured.
● The fill amount is measured by the stoke of piston, which on all machine
can be varied to a limited degree.
● This type of device is capable of accuracy to within fraction of milliliter.
● Volumetric filling encountered a problem when the product is viscous or
less dense.
Disadvantages:

● Highly viscous liquids can block the piston

causing loss of fill accuracy
● Highly thin liquids can cause dripping of
the drops from the filling point of
machine
● If container is oversized then filling
appears loose and if container is
undersized then filling appears overfill,
hence container to be filled should have
uniform size
Constant level filling

● In this, each container is filled to the same

level hence it is also called as fill-to-a
level method.
● It uses the container for controlling the
filling of each unit which means that any
change in size of the container causes
change in the net fill per unit.
Methods for constant level filling:
In older days, the siphon method was used. But due to slowness of this
method, slight modifications in siphon method are used which are following:
 Vacuum filling
 Gravity-vacuum filling
 Pressure-vacuum filling

Problems associated with liquid filling machines:

 Excessive foaming ability:

It can be minimized by following:

 Reduction in turbulence of the liquid
 Using the closed system to prevent the entry of air or other gases that
help in foaming
 Use of defoaming devices
 Decrease in speed of machine
Packaging

● Generally, glass or plastic materials are used as a packaging material for

the liquid dosage forms.
● Before using glass or plastic materials, They should not react with the
excipient or drug.
● Packaging material should be compatible with the solution.
GRAVIMETRIC FILLING & PACKAGING
Th a n k you
 Te s t 2
Fr ida y,
20 J a nua ry 20 22
10 a m - 12 pm
WDK-05