Pharmaceutical solution

PUSTAKA

1. Aulton ME, Taylor KMG, 2013, Aultons Pharmaceutics, The Design and
Manufacturing of Medicines, 4th Ed., London, Churchil Livingstone
Elsevier.
2. Allen LV, Popovich NG, Ansel HC, 2011, Ansel’s Pharmaceutical
Dosage Forms and Drug Delivery Systems, 9th Ed., Lippincott Williams
& Wilkins.
 Pharmaceutical solutions may be generally
defined :
as liquid preparations in which the therapeutic
agent and the various excipients are dissolved
in the chosen solvent system (aqueous or non
aqueous solvent).

may contain a range of excipients :

1. the vehicle, usually purified water
2. co-solvents, e.g. propylene glycol, glycerin, alcohol
3. agents specifically to enhance the solubility of the therapeutic
agent in the vehicle, e.g. surface-active agents
4. preservatives, e.g. parahydroxybenzoate esters
(methylhydroxybenzoate and propylhydroxybenzoate), boric
acid and borate salts, sorbic acid and sorbate salts, phenolics
5. sweeteners, e.g. glucose, saccharin, aspartame
6. rheology (viscosity) modifiers, e.g. hydrophilic
polymers (cellulose derivatives, alginic acid,
polyvinylpyrrolidone)
7. antioxidants, e.g. sodium formaldehyde sulphoxylate,
butylated hydroxyanisole, butylated hydroxytoluene
8. colours
9. flavours
10. buffers to regulate the pH of the formulation, e.g. citrate
buffer
 KeyPoints
Pharmaceutical solutions are extensively used as dosage forms for
the oral administration of therapeutic agents.
Pharmaceutical solutions are homogeneous, i.e. the therapeutic
agent(s) and excipients are dissolved in the vehicle
Pharmaceutical solutions for oral administration are non-sterile
dosage forms

All pharmaceutical solutions must be stable, and acceptable to

patients.
Parenteral and ocular solutions must be sterile,
Oral solutions must be palatable, solutions which
come into contact with body fluids must be isotonic
and at physiological pH, especially if large volumes
are used.
Multidose products o ten contain preservatives to ensure that the
growth o any microorganisms that are accidentally introduced
during product use is inhibited.
Solutions can be formulated for different
routes of administration

Orally Syrups, elixirs, drops

In mouth and throat Mouth washes, gargles,

throat sprays.

In body cavities Douches, enemas, ear drops,

nasal sprays.

On body Surfaces Collodions, lotions.

 Pharmaceutical Solutions

Aqueous Sweet &/or Viscid Nonaqueous

1. Douches 1. Syrups 1. Elixirs
2. Enemas 2. Honeys 2. Spirits
3. Gargles 3. Mucilages 3. Collodions
4. Mouthwashes 4. Jellies 4. Glycerins
5. Nasal washes 5. Liniments
6. Juices 6. Oleo Vitamin
7. Sprays
8. Otic solutions
9. Inhalations
 Advantages
1. Therapeutic agents can easily be administered orally to
individuals who have difficulty in swallowing, e.g. elderly
patients, infants
2. The therapeutic agent is dissolved in the formulation and is
therefore immediately available for absorption. Providing the drug
does not precipitate within the gastrointestinal tract, the
bioavailability of pharmaceutical solutions is greater than that of
oral solid-dosage forms

3. Taste-masking of bitter therapeutic agents may be readily

achieved
 Disadvantages
1. Less stable than solid dosage forms.
Major signs of instability:
colour change,
precipitation
microbial growth
chemical gas formation
2. The poor solubility of certain therapeutic agents may
prohibit their formulation as pharmaceutical solutions. The
reader should note that certain techniques are available to
enhance the solubility of poorly soluble drugs
3. Pharmaceutical solutions are expensive to ship and are
bulky
for the patient to carry due to the associated mass of the
product
 Solution stability
A pharmaceutical solution must be stable or the duration o its shelf-life
(period of storage and use).

It must retain the same properties that it possessed at the time of its
manufacture :

Physical (e.g. colour, clarity, viscosity, odour, taste),

Chemical (nature and potency)
Microbiological (remain sterile or resistant to microbial growth)
Therapeutic (efficacy must not change) and
Toxicological (no significant increase in toxicity)

Many drug molecules undergo chemical reactions, such as :

hydrolysis, oxidation, decarboxylation, epimerization.

 Drug solubility

Solubility is an equilibrium relationship between the solid and

dissolved states of a solute at saturation.
The numerical value of solubility is the concentration
(expressed as mole/L or mg/mL, etc.) of a saturated solution of the
solute, in a given solvent, under a fixed set of conditions
(temperature, pressure, pH, etc.).

Step 1: Removal of a solute

molecule from solid solute;
requires energy to break
solute–solute bonds
Step 2: Separation of solvent
molecules to create cavity for
solute; requires energy to break
solvent–solvent bonds
(hydrogen bonds in the case of
water)

Step 3: Insertion of solute

molecule into the cavity created
in the solvent; releases energy
due to formation of new solute–
solvent bonds

The process by which a solid solute dissolves in a solvent can be broken

down into three steps as shown
 Drug solubility

Initially there are possible scenarios regarding the formulation of

pharmaceutical solutions of a therapeutic agent for oral
administration:

1. The aqueous solubility of the therapeutic agent is high at the

selected pH of the formulation. Under these circumstances the
therapeutic agent may be readily incorporated into the vehicle and
formulated as an oral solution
2. The aqueous solubility of the therapeutic agent is moderate at the
selected pH of the formulation, i.e. the aqueous solubility is less
than the requested concentration of therapeutic agent.

Under these circumstances the solubility of the therapeutic agent in

the formulation must be enhanced using co-solvents
and related methods.
3. The aqueous solubility of the therapeutic agent is low at the
selected pH of the formulation

The difference between the aqueous solubility of the therapeutic

agent and the required concentration is too great to be bridged by
the use of cosolvents and related methods or the concentration of
cosolvents or surfactants in the solubilised formulation may be
toxic when administered orally
The drug may therefore be formulated as an alternative-dosage
form, e.g. a suspension
 Factors affecting the solubility of therapeutic agents

There are some empirical relationships between the

physicochemical properties and the solubility of therapeuticagents
that influence formulation strategies, as follows:

1. The solubilities of a chemically related series of therapeutic

agent are inversely related to their melting points.

2. The solubility of a therapeutic agent is directly affected by both

the type of chemical substituent groups and the
substituent position.

3. The solubilities of therapeutic agents that are either acids or

bases (representing the vast majority of drug substances) are
pH-dependent.
From these equations two invaluable conclusions may
be
drawn:
At pH values above the pKa, the solubility of
acidic drugs increases
At pH values below the pKa, the solubility of
basic drugs increases
 Formulation methods to enhance/optimise the solubility
of therapeutic agents

Enhancement of drug solubility

1. Optimisation of the pH of the formulation
.

the solubility of an ionised therapeutic agent is a function of both

the pKa of the compound and the pHof the formulation

Importantly, the acceptable pH range of solutions for oral

administration is large, ranging from circa 5 to 8 pH units. Therefore,
a common formulation strategy involves the selection of a pH value
for the formulation that optimises the ionisation and hence solubility
of the therapeutic agent
Control of the pH in the formulation is achieved using a buffer that
does not adversely affect the solubility of the therapeutic agent
 Solubility and pH
1. pH is one .of the most important factors involved in the
formulation
. process.

.
2. Two areas of critical importance are the effects of pH
on solubility and stability.

3. The effect of pH on solubility is critical in the

formulation of liquid dosage forms, from oral and
topical solutions to intravenous solutions and
admixtures.
pH is the pH below which the drug separates from solution as
the undissociatedacid. S is the overall solubility of the drug.
so is the solubility of unionized form

To ensure a clear homogeneous solution and maximum

therapeutic effectiveness, the preparations should be adjusted to
an optimum pH.
e.g. 1% solution of Phenobarbital sodium is soluble at high
pH values in the alkaline range
Decrease in pH, below 8.3, the drug begins to precipitate from
solution
* Kelarutan parasetamol dalam formulasi pelarut campur.
Kelarutan parasetamol : 11,1 mg/ml pKa = 9,5 & dosis
terapi = 120 mg/5 ml = 24 mg/ml

s  s0
pH p  pKa  log
s0

24  11,1
pH p  9,5  log  9,57
11,1
Di bawah pH = 9,57 parasetamol
mengendap ??
Diketahui : parasetamol stabil pada pH netral
Pada pH = 6  t90 = 21,8 tahun
pH = 9  t90 = 2,28 tahun
Di atas pH 9,0  t90 = 6 bulan
* Manipulasi pH untuk meningkatkan kelarutan
adalah tidak mungkin dilakukan
Kalau demikian  cosolven/ metode lain
 2. Use of co-solvents
Co-solvents are primarily liquid components that
are incorporated into a formulation to enhance the
solubility of poorly soluble drugs to the required
level

Commonly employed co-solvents include glycerol,

propylene glycol, ethanol and poly(ethylene glycol)

pelarut Pelarut dalam eliksir Kelarutan parasetamol

Bagian Mg/ml sumber
Air 5,6 1 dalam 90 11,1 Smith & Micchel
Etanol 11,8 1 dalam 8 125,0 Smith & Micchel
Propilen glikol 10,0 1 dalam 9 111,1 BP
Chloroform 0,1 1 dalam 50 20,0 Martindale
gliserin qs = 47,5 1 dalam 50 20,0 Smith & Micchel
Polar drugs generally dissolve in polar solvents and
non-polar drugs generally dissolve in non-polar solvents.
Non-polar drugs are poorly soluble in water – a polar
solvent.

To increase the solubility of such drugs (non-polar drugs)

in water, the latter’s polarity should be lowered.
This can be achieved by adding a third component such as
a water-miscible organic liquid with a low polarity. Such a
liquid, when used in this context, is called a co-solvent.
 log  c
log C s  f ( ) / 100  log  0
log  0
log γc
Untuk etanol log Cs = f ( ----------- ) + log C0
log γ0

log 125
Untuk etanol log Cs = 11,8 ( ) + log 11,1
log 11,1 100
= 11,8 (0,0105) + 1,0453
Karena bersifat aditif, kelarutan dalam eliksir adalah
Log Cs = 1,0453 + 11,8 (0,0105) + 10 (0,01) + 0,1 (0,0026) + 47,5 (0,0026)
(air) (etanol) (PG) (kloroform) (gliserin)

Cs = 24,7 mg/ml target = 24 mg/ml

3. Dielectric Constant
Substances has capacity to produce dipoles in another
molecule.
Dielectric constant is a measure of this capacity and it is a
physical property.
It is ffected by both the attractive force that exists between
atoms and also molecules.
Effect of solvent polarity

The solubility of the drug substance is attributable in large part to

the polarity of the solvent, often expressed in terms of dipole
moment, related to the dielectric constant.

Solvents with high dielectric constants dissolve ionic compounds

(polar drugs) readily by virtue of ion–dipole interactions, whereas
solvents with low dielectric constants dissolve hydrophobic
substances (non-polar drugs) as a result of dipole or induced
dipole interactions (Van der Waals, London, or Debye forces).

This principle is illustrated in Fig. 1. The former is classified as

polar solvents, with examples such as water and glycerin; the
latter are non-polar solvents, with example such as oils. Solvents
with intermediate dielectric constants are classified as semipolar.
The dielectric constants of some solvents are shown in Table
3.[9]
Konstanta dielektrik

Sifat suatu pelarut yang berhubungan dengan jumlah energi yang

dibutuhkan untuk dua tubuh (molekul) yang berbeda muatan dalam pelarut
(dibandingkan dengan energi yang dibutuhkan untuk memisahkan 2 masa
benda yang sama dengan muatan berbeda dalam vakum).

Misal : Kd air 250C = 78,5 air mengambil 78,5 kali lebih banyak untuk
memisahkan 2 tubuh dengan muatan yang berbeda dibandingkan
dalam vakum (Kd = 1).

Setiap solut menunjukkan kelarutan maksimum, pada sistem pelarut

tertentu, dengan suatu sistem yang mempunyai “konstanta dielektri
spesifik”.
Sedang konstanta dielektrik dari suatu sistem pelarut campur : Jumlah hasil
perkalian fraksi pelarut dengan konstanta dielektrik masing-masing pelarut
dari sistem pelarut campur tersebut.

Misal sistem etanol-air :

10% etanol Kd = (0,1 x Kd etanol) + (0,9 x Kd air)

Harga beberapa harga Kd pelarut pada 250C

Air : 78,5
Etanol : 24.3
Gliserin : 42,5
propilen glikol : 33,0
Contoh penggunaan sistem Kd

Misal sistem etanol-air

20% etanol, Kd = (0,2 x 24,3) + (0,8) (78,5)

= 67,66

diketahui kelarutan parasetamol dalam 20% etanol = 226,3 mg/5 ml

20% etanol ?? Bahaya turunkan

kosolven ..
 Target Etanol < 20%, misal 7%

Gliserin 15%

Hitung jumlah propilen glikol :

Kd = (0,07 x 24,3) + (0,15 x 42,5) + (X x 33) + (0,78 – X) 78,5

67,66 = 1,701 + 6,375 + 33X – 78,5X + 61,23

45,5X = 1,646

X = 0,036 % propilen glikol = 4%

4. Complexation with Cyclodextrins
Each cyclodextrin molecule can form complexes
with one or more drug molecules.
Drug-CD complexes can also self -associate, and the
water-soluble structures ormed can urther solubilize
the drug through non-inclusion complexation.

The interior cavity of cyclodextrins is apolar,

while their exterior is hydrophilic.
Upon administration, for example orally, of
a solution containing a drug-CD complex, the drug
can be released from the CD molecule and the free
drug can then be absorbed through the
gastrointestinal tract.
5. Surfactants and micelles
Surfactants (surfaceactiveagents) and amphiphiles are molecules
which have two distinct regions in their chemical structure.
One region is hydrophilic and the other hydrophobic.
Because of this, such molecules tend to accumulate at the
boundary between two phases, such as water-air or water-oil inter
aces.
They reduce the surface tension of liquids, and self -assemble to
form micelles once the critical micellar concentration (CMC) is
reached.
Critical micelle concentration (CMC)
CMC:concentration of surfactants at
which it begin to form micelles.

Increasing concentration of surfactant in

water slowly forming a layer on the
surface and eventually forming micelles
at or above the CMC
Peningkatan kelarutan yang lainnya : Pembentukan kompleks, hidrotropi,
modifikasi kimia obat, reduksi
ukuran partikel.
6. Hydrotropy
The term hydrotropic agent was first introduced by Neuberg
(1916) to designate anionic organic salts which, at high
concentrations, considerably increase the aqueous solubility
of poorly soluble solutes .
Hydrotropy is a solubilization phenomenon whereby addition
of large amount of second solute results in an increase in the
aqueous solubility of another solute.
Hydrotropy is one of the solubility enhancement techniques
which enhance solubility to many folds with use of
hydrotropes like sodium benzoate, sodium citrate, urea,
niacinamide etc.
Excipients used in pharmaceutical solutions for oral administration

Excipients in pharmaceutical formulations

are physiologically inert compounds that
are included in the formulation to facilitate
the administration of the dosage form, e.g.

pourability, palatability, to protect the

formulation from issues regarding physical
and chemical stability and to enhance the
solubility of the therapeutic agent.
The vehicle

The preferred and most commonly used vehicle in

solutions for oral administration is Purified Water USP,
due to the low cost and low toxicity of this ingredient.
Under normal circumstances tap (drinking) water
should not be used due to the possibility of chemical
imcompatibities within the formulation.

The main features of Purified Water USP are as

follows:
■ It is prepared by distillation, ion exchange methods
or by reverse osmosis.

■ The solid residue (obtained after evaporation) is less

than 1 mg per 100 ml of evaporated sample.

■ It must not be used for the preparation of parenteral

formulations.
 Co-solvents

As defined previously, co-solvents are employed to increase the

solubility of the therapeutic agent within the formulation.
The main co-solvents that are used in the formulation of oral
solutions are detailed below.

Glycerol
Glycerol (also termed glycerin) is an odorless,
sweet liquid that is miscible with water and
whose co-solvency properties are due to the
presence of three hydroxyl groups (termed a
triol)
Alcohol USP (CH3CH2OH)

Alcohol USP contains between 94.9 and 96.0% v/v ethyl

alcohol (ethanol) and is commonly used as a co-solvent,
both as a single co-solvent and with other co-solvents,
e.g. glycerol.

The known pharmacological and toxicological effects of

this co-solvent have compromised the use of alcohol in
pharmaceutical preparations.

As a result there are both labelling requirements for

preparations that contain alcohol and upper limits with
respect to the concentration of alcohol that may be used
in formulations.
Propylene Glycol USP

Propylene Glycol USP is an odourless,

colourless, viscous liquid diol that contains two
hydroxyl groups (Figure 1.2).
It is used in pharmaceutical preparations as a
co-solvent, generally as a replacement for
glycerin.
Poly(ethylene glycol) (PEG)

PEG (Figure 1.3) is a polymer composed of repeating units

of the monomer ethylene oxide (in parenthesis). The
physical state of the polymer is dependent on the number of
repeat units (n) and hence on the molecular weight.
Lower-molecular-weight grades (PEG 200, PEG 400) are
preferred as co-solvents in
pharmaceutical solutions.
Common excipients in pharmaceutical solutions

There are several excipients that are commonly employed in

the formulation of pharmaceutical solutions.

These include: (1) buffers;

(2) sweetening agents; and

(3)viscosity-enhancing agents.
 Buffers

Buffers are employed within pharmaceutical solutions to

control the pH of the formulated product and, in so doing,
optimise the physicochemical performance of the product.

■ to maintain the solubility of the therapeutic

agent in the formulated product. The solubility of
the vast number of currently available drugs is pH-
dependent and, therefore, the solubility of the
therapeutic agent in the formulation may be
compromised by small changes in pH

■ to enhance the stability of products in which the

chemical stability of the active agent is pH-
dependent.

■ acetates (acetic acid and sodium acetate): circa 1–2%

■ citrates (citric acid and sodium citrate): circa 1–5%
■ phosphates (sodium phosphate and disodium phosphate):
circa 0.8–2%.
Sweetening agents

Sweetening agents are employed in liquid formulations

designed for oral administration specifically to increase the
palatability of the therapeutic agent.

The main sweetening agents employed in oral preparations

are sucrose, liquid glucose, glycerol, sorbitol, saccharin
sodium and aspartame.

The use of artificial sweetening agents in formulations is

increasing and, in many formulations, saccharin sodium is
used either as the sole sweetening agent or in combination
with sugars or sorbitol to reduce the sugar concentration in
the formulation.
The use of sugars in oral formulations for children and
patients with diabetes mellitus is to be avoided.
Viscosity-enhancing agents

The administration of oral solutions to patients is usually performed

using a syringe, a small-metered cup or a traditional 5-ml spoon.

The viscosity of the formulation must be sufficiently controlled in

order to ensure the accurate measurement of the volume to be
dispensed.
Furthermore, increasing the viscosity of some formulations may
increase the palatability. Accordingly there is a viscosity range that
the formulation should exhibit to facilitate this operation.

Certain liquid formulations do not require the specific addition of

viscosity-enhancing agents, e.g. syrups, due to their inherent
viscosity.
The viscosity of pharmaceutical solutions may be easily
increased (and controlled) by the addition of non-ionic
or ionic hydrophilic polymers.
Examples of both of these categories are shown below:

■ non-ionic (neutral) polymers

– cellulose derivatives, e.g.:
● methylcellulose
● hydroxyethylcellulose
● hydroxypropylcellulose
– polyvinylpyrrolidone

■ ionic polymers
– sodium carboxymethylcellulose (anionic)
– sodium alginate (anionic).
Antioxidants

Antioxidants are included in pharmaceutical solutions to enhance

the stability of therapeutic agents that are susceptible to chemical
degradation by oxidation.

Typically antioxidants are molecules that are redox systems which

exhibit higher oxidative potential than the therapeutic agent or,
alternatively, are compounds that inhibit free radical-induced drug
decomposition.

Typically in aqueous solution antioxidants are oxidised (and

hence degraded) in preference to the therapeutic agent, thereby
protecting the drug from decomposition. Both water-soluble and
water-insoluble antioxidants are commercially available, the
choice of these being made according to the nature of the
formulation.
 Examples of antioxidants that are commonly used for
aqueous formulations include:

sodium sulphite, sodium metabisulphite, sodium

formaldehyde sulphoxylate and ascorbic acid.

Examples of antioxidants that may be used in oil based

solutions include:

butylated hydroxytoluene (BHT), butylated hydroxyanisole

(BHA) and propyl gallate.

Antioxidants may also be employed in conjunction

with chelating agents, e.g. ethylenediamine
tetraacetic acid, citric acid, that act to form
complexes with heavy-metal ions, ions that are
normally involved in oxidative degradation of
therapeutic agents.
Flavours and colourants

Unfortunately the vast majority of drugs in solution are

unpalatable and, therefore, the addition of flavours is often
required to mask the taste of the drug substance.
Taste-masking using flavours is a difficult task; however, there
are some empirical approaches that may be taken to produce
a palatable formulation.

– Flavours that may be used to mask a salty taste include:

● butterscotch
● apricot
● peach
● vanilla
● wintergreen mint.
– Flavours that may be used to mask a bitter taste include:
● cherry
● mint
● anise.

– Flavours that may be used to mask a sweet taste include:

● vanilla
● fruit and berry.

– Flavours that may be used to mask a sour taste include:

● citrus flavours
● raspberry.
Preservatives

Preservatives are included in pharmaceutical solutions to

control the microbial bioburden of the formulation.

Ideally, preservatives should exhibit the following properties:

■ possess a broad spectrum of antimicrobial activity

encompassing Gram-positive and Gram-negative bacteria
and fungi
■ be chemically and physically stable over the shelf-life of
the product
■ have low toxicity.

■ benzoic acid and salts (0.1–0.3%)

■ sorbic acid and its salts (0.05–0.2%)
■ alkyl esters of parahydroxybenzoic acid (0.001–0.2%).
Pharmaceutical solutions,and
their route of administration
Route of
administration
Oral
Oral solutions are
swallowed, in which case,
the drug may exert a local
effect on the
gastrointestinal tract or be
absorbed into the blood
and exert a systemic
action.
Requirements of the solution
Liquid oral solutions are aqueous formulations.
To be acceptable to patients, these must be
palatable.
Flavouring, colouring and sweetening agents are
therefore added to enhance their appearance
and taste.
Solution pH is usually 7.0, although a range of pH
2–9 can be tolerated.
Viscosity should be appropriate for palatability
and pourability.
Pharmaceutical solutions,and
their route of administration
Route of administration
Topical Skin/Nail/Hair
Solutions are applied to the
skin for local and/or systemic
effect.
The vehicle may be aqueous
or non-aqueous.
Solutions are also applied to
the nail or hair for local effect.
Requirements of the solution
A lotion is aqueous-based, and is
intended for application without friction.
A liniment is an alcoholic or oily solution
(or emulsion) designed to be
rubbed into the skin.
Paints and tinctures are concentrated
aqueous or alcoholic antimicrobial
solutions.
Pharmaceutical solutions,and
their route of administration

Route of Requirements of the solution

administration
Topical
Skin/Nail/Hair
(continued)
A collodion is a solution of a polymer, in a volatile
organic solvent system (a mixture of ethanol and
Solutions are also
ether).
applied to the nail or
Following application to the skin, the solvents
hair for local effect
evaporate, leaving a polymeric film on the skin.
All preparations must be acceptable to the patient.
Easy to transfer from the container and will spread
easily and smoothly are preferred.
Formulation must adhere to site of application,
without being tacky or difficult to remove.
Pharmaceutical solutions,and
their route of administration

Route of administration Requirements of the solution

Otic (ear, aural)
Solutions are instilled in Aqueous or non-aqueous solutions.
the outer ear to exert Water, glycerol, propylene glycol and oils may
a local effect. be used as solvents.
Used to remove ear Non-aqueous vehicles for removed ear wax
wax or to deliver anti- Viscosity of aqueous solutions is increased by
infective, antiin the use of polymers.
flammatory and analgesic Propylene glycol and glycerol solutions are
drugs. naturally viscous and these
enhance residence time.
Solutions do not need to be isotonic as they
are external preparations.
Pharmaceutical solutions,and
their route of administration
Route of administration
Ocular
Eye drops are used to treat
local disorders of
the eye, e.g. infection.
Ocular solutions used to
treat intraocular disorders,
such as glaucoma.
Eye lotions are solutions
for rinsing or bathing
the eye, or for
impregnating eye
dressings.
Requirements of the solution
Most ocular solutions are aqueous.
They must be manufactured sterile as the
product is to come in contact with tissues that
are very sensitive to contamination.
Once opened, a multidose ocular product
should remain free from viable
microorganisms during its period of use and
must contain antimicrobial preservatives.
Ocular solutions must be isotonic with the
tears to minimize irritation and discomfort.
Most products have a viscosity of 15–25 mPas
An increase in viscosity prolongs the
solution’s residence in the eye.
Pharmaceutical solutions,and
their route of administration
Route of administration
Nasal
Nose drops, nasal sprays,
(local, decongestant effect)
or for systemic drug
delivery.
Requirements of the solution
1. Nasal solutions are aqueous formulations.
2. Solution pH pH 5.5 - 6.5.
3. Isotonic to nasal fluids.
4. Viscosity is similar to that of nasal mucus
5. Flavouring or sweetening agents are
sometimes used to mask taste
6. Multidose solutions require preservatives.
Pharmaceutical solutions,and
their route of administration
Route of Requirements of the solution
administration
Pulmonary
Inhaled solutions are Solutions of drug and excipients dissolved in liquefied
administered by propellants (trifluoromono fluoroethane, in pMDIs).
pressurized metered-dose Solutions used in nebulizers are aqueous formulations, large
volumes in nebulizers, isotonic and have a pH 3-8,50
inhalers (pMDIs) or by Multidose preparations containing preservatives
nebulizers for local or Generally, sterile, single unit doses without a preservative are
systemic effect. used.
Pharmaceutical solutions,and
their route of administration

Route of administration Requirements of the solution

Rectal
Solution enemas are usually Enemas can be aqueous or oily solutions.
administered for local or Micro-enemas have a volume of 1 to 20 mL,
systemic drug action. while macro-enemas have volumes of 50 mL
or more.
Macro-enemas should be warmed to body
temperature before administration.
Vaginal
Vaginal solutions are Vaginal solutions are aqueous.
administered for local Excipients to adjust pH may be included.
effect, for irrigation or for
diagnostic purposes.
Pharmaceutical solutions,and
their route of administration
Route of
administration
Parenteral
Drugs are most commonly
injected into the veins
(intravenous), muscles
(intramuscular) and into the
Skin.
Requirements of the solution
Parenteral solutions must be sterile and
pyrogen-free.
Intravenous – aqueous,
Intramuscular and subcutaneous – The solution
can be aqueous or non-aqueous.
Parenteral solutions must be isotonic when large
volumes are administered by intravenous
infusion.
When smaller volumes are used, a wider range
of tonicity can be tolerated as dilution with body
fluids occurs.
Oral elixirs

An elixir is a clear, hydroalcoholic solution that is formulated for

oral use. The concentration of alcohol required in the elixir is
unique to each formulation and is sufficient to ensure that all of
the other components within the formulation remain in solution.

For this purpose other polyol co-solvents may be incorporated

into the formulation. The presence of alcohol in elixirs presents a
possible problem in paediatric formulations and, indeed, for
those adults who wish to avoid alcohol.
The typical components of an elixir are as follows:

■ Purified water.

■ Alcohol. This is employed as a co-solvent to ensure solubility

of all ingredients. As highlighted above, the concentration of
alcohol varies depending on the formulation.
Generally the concentration of alcohol is greater than 10% v/v;
however, in some preparations, the concentration of alcohol may
be greater than 40% v/v.

■ Polyol co-solvents. Polyol co-solvents, e.g. propylene glycol,

glycerol, may be employed in pharmaceutical elixirs to enhance
the solubility of the therapeutic agent and associated excipients.
The inclusion of these ingredients enables the concentration of
alcohol to be reduced.
Two examples in the USP that illustrate the range of
concentrations of co-solvents are Phenobarbital Elixir and
Theophylline Elixir (Tables 1.1 and 1.2).
■ Sweetening agents.
The concentration of sucrose in elixirs is less than that
in syrups and accordingly elixirs require the addition of
sweetening agents. The types of sweetening agents
used are similar to those used in syrups, namely
syrup, sorbitol solution and artificial sweeteners such
as saccharin sodium (Figure 1.8).

It should be noted, however, that the high

concentration of alcohol prohibits the incorporation of
high concentrations of sucrose due to the limited
solubility of this sweetening agent in the elixir vehicle.
To obviate this problem, saccharinsodium, an agent
which is used in small quantities and which exhibits
the required solubility profile in the elixir, is employed.
■ Flavours and colours.

All pharmaceutical elixirs contain flavours and colours to

increase the palatability and enhance the aesthetic qualities
of the formulation.
The presence of alcohol in the formulation allows the
pharmaceutical scientist to use flavours and colours that
may perhaps exhibit inappropriate solubility in aqueous
solution.
For example, it may be observed that in the two formulations
cited above, essential oils were used as the flavouring
agents.
As before, the selected colour should optimally match the
chosen flavour.
■ Ancillary comments

– Preservatives are not required in pharmaceutical

elixirs that contain greater than circa 12% v/v
alcohol, due to the antimicrobial properties of this
co-solvent.

– Due to the volatile nature of some of the

components of elixirs, elixirs should be packaged
in tight containers and not stored at high
temperatures.

– The addition of viscosity-enhancing agents, e.g.

Hydrophilic polymers, may be required to
optimise the rheological properties of elixirs.
FORMULA

1. Sirop yang mengandung parasetamol Anak-anak

The Pharmaceutical Codex, 1994

Parasetamol 24 g

Larutan amaran 2 ml
Kloroform spirit 20 ml
Rasberi jus 25 ml
Etanol 96% 100 ml
Propilen glikol 100 ml
Invert syrop 275 ml
Gliserol ad 1000 ml
2. Eliksir :
Fenobarbiton 400 mg

Etanol 90% 40 ml

Compound orange spirit 2,5 ml

Gliserol 40 ml

Larutan amaran 1 ml

Air ad 100 ml
Evaluasi sediaan larutan

1. Evaluasi fisik

a. Evaluasi organoleptik : - Kejernihan, rasa, bau, warna

- Kelengkapan dan kebersihan

Uji kejernihan FI IV TUGAS !!!

b. Bobot jenis FI IV

Penetapan bobot jenis berdasar pada perbandingan bobot zat di

udara pada suhu 25 °C (atau suhu yang ditetapkan dalam
monografi) terhadap bobot air dengan volume dan suhu sama
 c. Penetapan pH FI IV

1. Kalibrasi pH meter dengan larutan dapar pH 7 atau 10 sesuai pH

yang akan diukur dengan larutan dapar pH 4

2. Ukur pH cairan menggunakan pH meter yang telah dikalibrasi

d. Penetapan volume terpidahkan FI IV

2. Evaluasi Kimia

a. Identifikasi bahan obat

b. Penetapan kadar bahan obat
c. Penetapan kadar etanol

3. Evaluasi Mikrobiologi

a. Jumlah cemaran mikroba

b. Potensi