DOSAGE FORM DESIGN

TOPIC: SOLUTIONS
SOLUTION DOSAGE FORMS
 Prepared by dissolving drug(s) in the solvent(s)
 Drug disperse at molecular level
 Can be formulated for different route of administrations
Advantages
 Easier to swallow
 Ready to be absorbed
 Faster to give effect
 Drug will be uniformly distributed
 Reduce irritation effect (egs. Aspirin, potassium chloride, KI, KBr)
Disadvantages
 Bulky
 Poor stability
 Provide suitable media for the growth of microorganism
 Accurate dosage depends on the ability of patients to measure the
dosage accurately
 The unpleasant taste of drug is more pronounce in solution
Formulations of solutions:

Rx: Active ingredient/s

Solvent/s
Additives

Questions for tutorial:

What is solution dosage forms? Define
Name advantages and disadvantages solution dosage
Forms
Write formulation of solution dosage
Forms
Formulations of solutions:
Active ingredients

Solvents
 Aqueous solvent
 Non-aqueous solvent

Factors to be considered in selecting of a suitable solvent:

solubility, stability, compatibility, toxicity, irritancy,
sensitivity, flammability and cost.
Formulations of solutions:

Aqueous solvent

 Water; preferred vehicle:

generally available, inexpensive, palatable & nontoxic, universal solvent
for most substances.

 Types of pharmaceutical waters (For detail see Pharmacopoeias: BP,

USP etc.
 Potable water
 Purified water; prepared by distillation or deionization, reverse
osmosis
 Water for injection; obtained by sterilizing pyrogen free distilled
water
Formulations of solutions:

Non-aqueous solvents

Reasons of not using aqueous solvent:

 Drugs are not completely dissolve or
unstable
 Drugs are designed for depot
therapy purposes,
eg. propionate and benzoate esters
of testosterone and estradiol
Formulations of solutions:

Non-aqueous solvents in pharmaceuticals

 Fixed oils of vegetable origin
 Non volatile oils consist of fatty acid esters of glycerol
 Almond oil, arachis oil, olive oil, sesame oil, maize oil,
cottonseed oil, soya oil, fractionated coconut oil.
 As solvents for injection/parenteral preparations
Formulations of solutions:
 Ethanol: useful for external preparations (salicylic
acid lotion). It is used orally or parenterally at low
concentration due to its toxicity. Usually as
cosolvent with water
 IMS (industrial methylated spirit): contain 5%
methyl alcohol, solvent for external preparations
 Propylene glycol: as a cosolvent, solvent for
injection, ear drops, eye drops and oral
preparations
CH3 CH (OH) CH2OH
Formulations of solutions:

 Polyethylen glycols (PEG) or macrogols: available in a range of viscosity

grade. Eg. PEG 400 used solvent in a topical solution. Dipropylene
glycol, ethylene glycol, glycerol is also used as a cosolvent for oral
preparations

HOCH2 (CH2CH2O)n CH2OH

 Dimethylsulphoxide, ethyl ether, liquid paraffin, isopropyl myristate,

isopropyl palmitate..etc.

Q: Briefly explain type of solvents used in S0lution

Dosage Forms
Formulations of solutions:
Formulation considerations

 Two important factors: SOLUBILITY and stability, can be

approach through application of the scientific method

 The other factors such as flavouring and other organoleptic

characteristics remain subjective factors

 “Compatibility of the ingredients involved in the formulations’

 The successful formulation of liquid solutions, requires a blend

of scientific acuity and pharmaceutical “art”

”
Formulations of solutions:
Formulation considerations

Solubility: amount of solute that passes into solution to produce saturated

solution at a given temperature

Saturated solutions: the solvent contents the maximum amount of solute

Non-saturated solutions: the solvent contents less than the maximum a

mount of solute

Non-saturated solutions: the solvent contents more than the maximum

amount of solute
Solubility curve
Descriptive solubility
Description Approximate weight of solvent
necessary to dissolve 1 g of solute
Very soluble ‹1

Freely soluble Between 1 and 10

Soluble Between 10 and 30

Sparingly soluble Between 30 and 100

Slightly soluble Between 100 and 1000

Very slightly soluble Between 1000 and 10 000

Practically insoluble › 10 000

Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

pH
 A large number of drugs are either weak acids or weak bases
 Their solubility can be influenced by their pH environment
 Weak acids less soluble in solution with low pH
 Weak basics less soluble in solution with high pH
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

 In selecting the pH environment that satisfy the

solubility, there must not conflict with other
requirements, such as stability and physiologic
compatibility
 If pH is critical to maintaining solubility, the
system must be adequately buffered.
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

 Buffer criteria: must have adequate capacity in
desired pH range, biologically safe, have little or no
deleterious effect on the stability of the product,
should permit acceptable flavouring and and
colouring products
 Example of pharmaceutical buffers: boric,
carbonic, phosphoric, citric, acetic etc
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

Cosolvency
 Process to increase water solubility of substances by the
addition of a water-miscible solvent. The solvents used in
combination to increase the solubility are known as a
cosolvents
 A cosolvent system works by reducing interfacial tension
between predominately aqueous solution and hydrophobic
solute
 Examples: ethanol, sorbitol, glycerin, propylene glycol
 Cosolvents are also employed to improve solubility of
volatile constituent (flavouring and odouring agents)
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

 Solubilisation
 Process whereby water insoluble
substances are brought into solution
in the interior of micelles.

 Substance being solubilised is

called solubilisate.

 Site of solubilisate
 Non polar hydrocarbons →in the interior of micelles
 Polar molecules → adsorbed at the micelle water interface
 Amphiphatic molecules → oriented in palisade layer
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

Complexation
 In some cases it may possible to increase solubility
 Egs. Complexation of iodine with
polyvinilpyrrolidone
Interaction of salicylates and benzoates with
xantines (theophylline, caffeine)
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

Chemical modification
 By converting into salt forms
 chlorpromazine  chlorpromazine hydrochloride
 Hydrocortisone  Hydrocortisone sodium phosphate,
 prednisolone  prednisolone sodium phosphate,
 betamethasone  betamethasone sodium phosphate
 Chloramphenicol  Chloramphenicol sodium succinate
Formulations of solutions:
Formulation considerations

Approach to improve aqueous solubility

Particle size control

 Since surface area increases with decreasing particle
size, higher solubility may be achieved with decreasing
particle size

Discuss ways to improve solubility

Formulations of solutions:
Formulation considerations

Additives

Preservatives
 To improve antimicrobial stability of the products
 Sources of contaminations: raw materials, processing containers and
equipments, manufacturing environments, operators, packaging
materials, and the user.
 Ideal preservative:
 exert a wide spectrum of antimicrobial activity at low inclusion levels.
 maintain activity throughout product manufacture, shelf life and usage.
 not compromise the quality or performance of product, pack or delivery
system.
 not adversely affect patient safety or tolerance of the product
Formulations of solutions:
Formulation considerations

Additives

Preservatives
 Four major groups:
 Acidic: phenol , chlorocresol, alkyl esters of parahydroxybenzoic acid
(paraben), bezoid acid and its salts, sorbic acid and its salt etc,
 Neutral: Chlorobutanol, benzyl alcohol etc
 Mercurial: thimerosal, phenilmercuric acetate etc
 quaternary ammonium compounds: benzalkonium chloride

 Frequently, a combination of two or more preservatives are needed to

achieve the desired antimicrobial effect
Formulations of solutions:
Formulation considerations

Additives
Sweetening agents
 Sucrose, sorbitol, glycerin, dextrose, honey,
glucose, cyclamate
 saccharine (250-500 time as sweet as sugar),
aspartame (synthetic sweetener) 200 times sweeter
than sugar.
Formulations of solutions:
Formulation considerations

Additives

Viscosity controller / thickening agents

 Sugar, cellulose derivatives (e.g. methylcellulose,
carboxymethylcellulose, sodium
carboxymethylcellulose, polyvinylpyrrolidone),
 For palatability or to improve pourability, to
improve stability
 Viscosity inducing polymers should be used with a
degree of caution
Formulations of solutions:
Formulation considerations

Additives
 Buffers
To control the pH of the solution product

 Reducing agents/Antioxidants:
 Sodium sulphite, sodium metabisulphite, sodium
formaldehyde, ascorbic acid
 Butylated hydroxyanisole, butylated hydroxytoluene,
propyl gallate
 Ethylenediamine, tetraacetic acid, citric acid
Formulations of solutions:
Formulation considerations

Additives
 Flavors

Taste sensation: four Recommended flavour

basic taste sensations)
Salt Maple, apricot, vanilla,
wintergreen mint
Bitter Wild cherry, walnut,
chocolate, passion fruit,
mint spice, anise
Sweet Fruit and berry, vanilla
Sour Citrus flavour, licorice,
root beer, raspberry
Formulations of solutions:
Formulation considerations

Additives

Colouring agents
 Appearance of liquid products depend on their colour and
clarity
 Colour selection should be consistent with flavour
 Blue or green for mint, red for berry
 Natural: carotenoids, chlorophyll, anthocyanins, riboflavin,
caramel, extract beetroot
 Synthetic (dyes); ammarant, coal tar
Formulations of solutions:
Manufacturing considerations

Raw materials
 Raw materials used in manufacturing should comply with the
specifications for pharmaceutical grade, which cover identity,
purity, uniformity, freedom from excessive microbial
contaminations

 Incoming raw materials should be thoroughly tested

before they are released for manufacturing

 Additional processing may be required to obtain a

desirable property such as particle size (size reduction)

 Water used must comply with the requirement for purified

water. It may be obtained by distillation or ion-exchange treatment
Formulations of solutions:
Manufacturing considerations

Equipments

 Jacketed stainless steel mixing tanks equipped with a mean of agitation,

 measuring devices for large and small amount of solids and liquid,
 filtration systems and/or sterilization of the solution
 All equipment must be clean and sanities (sterilised if possible) before used
Formulations of solutions:
Manufacturing considerations

Operators

 A major source of microbial contamination is processing operators

 Head covering should be worn at all times. Gloves and face masks should be
worn as necessary
 An ongoing education program is recommended to maintain operator interest
and concern for good work habit
Formulations of solutions:
Manufacturing considerations

Compounding procedure

 For simple formulations (from rapidly dissolving materials) and dilute

solutions, are simply prepared by charging the solute to the solvent and
agitating until the solution is homogeneous.
 For complex formulations (slowly dissolving materials) and
concentrate solutions, may use heat to facilitate solubility. Size
reduction of solid materials may be conducted to fasten the process of
dissolution
 Solute present in small concentrations (e.g dye) are predissolved in a
small volume of the solvent, then only added to the compounding tank
 Volatile materials (flavouring agents) are added at the last process and
after any cooling to reduce loss by evaporation.
Formulations of solutions: Manufacturing considerations
Compounding procedure
Example of syrup formula and manufacturing method

Formula Per ml Per batch

(5000L)

Drug 2 mg 10 kg

Sodium benzoate 1mg 5 kg

Menthol 0.1 mg 0.5 kg

Alcohol 0.00 5ml (40.8 mg) 250 L (204 kg)

Flavor 0.0005 ml(4.5 mg) 23 L (22.5kg

Dye FD &C no 6 0.1 mg 0.5 kg

Glycerin 0.05 ml (62.45 mg) 250L (312.250 kg)

Sorbitol solution 0.1 ml (128.5 mg) 500 L (642.5 kg)

Granulated sugar 550 mg 2750 kg

Purified water to 1ml 5000 L

Formulations of solutions:
Manufacturing considerations
Compounding procedure
 Charge 2000L of purified water into compounding tank, heat to about 50C
 To the compounding tank, Charge the materials, dissolve each one with the agitation,
before the next (a) drug, (b) sodium benzoate, (c) granulated sugar. Agitate until the
batch is homogeneous
 Charge glycerin to the compounding tank. Agitate until the batch is homogeneous
 Charge sorbitol to the compounding tank. Agitate until the batch is homogeneous
 Measure 20L of alcohol into a suitable container. Add and dissolve the menthol and
flavour
 Charge the alcohol solution of menthol and flavour to the compounding tank. Agitate
until the batch is homogeneous
 Charge the balance of alcohol to the compounding tank. Agitate until the batch is
homogeneous
 Charge 10L purified water to a clean stainless steel container. Add to the water and
dissolve the specific amount of FD&C No.6
 Charge the day solution, add into the tank, agitate until the batch is homogeneous
 Charge the sufficient purified water into the tank up to the batch volume to 5000L
 Do filtration, sample the batch (product) for quality control tests
 Filling product
Formulations of solutions:
Manufacturing considerations

Filling product
 Filling machines: based on gravimetric, volumetric and constant level
 Evaluations
Formulations of solutions:
Evaluations

Evaluations

 Physical: clarity, colour, odour, viscosity etc

 Chemical: assay of active ingredient, assay of preservative contents
 Biological: microbial growth/contamination test

Questions:
Discuss factors to be consider to design SDFs
Discuss briefly evaluations SDFs
TYPE OF SOLUTIONS
 DOUCHES
 A douche is an aqueous solutions
directed against a part of into
a cavity of the body with bulb syringes.
.
 Dispensed usually in the form of a powder or a
tablet which need to be diluted or dissolve in a
specific amount of warm water prior to use.

 Eg. an eye douche: to remove foreign particles or discharges from eyes.

a pharyngeal douche: to cleanse interior of throat.
a nasal douche, a vaginal douche

 It functions as cleansing or antiseptic agents. Ingredients used may be:

antimicrobial agents, anaesthetic, astringents, surface active agents
ENEMAS

These are rectal solutions employed to:

- evacuate the bowl (evacuation enemas)
Aqueous based those containing sodium chloride, sodium
bicarbonate, sodium monohydrogen phosphate and sodium
dihydrogen phosphate = alone or in combination with
irritants such as soap.
Arachis oil retention enema.
- influence the general system by absorption (retention
enemas) eg. those containing aminophylline, hydrocortisone
and methyl prednisolone.
- to effect locally the seat of the disease eg. sulfasalazine for
the treatment of ulcerative colitis or barium sulfate enema.
GARGLES
 These are aqueous solutions used for treating the pharynx and
nasopharynx. Eg. thymol compound gargle.
 Many gargles must be diluted prior to use.
 Must be labeled to prevent it from being mistaken for internal
preparations.
MOUTHWASHES
 These are aqueous solutions
which are used most often for
their deodorant, refreshing or
antiseptic effect or for the
control of plaque.
eg. those containing hexetidine, cetylpyridinum
chloride, dibucaine hydrochloride or compound sodium
chloride mouthwash comprising of sodium chloride,
sodium bicarbonate, conc. peppermint emulsion &
chloroform water.
 May contain alcohol, glycerin, synthetic sweeteners
and surface active, flavouring and colouring agents.
NASAL SOLUTIONS

 These are usually aqueous solutions designed to be administered to

the nasal passages in drops or sprays.
 They are usually isotonic and slightly buffered to maintain a pH of 5.5
- 6.5.
 Drugs: antibiotics, antihistamines, anti asthmatics.
OTIC SOLUTIONS

 These are also called aural preparations/ear preparations.

 Drugs: analgesic, antibiotics, anti-inflammatory agents
(eg.steroids),
 Solvents: Glycerin or water.
The viscous glycerin vehicle permits the drug to remain in the ear
for a long time.
IRRIGATION SOLUTIONS
 These are used to wash or bathe surgical incisions, wounds or
body tissues. Need to be sterile because they come into contact
with exposed tissues.
 Eg. acetic acid irrigation for bladder irrigation, aminoacetic acid
irrigation for urethral surgery and sodium chloride irrigation for
washing wounds.
COLLODIONS
 Liquids preparations containing pyroxylin (a nitrocellulose) in a
mixture of ethyl ether & alcohol for external use.
 Applied to the skin
Eg. salicylic acid collodion USP-contains 10% salicylic acid
Flexible collodion-addition of castor oil and camphor.
ELIXIRS

 These are clear, pleasantly flavoured, sweetened

hydroalcoholic liquids intended for internal use.
 Main ingredients are alcohol and water, but glycerin, sorbitol, propylene
glycol, flavour, preservatives & syrup can be added.
 Content of alcohol can vary.
 Usually the water soluble ingredients are dissolved in the water & the alcohol
soluble ingredients are dissolved in the alcohol, then the water phase are
added in the alcohol phase……product should be brilliantly clear.
 Eg. Ephedrine elixir BPC
- contain syrup and 100 ml alcohol per 1000 ml
Ephedrine sulphate elixir USP
- contain 20 - 40 ml alcohol per 1000 ml

 Elixir must be stored in a tightly closed and light resistant container

 away from direct heat and sunlight
Examples
Phenobarbital Elixir
 Phenobarbital elixir (0.4%)
 Orange oil (0.025%)
 Propylene glycol (10%)
 Alcohol (20%)
 Sorbitol solution (60%)
 Colour(as required)
 Purified water (ad 100%)
Theophylline Elixir
 Theophylline
 Citric acid
 Liquid glucose
 Syrup
 Saccharin sodium
 Glycerin (5%)
 Sorbitol solution (32.4%)
 Alcohol (20%)
 Lemon oil
 FDC yellow no.5
 Purified water (ad 100%)
LINIMENTS
 These are solutions or
mixtures of various substances
in oil, alcoholic solutions of
soap or emulsions and are
intended for external application,
need to be rubbed.
 also called embrocations
 alcoholic liniments penetrate the
skin more readily than those with an oily base.
 Not to be applied to bruised or broken skin.
 Eg. Methyl salicylate liniments
OLEOVITAMINS

 These are fish liver oils diluted with edible

vegetable oil or solutions of concentrated
vitamins (usu. Vit. A & D) in fish liver oils.
 Can get rancid
 should be stored under vacuum or under an
atmosphere of inert gas and protected from
light.
SYRUPS

 Simple syrup (syrup simplex)

These are concentrated solutions of sugar such as
sucrose in water.

Concentration of syrup: in conc. of 65% w/w or more, the

osmotic pressure is sufficiently great to inhibit growth of
most bacteria and fungi.

Eg. Syrup BP
SYRUPS
 Medicated syrup

Medicated syrups provide a convenient

form of stock solution of certain drugs for
use in extemporaneous preparations.
 SYRUPS
 Flavoured syrup

Contain various aromatic or pleasantly flavoured

substances and are intended to be used as
vehicles or flavours for extemporaneous
preparations.

Eg. acacia syrup, raspberry syrup, orange syrup

(syrupus aurantii)
SYRUPS
Syrup Preparation

 Solution with heat. Eg. Syrup BP

 Agitation without heat: used in cases where heat would cause the
loss of valuable, volatile constituents.

 Percolation. Eg. Syrup USP

 Reconstitution: dry syrup formulation may be prepared and purified

water added just prior to dispensing or use
MIXTURES and DRAUGHT

 Mixtures are liquid medicines for oral administration, which contain

medicaments dissolved and/or suspended in water.
A mixture is multi-dose preparation and each dose may or may not
be needed to be diluted before taking.

The term “mixtures” includes solutions and suspensions.

Manufactured on small scale as required and allocated a shelf life of

a few weeks before dispensing

 Draught: A liquid medicine consisting of one or two doses only (50 ml. usu.)
LINCTUS

 A preparation prescribed for the treatment of

a cough and is rendered viscous by the
inclusion of glycerin or syrup, to be
administered undiluted to obtain the lubricant
effect of the vehicle.