Liquid pharmaceutical Preparations
A solution is a homogenous one-phase system consisting of two or more components.
→solvent + solute
• The solvent is that phase in which the dispersion occurs and the solute is that component that is dispersed as small
molecules or ions in the solvent.
• Liquid preparations: the formulation prepared by dispersing drug substance in the appropriate solvents and used
internally or externally.
Homogeneous formulations: should be a clear solution.
Non-homogeneous formulations: particles should be small with a narrow particle size distribution.
Liquid formulations for oral should be palatable.
For all liquid formulations:
- With an accurate content
- Convenient package
Classification of liquid preparations
1. According to the dispersion system
• Homogeneous system: thermodynamic stable
➢ Low molecular solutions: solute < 1 nm
➢ High molecular solutions: solute 1~100 nm
• Non-homogeneous system: unstable system
➢ Sol (lyophobic colloid): molecular aggregate (1~100 nm)
➢ Emulsion: >100 nm
➢ Suspensions: >500 nm
2. According to the administration route
- Drops, syrups, emulsions, suspensions, mixture
- Dermal: lotion, liniment
- For ENT (ears, nose, throat): nasal drops, auristillae
- For ophthalmic administration: eye drops, collyria
- For rectal, vaginal, and urethral administration: enema, irrigations
Advantages of liquid formulations
- A drug administered in the form of a solution is immediately available for absorption.
- Irritation is reduced by administration because of the immediate dilution of drugs by the gastric contents.
- Liquids are easier to swallow than solids and therefore particularly acceptable for pediatric and geriatric use.
- Especially suitable for oil drugs (emulsion)
- A broad administration route.
Disadvantages of liquid dosage form
- Chemical stability: hydrolysis, oxidation
- Physical stability: emulsion, suspension
- Liquids are bulky and therefore inconvenient to transport and store.
- Solutions often provide suitable media for the growth of micro-organisms and may therefore require the addition of a preservative.
Solvents for liquid preparations
1. Aqueous solvent
– Distilled water
• – Alcohol
• – Glycerin
• – Propylene glycol
• – Polyethylene glycol (PEG)
• – Dimethyl sulfoxide (DMSO)
• – Fatty oils
Water is the most widely used solvent for use as a vehicle for pharmaceutical products because of its lack of toxicity,
physiological compatibility and its ability to dissolve a wide range of materials.
- Distilled water
- Free of salt
- Free of pyrogen
- Free from carbon dioxide or free from air
Ethanol (ethyl alcohol)
- Next to water, it is the most useful solvent in Pharmacy.
- In Chinese Pharmacopoeia:95%(V/V)
- primary solvent for many organic compounds.
- Together with water, it forms a hydroalcoholic mixture that dissolves both alcohol-soluble and water-soluble
- Particularly for external applications.
- particularly useful for the extraction of crude drugs being more selective than water
Glycerin (USP: glycerol)
- Glycerin is a clear syrupy liquid with a sweet taste.
- Miscible with both water and alcohol.
- Widely used particularly as an auxiliary solvent in conjugation with water or alcohol.
- Used in many internal preparations.
- 10% water-containing glycerin no irritation
- >30% glycerin has preservative qualities.
- For pharmaceutical use: 1,2-propylene glycol.
- Useful solvent with a wide range of applications and is miscible with water and alcohol.
- Frequently substituted for glycerin in modern pharmaceutical formulations.
- A mixture of propylene glycol and water can decrease the hydrolysis of drug substances and increase stability.
Molecular Weight < 1000, liquid state, such as PEG 200, 300, 400, 600.
• Commonly used in the liquid formulation: PEG 300~600.
• Because of the strong H-bonding between PEGs and water, they are freely soluble in water and in many organic solvents, often used in conjunction with water or glycerol as a cosolvent.
• Used in the formulation of water-miscible ointment bases.
Dimethyl sulfoxide (DMSO)
- is a highly polar compound and increases the rate of absorption of drugs through the skin, it can be used as a drug delivery system.
- Dissolves a broad range of substances therefore called alcahest (universal solvent).
- Including sesame oil, castor oil, cotton seed oil, soya oil, maize oil, olive oil
- Dissolves hormones, volatile oil, free alkaloids, and a great deal of aromatic compounds.
- For external use: nasal drops, lotion, liniment.
- For internal: VA and VD solutions.
- oily substance used as solvents for external use, particularly in cosmetics where low viscosity, lack of
greasiness, and good absorption through the skin are desired.
Excipients in liquid formulations
- Solubilizer – surfactant
- Hydrotropy agent
- The molecules at the surface do not have other molecules on all sides of them and therefore are pulled inwards.
- This creates some internal pressure and forces liquid surfaces to contract to the minimal area.
Surfactants are substances that absorb to surfaces or interfaces, causing a marked decrease in surface tension.
All surfactants are characterized by having two regions in their molecular structure:
A) a hydrophobic group, such as a hydrocarbon chain, which has no affinity for aqueous solvents
B) a hydrophilic group that has an affinity for water.
A molecular or ion that possesses this type of structure is termed amphipathic (amphiphilic).
Classification of Surfactants
Dependent on the molecular composition and the nature of dissociation of their polar head groups the surfactants are classified as ionic (cationic, anionic, amphiphilic) or nonionic.
A- Ionic surfactants:
1.quaternary ammonium compound: [R1R2N + R3R4]X-， such as Benzalkonium chloride and Benzalkonium bromide.
2. amine salt: [RNH3 + ]X-，[R2NH2 + ]X
- Toxic used only as antiseptics;
- Incompatible with anionic surfactants and polyvalent anions ;
- Unstable at high pH
B- Anionic surfactants
•Salts of higher fatty acids (soaps)
•Sodium dodecyl sulfate (SDS) (Sodium lauryl sulfate (SLS) (widely used to produce o/w emulsions).
•Alkylbenzene sulfonates (detergents)
- Toxic, used only for externally applied preparations;
- Incompatible with polyvalent cations and deionized water be used for their preparations.
C- Amphiphilic surfactants
- This type of surfactant possesses both positively and negatively charged groups depending on the pH of the
system. They are cationic at low pH and anionic at high pH.
- Lecithin: is used to stabilize intravenous fat emulsions.
- Low toxicity and irritancy.
- Can be used for orally and parenterally administered preparations.
- A greater degree of compatibility.
- Less sensitive to changes in pH or to the addition of electrolytes.
Non-ionic surfactants Examples –
- Polyhydric alcohol: Tween, Span
- Pluronic (Poloxamer)
- Sucrose esters (SE)
Spans (fatty acid esters of sorbitan)
Produced by the esterification of one or more of the hydroxyl groups of sorbitan with either lauric, palmitic, or stearic acid.
- span 20 (Sorbitan monolaurate)
- span 40 (Sorbitan monopalmate)
- span 60 (Sorbitan monostearate)
- span 65 (Sorbitan tristearate)
- span 80 (Sorbitan mono-oleate)
- span 85 (Sorbitan trioleate)
Application: This range of surfactants exhibits lipophilic properties and tends to form w/o emulsions.
Variations in the type of fatty acid used and in the number of oxyethylene groups in the polyethylene glycol chains
produces a range of products of differing oil and water solubility.
Tween 20， Tween 40， Tween 60, Tween 80， Tween 85 (o/w)
Properties of surfactants
- Critical micelle concentration (CMC)
- Hydrophile-lipophile balance (HLB)
Critical micelle concentration (CMC)
Micell: The surfactants consist of long molecules with two very different types of ends. One end likes water, and is
called hydrophilic, the other end likes oil and dislikes water, and is called hydrophobic. When these surfactants are placed in water, the hydrophobic ends attract each other and repel water. They arrange themselves into a spherical structure with the hydrophobic ends inside the sphere with the hydrophilic ends on the outer surface of the sphere, which is called a micelle.
Critical micelle concentration (CMC)
CMC: concentration of surfactants at which it begins 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
Hydrophile-lipophile balance (HLB)
• Hydrophile-lipophile balance： surfactants contain both hydrophilic groups and lipophilic groups with one or the
other being more predominant, the hydrophile-lipophile balance (HLB) number is used as a measure of the ratio of
these groups. It is a value between 0-40 defining the affinity of a surfactant for water or oil.
The HLB value of nonionic surfactants ranges from 0-20. HLB numbers >10 have an affinity for water (hydrophilic) and numbers <10 have an affinity for oil (lipophilic).
The HLB value can also be used to predict the other properties of a surfactant:
• A value from 3 to 6 indicates a W/O (water in oil) emulsifier
• A value from 8 to 18 indicates an O/W (oil in water) emulsifier
• A value from 7 to 9 indicates a wetting agent
• A value of 13 to 18 indicates a solubilizer
Above the surfactants’ CMC, the solubility of poorly-soluble drugs increases dramatically due to the formation of
surfactant micelles. the ability of surfactants is called solubilization, the surfactants are called solubilizers and the solutes are called solubilizates. Surfactants with HLB values 15~18 are the best solubilizing agents.
The commonly used solubilizers: Tweens
Solubilization is the process of incorporation of the solubilizate into or onto the micelles.
Definition: The apparent solubility of a sparely- soluble solute in a particular liquid may be increased by the
addition of a third substance that forms an intermolecular complex, double salt, or molecular association with the
solute. The third substance is called a hydrotropic agent.
• Hydrotropy agents are small molecular compounds instead of surfactants. •
For example, I2+KI→KI3
– Iodine solubility: 1g: 2950 ml (~0.03%)
– In 10% KI or NaI, 5%
Classification of hydrotropy agents
Organic acids and their sodium salts
- sodium benzoate
- Sodium salicylate
- para-amino benzoic acid (PABA)
Definition: The solubility of weak electrolytes and nonpolar molecules can be increased by the addition of water-miscible solvents. This process is known as solvency or solvent blending, and the solvents used in combination to
increase the solubility of the solute are called cosolvents.
Cosolvents: ethanol, propylene glycol, glycerin, sorbitol, and polyethylene glycol.
1) change the dielectric constant.
DC of a good cosolvent: 25~80.
2) hydrogen bonding in two solvents
Solubility of phenobarbital in different concentrated alcohols
A preservative is a substance that is added to products such as foods, pharmaceuticals, cosmetics, etc. to prevent microbial contamination.
• must be nonirritating, non-sensitizing, and non-toxic in the amount administered.
• must be soluble enough in the water to achieve adequate concentrations in the aqueous phase of a system
• must have adequate stability.
• must be completely compatible with all other formulation ingredients.
• must not interact with a container, such as a plastic medication bottle.
Commonly used preservatives
• Esters of para hydroxy benzoic acid (Parabens)(0.1- 0.2%)
• Benzoic acid and sodium benzoate( 0.1-0.2%)
• Sorbic acid
• Benzalkonium bromide(0.002-0.01%）
• Alcohol (15-20%)
• Phenol (0.1-0.5%)
• Cresol (0.1-0.5%)
• Phenylmercuric nitrate and acetate ( 0.002-0.01%)
• The methyl, ethyl, propyl, and butyl esters and their sodium salts are probably the most widely used group of
• They are most effective at a pH of 7~9.
• Concentrations of 0.1~0.2% are normally used and they are suitable for both external and internal use.
• They are usually used in combination, such as ethyl: propyl ester (1:1) or ethyl: butyl ester (4:1).
Benzoic acid and sodium benzoate
- good antifungal and antibacterial preservatives used at a pH of less than 4.
- A concentration of 0.03~0.1% is recommended.
- Sodium benzoate: 0.1~0.25%.
- Only the undissociated fraction or molecular form of a preservative possesses preservative capacity because the ionized portion is incapable of penetrating the microorganism.
Sorbic acid and its salts (sorbates)
- Sorbic acid has similar properties to benzoic acid.
- It is also only effective in acidic conditions (pH 4.5).
- Concentrations of 0.05~0.3% are used.
- Suitable for oral use.
- In general, the salts are preferred over the acid form because they are more soluble in water, but it is the acid form that is active
- Chlorhexide acetate, also called hibitane（0.02%~0.05%)
- Glycerin (>30%)
- Spearmint oil (0.05%)
- Cinnamyl aldehyde (0.01%)
- Eucalyptus oil (0.01%~0.05%)
- Liquid glucose
- Stevioside: 300 times sucrose, 0.025~0.05%, used together with sucrose and saccharin.
- Saccharin/ Saccharin sodium : 200~700 times sucrose, 0.03%.
- Aspartame：150~200 times of sucrose, no bitterness.
- Natural products
- fruit juices
- aromatic oils such as peppermint and lemon oils
- herbs and spices and distilled fractions of these, They are available as concentrated extracts, alcoholic or
aqueous solutions, syrups, or spirits.
- Artificial products: they tend to be cheaper, more readily available, less variable in chemical composition, and more stable than natural products. They are usually available as alcoholic or aqueous solutions or as powders.
- Used for the masking of sour.
- Commonly used :
– Sodium Alginate
- Composition: sodium bicarbonate +organic acid ( citric acid, tartaric acid).
- Produce CO2 when it comes in contact with water.
- Application: for the mask of bitter, salty, and astringent taste.
- Natural colorants
Red: beet red, carmine red.
Yellow: turmeric yellow, carotene
Blue: pine leaf
Green: sodium copper chlorophyllin
Brown: burnt sugar
– Mineral: ferric oxide
- Synthesized colorants
carmine red, lemon yellow, indigo blue (0.0005%~0.001%)
– External: eosin, aniline red, methylene blue.