1. Liquid pharmaceutical Preparations
Murat Kizaibek
Apr 22, 2012

2. Introduction
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 which 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.
Attention: injections and extractions are not included in this chapter

3. Classification of liquid preparations (I)
According to 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 (lypophobic colloid): molecular aggregate
(1~100 nm)
Emulsion: >100 nm
Suspensions: >500 nm

4. colloid
solution
emulsion
suspension

5. Classification of liquid preparations (Ⅱ)
According to administration route
– oral:
drops, syrups, emulsions, suspensions, mixture
– External:
• 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

6. 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

7. 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-organism and may therefore require the addition of a preservative.

8. Quality control of liquid dosage forms
Homogeneous formulations: should be 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 accurate content
stable
conservative
convenient package

9. Solvents for liquid preparations
Aqueous solvent
– Distilled water
Non-aqueous solvents
– Alcohol
– Glycerin
– Propylene glycol
– Polyethylene glycol (PEG)
– Dimethyl sulfoxide (DMSO)
– Fatty oils

10. water

11. Water
Water is the most widely used solvent for use as a vehicle for pharmaceutical products because of 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

12. Ethanol (ethyl alcohol)

13. 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 substances.
particularly for external application.
particular useful for the extraction of crude drugs being more selective than water.

14. Glycerin (USP: glycerol)

15. Glycerin (USP: glycerol)
Glycerin is a clear syrupy liquid with a sweet taste.
miscible with both water and alcohol.
widely used particularly as a auxiliary solvent in conjugation with water or alcohol.
used in many internal preparations.
10% water-containing glycerin no irritation
>30% glycerin has preservative qualities.

16. Propylene glycol

17. Propylene glycol 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.
Mixture of propylene glycol and water can decrease the hydrolysis of drug substance and increase stability.

18. Polyethylene glycol (PEG)
Type
Appearance
(25℃)
Molecular
 Weight pH
PEG 200
Colorless liquid
180~220
5.0~7.0
PEG 300
270~330
PEG 400
360~440
PEG 600
540~660
PEG 800
White paste
720~880
PEG 1000
900~1100
PEG 1500
White solid
1350~1650
PEG 2000
1800~2200
PEG 3000
2700~3300
PEG 4000
3600~4400
PEG 6000
5400~7000
PEG 8000
7200~8800

19. Polyethylene glycol (PEG)
General formula:
MW< 1000, liquid state, such as PEG 200, 300, 400, 600.
Commonly used in liquid formulation: PEG 300~600.
Because of 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.

20. 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 substance, therefore called alcahest (universal solvent).

21. Fatty oils
Including sesame oil, castor oil, cotton seed oil, soya oil, maize oil, olive oil
Dissolves hormones, volatile oil, free alkaloids, a great deal of aromatic compounds.
Commonly for external use: nasal drops, lotion, liniment
For internal: VA and VD solutions.

22. Isopropyl myristate
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.

23. Excipients in liquid formulations
Solubilizer surfactant
Hydrotropy agent
Cosolvent
Preservatives
Flavours
Colours

24. Surfactants Definition Surface tension:
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 the surface tension.

25. Surfactant structure
All surfactants are characterized by having two regions in their molecular structure:
A) a hydrophobic group, such as a hydrocarbon chain, that 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).

26. 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.
Ionic surfactants:
Cationic surfactants
1.quaternary ammonium compound: [R1R2N + R3R4]X-，such as Benzalkonium chloride and Benzalkonium bromide.
2.amine salt: [RNH3+]X- ，[R2NH2+]X-
Notes: 1. toxic, used only as antiseptics; 2. incompatible with anionic surfactants and polyvalent anions ; 3. unstable at high pH

27. Anionic surfactants
Salts of higher fatty acids (soaps)
Sodium dodecyl sulfate (SDS) (Sodium lauryl sulphate (SLS)) (widely used to produce o/w emulsions).
Sodium glycocholate
Sodium taurocholate
Alkylbenzene sulfonates (detergents)
Notes: 1. Toxic, used only for externally applied preparations; 2. Incompatible with polyvalent cations and deionized water be used for their preparations .

28. 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.
• General formula:
• Lecithin: is used to stabilize intravenous fat emulsions.

29. Structure of a phosphatidylcholine, a type of phospholipid in lecithin

30. Non-ionic surfactants
Advantages:
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.

31. Non-ionic surfactants Polyhydric alcohol:Tween, Span Polyoxyethylene
Pluronic (Poloxamer)
Sucrose esters (SE)
Tweens Spans

32. 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)
The general formula
Application:This range of surfactants exhibits lipophilic properties and tends to form w/o emulsions.

33. Tweens (Polysorbates)
R-represents a fatty acid chain
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)

34. Polyoxyethylene type
polyoxyethylene fatty acid esters: The general formula ： RCOOCH2(CH2OCH2)nCH2OH, belongs to Myrij surfactants. e.g. Polyoxyethylene 40 stearate (Myrij 52) is a water- soluble material often used with stearyl alcohol to give o/w emulsions.
polyoxyethylene fatty ethers: The general formula：RO(CH2OCH2)nH，are condensation products of polyethylene glycol and fatty alcohols, usually cetyl or cetostearyl, where R is a fatty alcohol chain. It belongs to Brij surfactants.

35. Poloxamer (Pluronic)
polyoxyethylene/polyoxypropylene copolymers with the general formula
HO(C2H4O)a-(CHCH2(CH3)O)b-(C2H4O)aH
It comprises a very large group of compounds with Mw , HLB value is 0.5~30;
Poloxamer 188 (F68): used as emulsifying agents for intravenous fat emulsions.

36. Properties of surfactants
Critical micelle concentration (CMC)
HLB

37. 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.

38. micell

40. 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

41. 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. HLB value of nonionic surfactants ranges from HLB numbers >10 have an affinity for water (hydrophilic) and number <10 have an affinity of oil (lipophilic). .
                                                       
HLB
lipophilic
hydrophilic

42. 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 a O/W (oil in water) emulsifier
A value from 7 to 9 indicates a wetting agent
A value of 13 to 18 indicates a solubiliser

43. Solubilization
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 solubilizer and the solutes are called solubilizates. Surfactants with HLB values 15~18 are the best solubilizing agents.
The commonly used solubilizers: Tweens

44. The mechanism for solubilization
Solubilization is the process of incorporation of the solubilizate into or onto the micelles.

45. Hydrotropy Hydrotropy
Definition: The apparent solubility of a sparely- soluble solute in a particular liquid may be increased by the addition of a third substance which forms an intermolecular complex, double salt or molecular association with the solute. The third substance is called hydrotropy 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%

46. Classification of hydrotropy agents
Organic acids and their sodium salts
sodium benzoate
Sodium salicylate
para-amino benzoic acid (PABA)
Amide compounds
urethane
Urea
nicotinamide
acetamide

47. Cosolvency Cosolvency
Definition: The solubility of weak electrolytes and nonpolar molecules can be increased by the addition of water-miscible solvents. This process is known as cosolvency 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.
Mechanism:
1) change the dielectric constant.
DC of a good cosolvent: 25~80.
2) hydrogen bonding in two solvents

48. Solubility of phenobarbital in different concentrated alcohols

49. Preservatives
A preservative is a substance that is added to products such as foods, pharmaceuticals, cosmetics, etc. to prevent microbial contamination.

50. The preservative
must be nonirritating, non-sensitizing and non-toxic in the amount administered.
must be soluble enough in water to achieve adequate concentrations in the aqueous phase of a system
must have adequate stability.
must be completely compatible with all other formulative ingredients.
must not interact with a container, such as a plastic medication bottle….

51. Commonly used preservatives
Esters of parahydroxy benzoic acid (Parabens)( %)
Benzoic acid and sodium benzoate( %)
Sorbic acid
Benzalkonium bromide( %）
Chlorhexideacetate（0.02~0.05%）
Alcohol (15-20%)
Chlorobutanol
Phenol ( %)
Cresol ( %)
Phenylmercuric nitrate and acetate ( %)

52. Parabens
The methyl, ethyl, propyl and butyl esters and their sodium salts are probably the most widely used group of preservatives.
They are most effective at a pH 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:propylester (1:1) or ethyl:butylester(4:1).

54. Benzoic acid and sodium benzoate
a good antifungal and antibacterial preservative 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.

55. 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

56. Others
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%)

57. Sweeteners
Sucrose
Dextrose
Liquid glucose
honey
Glycerin
Sorbitol
Mannitol
Stevioside: 300 times of sucrose, 0.025~0.05% ,used together with sucrose and saccharin.
Saccharin/ Saccharin sodium : 200~700 times of sucrose, 0.03%.
Aspartame：150~200 times of sucrose, no bitterness

58. Flavorings
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.

59. Selection of suitable flavorings
Taste of product
Suitable masking flavor
Salty
Apricot, butterscotch, cinnamon, orange, liquorice, peach, raspberry, vanilla (ваниль)
Bitter
Anise(бәден) , chocolate, mint, passion fruit, wild cherry
Sweet
Vanilla, fruits, berries
Sour
Fruit or citrus flavors: Citrus fruits, liquorice, raspberry

60. Mucilage
Used for the masking of sour.
Commonly used :
– CMC-Na
– MC
– Starch
– Sodium alginate
– Acacia
– Gelatin

61. Effervescent (көпіршіктіш)
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.

62. Colorants (бояуыштар)
Natural colorants
– Vegetative:
Red: beet red, carmine red.
Yellow: turmeric yellow, carotene
Blue: pine leaf
Green: sodium copper chlorophyllin
Brown: burnt sugar
– Mineral: ferric oxide
Synthesized colorants
– Edible:
carmine red, lemon yellow, indigo blue (0.0005%~0.001%)
– External: eosin, aniline red, methylene blue

63. Other excipients
pH adjuster Antioxidants Chelating agents
(Кешеншелер)

64. рахмет сіздерге