Transcript Document

Liquid pharmaceutical
Preparations
Murat Kizaibek
Apr 22, 2012
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
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
colloid
solution
emulsion
suspension
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
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-organism and may therefore require the addition of a
preservative.
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
Solvents for liquid preparations
Aqueous solvent
• – Distilled water
Non-aqueous solvents
• – Alcohol
• – Glycerin
• – Propylene glycol
• – Polyethylene glycol (PEG)
• – Dimethyl sulfoxide (DMSO)
• – Fatty oils
water
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
Ethanol (ethyl alcohol)
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.
Glycerin (USP: glycerol)
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.
Propylene glycol
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.
Polyethylene glycol (PEG)
Type
Appearance
(25℃)
Molecular
Weight
pH
PEG 200
Colorless liquid
180~220
5.0~7.0
PEG 300
Colorless liquid
270~330
5.0~7.0
PEG 400
Colorless liquid
360~440
5.0~7.0
PEG 600
Colorless liquid
540~660
5.0~7.0
PEG 800
White paste
720~880
5.0~7.0
PEG 1000
White paste
900~1100
5.0~7.0
PEG 1500
White solid
1350~1650
5.0~7.0
PEG 2000
White solid
1800~2200
5.0~7.0
PEG 3000
White solid
2700~3300
5.0~7.0
PEG 4000
White solid
3600~4400
5.0~7.0
PEG 6000
White solid
5400~7000
5.0~7.0
PEG 8000
White solid
7200~8800
5.0~7.0
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.
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).
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.
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.
Excipients in liquid formulations
 Solubilizer
 Hydrotropy agent
 Cosolvent
 Preservatives
 Flavours
 Colours
surfactant
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.
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).
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+]XNotes: 1. toxic, used only as antiseptics; 2. incompatible
with anionic surfactants and polyvalent anions ; 3.
unstable at high pH
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 .
• 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.
Structure of a phosphatidylcholine, a type of phospholipid in lecithin
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.
Non-ionic surfactants
 Polyhydric alcohol:Tween, Span
 Polyoxyethylene
 Pluronic (Poloxamer)
 Sucrose esters (SE)
85
80
Tweens
60
85
80
Spans
60
• 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.
• 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)
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 watersoluble 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.
• 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
1000- 14000, HLB value is 0.5~30;
Poloxamer 188 (F68): used as emulsifying agents for
intravenous fat emulsions.
Properties of surfactants
• Critical micelle concentration (CMC)
• 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.
micell
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
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 0-20. HLB numbers >10 have an
affinity for water (hydrophilic) and number <10 have an
affinity of oil (lipophilic).
0
lipophilic
HLB
10
20
hydrophilic
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
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
The mechanism for solubilization
Solubilization is the process of incorporation of the
solubilizate into or onto the micelles.
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%
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
Cosolvency
Cosolvency
• Definition: The solubility of weak electrolytes and nonpolar
molecules can be increased by the addition of watermiscible 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
Solubility of phenobarbital in different concentrated alcohols
Preservatives
• A preservative is a substance that is added to products
such as foods, pharmaceuticals, cosmetics, etc. to
prevent microbial contamination.
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….
Commonly used preservatives
• Esters of parahydroxy benzoic acid (Parabens)(0.1- 0.2%)
• Benzoic acid and sodium benzoate( 0.1-0.2%)
• Sorbic acid
• Benzalkonium bromide(0.002-0.01%）
• Chlorhexideacetate（0.02~0.05%）
• Alcohol (15-20%)
• Chlorobutanol
• Phenol (0.1-0.5%)
• Cresol (0.1-0.5%)
• Phenylmercuric nitrate and acetate ( 0.002-0.01%)
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).
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.
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
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%)
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
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.
Selection of suitable flavorings
Taste of
Suitable masking flavor
product
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
Mucilage
• Used for the masking of sour.
• Commonly used :
– CMC-Na
– MC
– Starch
– Sodium alginate
– Acacia
– Gelatin
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.
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
Other excipients
pH adjuster
Antioxidants
Chelating agents
(Кешеншелер)