liquid preparations pharmaceutics chapter 6. in this chapter, we should focus on the definition of...
TRANSCRIPT
In this chapter, we should focus on
the definition of liquid preparations preparation method and quality control
Contents of this chapter
Section 1 Introduction of liquid preparations
Section 2 Solvents and additives
Section 3 Solutions
Section 4 Suspensions
Section 5 Emulsions
Section 6 Macromolecule solutions (self-study)
drug — solid, liquid, gas dissolved or dispersed
— method: dissolve, colloidal dissolve, emulsify, suspense — degree of dispension: ion, molecular, colloidal particles, droplets, microparticles
Liquid preparations are defined as the preparations that contain drug dissolved or dispersed in a suitable solvent or mixture of solvents
Definition
Classification
Dispersion system
A disperse system is defined as a heterogenous, two phase system which the internal (dispersed, discontinuous) phase is distributed or dispersed within the continuous( external) phase or vehicle.
solid
liquid
gas
liquid
gas
solid
Dispersed phaseDispersion medium
For example: A suspension ------ solid/liquid dispersion
An emulsion ------ liquid/liquid dispersion
One classification scheme is based on the size of the dispersed particles within the dispersion medium
Molecular dispersions
Colloidal dispersions
Coarse dispersions
Homogeneous True solutions
Intermediate in size between true solutions and coarse dispersions
Dipersions containing larger dispersed phases, usually 10
to 50μm in size
oral preparations
topical preparations
Oral solutions , syrups, emulsions, suspensions, mixtures
•lotion, linimentum for skin-administration•nasal drops, eye drops, eye-lotion, throat wash, ear-drops for five sensory organs administration• enema, irrigation for rectum, vagina, and urethra administation
Administration routes
Characteristic of liquid preparations
easily swallowed and flexibly dosed
advantage
disadvantage
chemical stability, physical stability is uneasy to control
volume not convenient for carrying, transport, and storage
preservatives are needed
The small particle size a large specific surface areaa higher rate of drug dissolution possibly a superior bioavailability
Some solvents for liquid preparations
purified water( distilled water or deionized water)
alcohol
glycerin
propylene glycol
polyethylene glycol, PEG
dimethyl sulfoxide, DMSO
fatty oils
liquid paraffin
Formulation Additives solubilizer
hydrotropy agent
cosolvent
preservatives
correctant
coloring agent
pH-controlling agents
antioxidants
Solubilization is a process the solubility or miscibility of the drug in liquid phases tending to be insoluble is improved to form a solution in the presence of the surfactant.
solubilizer : the material with the ability of solubilizationsolubilizates: the materials to be solubilized
Solubilization mechanism
a solubilizer modifies the solvent to increase the solubility of an insoluble substance creates micellar or mixed micellar structures
Solubilizer
Hydrotropy is a process the solubility of insoluble drug is improved with the addition of the third substances with which the soluable molecular complex or compound salt of the drug can be formed
hydrotropy agent
Some sorts of organic acid substances or salts thereof amide chemicals
Hydrotropy
Cosolvency is a process the solubility of insoluble drug is improved in the presence of the mixed solvent. Mixed solvent is reffered to the solvents which can be mixed together with water in any proportion and change their dielectric constant.
Cosolvent
of ben
barb
italC
oncen
tration
50 1000ethanol
90
Preservatives are substances which are added to prevent microbial growth
Preservatives
• parabens• benzioc acid and sodium benzoate• sorbic acid• benzalkonium bromid• others
• sweeting agents
• flavoring agent
• mucilage
• effervescent
Correctant
• natural pigment
• synthetized pigment
edible pigment
external application pigment
Coloring agent
A solution is a homogeneous mixture that is prepared by dissolving a solid, liquid or gas in another liquid.
Molecular solutions include:
water solutions aromatic waters syrups tincture spirits Glycerins
Preparation of Solutions
Weigh the sample
Dissolve the sample
filtrate
quality test
package
Water Solutions
A solution is formed in water as a solvent
Aromatic Waters are saturated solutions (unless otherwise specified) of volatile oils or other aromatic or volatile substances in distilled water.
Aromatic Waters
Preparation method of Aromatic Waters
1. Distillation
2. Solution
3.Dilution
Suspensions
Suspensions may be defined as preparations containing finely divided drug particles distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.
Basic Requirements for suspensions
QualificationQualities to suspensions
1 settle slowly and be readily redispersed upon the gentle shaking of the container2 the particle size of the suspensiod remains fairly constantthroughout long periods of undisturbed standing
Physical stability and influencing factors
flocculation and deflocculation
sedimentation
crystal growth and polymorphism
When the forces of repulsion are sufficiently small that the forces of attraction start to predominate, the particles may approach each ther closely and form loose agglomerates, termed floccules
flocculation and deflocculation
Sedimentation behavior is induced by gravitation.
Srokes’ law
r―particle radiusd―particle diameterρ1 ― the density of the particle ρ2 ― the density of dispersion medium g ―acceleration caused by gravityη ― the viscosity of the medium
sedimentation
189
2 212
22
gdgrv
In order to enhance the stability of suspensionsa) particle size reductionb) increasing the viscosity of the continuous phase
crystal growth― the growth of large particles at the expense of smaller ones as a result of a difference in the solubility of the particles of varying sizes.
Ostwald Freundlich equation
121
2 112
S
Slog
rrRT
M
crystal growth and polymorphism
Polymorphism refers to the different internal crystal structures of a chemically identical compound.
To prevent crystal growth and possible changes
selection of particles with narrow size range selection of a more stable crystalline form of the drugAvoidance of the use high-energy milling during particle size reductionincorporation of a wetting agent.
Stabilizers for suspentions
suspending agents wetting agents
flocculating agents and deflocculating agents pH-controlling agents
others
Preparation method for suspensions
dispersion method
coacervation
Methods of evaluating suspensions
detection of the particle size
detection of sedimentation volume ratio
%1000
V
VF U
Where Vu is the equilibrium volume of sediment, V0 is the total volume of the suspension.
detection of flocculation value
the ratio of the sedimentation volume of the flocculatedto the sedimentation olume of the suspension when deflocculated. It is expressed as:
F
F
detection of ζ potential
reconstitution
Packaging and Storage of Suspensions: 1) Should be packaged in wide mouth containers
having adequate air space above the liquid. 2) Should be stored in tight containers protected
from: freezing and excessive heat & light 3) Label: "Shake Before Use" to ensure uniform
distribution of solid particles and thereby uniform and proper dosage.
Contents of this section
Type, constitution, characteristicEmulsifying agentsAdditivesPreparation methodPhsical stabilityQuanlity control
dispersion
B phase A phase Emulsion solution
Definition
An emulsion is a dispersion in which the dispersed phase
is composed of small globules of a liquid distributed
throughout a vehicle in which it is immiscible.
Type, constitution, characteristic
• water phase ( W )
preservatives, correctantspreservatives, correctants
• oil phase ( O )• emulsifier/emulsifying agent
Based constitution
others
O/W W/O
Types of emulsionsTypes of emulsions
W/O/W O/W/O
Internal phase
External phase
oil-in-water water-in-oil
Water in-oil-in-water
Oil-in-water-in-oil
Internal phase
External phase
Basic types multiple
O/W W/O
appearance ivory white greasy
phase dilution test diluted with water diluted with oil
conductivity test a current passing fails to carry the current
dye solubility testthe water-solubility
dye is soluble in external phase
the water solubility dye is soluble in internal phase
Methods to determine type of emulsionsMethods to determine type of emulsions
classificationclassificationclassificationclassification
1 emulsion — 1~100m 。2 Submicroemulsion — 0.1~1.0m
3 millimicroemulsion— 10~100nm
4 multiple emulsions — <50 m
•The basic requirements for emulsifier
•Types of emulsifier
•Emulsifying mechanism
emulsifieremulsifier
2. surfactants
⑴anionic surfactants⑴anionic surfactants
polarityhydrophili
c
Nonpolarity
hydrophobic
Na+
-
Active part ( - )
General topical used emulsions!
Sorbitan( 脂肪酸山梨坦 )—— ( W/O type ) span20 , 40 , 60 , 80 ;
Polyoxyethylene sorbitan monolaurate( 聚 山 梨 酯 )—— ( O/W type )
tween20 , 40 , 60 , 80 ,Polyxyethylene fatty acid ester( 聚氧乙烯脂肪酸酯类 )( Myrij )——( O/W type )
Myrij 45 , 49 , 52 ,
⑵nonionic surfactants⑵nonionic surfactants
Charateristic of nonionic surfactant :for oral use : nontoxicIV administration toxic(haemocytolysis ) Pluronic F68 : with the potential possibility of IV administration
Finely divided solids , can be aggregated atsurface between oil and water to form solid particle membrane
Finely divided solids , can be aggregated atsurface between oil and water to form solid particle membrane
3. Solid power surfactants
contact angle of solid powder with water phase determine the types of emulsionscontact angle of solid powder with water phase determine the types of emulsions
θ<90° O/W ;θ>90°W/O
θ<90° O/W ;θ>90°W/O
Methods of emulsion preparationMethods of emulsion preparation
• Prescription laying for emulsions• Drug addition • Preparation method• emulsification facilities • The influcing factors on emulsification• examples
Preparation method
1 . hand-made method ( 1 ) dry gum method :
oil + emulsifer( 2 ) wet gum method :
water + emusifier
( 3 ) direct mixture method
water
emulsion
oil
emulsion
oil + water + emulsifer emulsion
CreamingCreaming (分层) (分层)
Aggregates of globules of the internal phase have a greater tendency than do individual particles to rise to the top of the emulsion or fall to the bottom
The difference in the density between the phasesThe difference in the density between the phases
Flocculation
The association of particles within an emulsion to form large aggregates, which can be easily be redisper
sed upon shaking.
Physical stability of emulsionsPhysical stability of emulsions
phase inversion
O/W type W/O typeO/W type W/O type
W/OO /W
The reason for phase inversion :The reason for phase inversion :property of emulsifier :phase volume ratio :
W/O type——ф50%~60%
O/W type——ф90%
Coalescence and breaking
coalescence—— the mechanical of electrical barrier is insufficient to prevent the formation of progressively larger droplets. breaking or creaking—— The coalescence of the globules of the internal phase and the seperation of that phase into a layer Coalescence and breaking are irreversible
irreversibleirreversible
antioxidants
preservatives
light 、 heat 、 air microorganisms
spoilage
Effective measure
to protect emulsions
acidification
Evaluation of emulsion stability ( self-study )
detection of particle size and size distribution
observation on creaming phenominean
detection of the combination rate of droplets
detection of stability constant
detection of viscosity
detection of particle size and size distribution
observation on creaming phenominean
detection of the combination rate of droplets
detection of stability constant
detection of viscosity