Liquid Preparations

Pharmaceutics Chapter 6

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)

Section 1 Introduction of liquid preparations

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

Section 2 Solvents and additives

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

polarity

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

Section 3 Solutions

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

Section 4 Suspensions

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.

Section 5 Emulsions

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.

Fig.1 Mineral oil in water emulsion

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

Mechanism of emulsion forming

• Surface-tension theory

•interfacial-film theory

Type of emusifierType of emusifier

1. high molecular compound

2. surfactants

3. solid powder

1. high molecular compound

acacia tragacanthgelatin lecithin almond cholesterol others

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

1. coemulsifier2． preservatives3． antioxidants4. sweeting agent

Additives of emulsions

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