Transcript chapter 6
Liquid Preparations Pharmaceutics Chapter 6 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) In this chapter, we should focus on the definition of liquid preparations preparation method and quality control Section 1 Introduction of liquid preparations Definition Liquid preparations are defined as the preparations that contain drug dissolved or dispersed in a suitable solvent or mixture of solvents drug — solid, liquid, gas dissolved or dispersed — method: dissolve, colloidal dissolve, emulsify, suspense — degree of dispension: ion, molecular, colloidal particles, droplets, microparticles 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. Dispersion medium Dispersed phase solid solid liquid liquid gas gas 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 Administration routes oral preparations Oral solutions，syrups, emulsions, suspensions, mixtures topical preparations •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 Characteristic of liquid preparations advantage The small particle size a large specific surface area a higher rate of drug dissolution possibly a superior bioavailability easily swallowed and flexibly dosed disadvantage chemical stability, physical stability is uneasy to control volume not convenient for carrying, transport, and storage preservatives are needed 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 Solubilizer 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 solubilization solubilizates: 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 polarity Hydrotropy 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 Cosolvent 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. of benbarbital Concentration 0 50 ethanol 90 100 Preservatives Preservatives are substances which are added to prevent microbial growth • parabens • benzioc acid and sodium benzoate • sorbic acid • benzalkonium bromid • others Correctant • sweeting agents • flavoring agent • mucilage • effervescent Coloring agent • natural pigment edible pigment • synthetized pigment external application pigment 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 Water Solutions A solution is formed in water as a solvent Preparation of Solutions Weigh the sample Dissolve the sample filtrate quality test package Aromatic Waters Aromatic Waters are saturated solutions (unless otherwise specified) of volatile oils or other aromatic or volatile substances in distilled water. 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 Qualification Qualities to suspensions 1 settle slowly and be readily redispersed upon the gentle shaking of the container 2 the particle size of the suspensiod remains fairly constant throughout long periods of undisturbed standing Physical stability and influencing factors flocculation and deflocculation sedimentation crystal growth and polymorphism flocculation and deflocculation 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 sedimentation Sedimentation behavior is induced by gravitation . 2 2 2 gr gd 1 2 2 Srokes’ law v 9 r―particle radius d―particle diameter ρ1 ― the density of the particle ρ2 ― the density of dispersion medium g ―acceleration caused by gravity η ― the viscosity of the medium 18 In order to enhance the stability of suspensions a) particle size reduction b) increasing the viscosity of the continuous phase crystal growth and polymorphism 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 S2 2M log S1 RT 1 1 r2 r1 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 drug Avoidance of the use high-energy milling during particle size reduction incorporation 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 VU F 100% V0 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 flocculated to 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, characteristic Emulsifying agents Additives Preparation method Phsical stability Quanlity control 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. dispersion B phase A phase Emulsion solution Fig.1 Mineral oil in water emulsion Type, constitution, characteristic Based constitution • water phase（W） • oil phase（O） • emulsifier/emulsifying agent others preservatives, correctants Types of emulsions Basic types O/W multiple W/O W/O/W Internal External Internal External phase phase phase phase oil-in-water water-in-oil O/W/O Water inoil-in-water Oil-in-waterin-oil Methods to determine type of emulsions 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 test the water-solubility dye is soluble in external phase the water solubility dye is soluble in internal phase classification 1 emulsion —1~100m。 2 Submicroemulsion — 0.1~1.0m 3 millimicroemulsion— 10~100nm 4 multiple emulsions — <50 m emulsifier •The basic requirements for emulsifier •Types of emulsifier •Emulsifying mechanism Mechanism of emulsion forming • Surface-tension theory •interfacial-film theory Type of emusifier 1. high molecular compound 2. surfactants 3. solid powder 1. high molecular compound acacia tragacanth gelatin lecithin almond cholesterol others 2. surfactants ⑴anionic surfactants Active part（-） Na+ - polarity hydrophilic Nonpolarity hydrophobic General topical used emulsions！ ⑵nonionic surfactants 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， Charateristic of nonionic surfactant： for oral use ：nontoxic IV administration toxic(haemocytolysis ）Pluronic F68：with the potential possibility of IV administration 3. Solid power surfactants Finely divided solids，can be aggregated at surface between oil and water to form solid particle membrane contact angle of solid powder with water phase determine the types of emulsions θ<90° O/W； θ>90°W/O Additives of emulsions 1. coemulsifier 2．preservatives 3．antioxidants 4. sweeting agent Methods 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： water oil＋emulsifer （2）wet gum method： water＋emusifier （3）direct mixture method oil＋water＋emulsifer emulsion oil emulsion emulsion Physical stability of emulsions Creaming（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 phases Flocculation The association of particles within an emulsion to form large aggregates, which can be easily be redispersed upon shaking. O /W phase inversion O/W type W/O type The reason for phase inversion： property of emulsifier： phase volume ratio： W/O type——ф50%~60% O/W type——ф90% W/O irreversible 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 acidification light、heat、air microorganisms spoilage Effective measure to protect emulsions antioxidants preservatives 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