1. Liquid Preparations Pharmaceutics Chapter 6

2. 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)

3. Section 1 Introduction of liquid preparations

4. 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

5. 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.

6. solid liquid gas liquid gas solid Dispersed phaseDispersion medium For example: A suspension ------ solid/liquid dispersion An emulsion ------ liquid/liquid dispersion

7. 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

8. 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

9. 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 area a higher rate of drug dissolution possibly a superior bioavailability

10. Section 2 Solvents and additives

11. 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

12. Formulation Additives solubilizer hydrotropy agent cosolvent preservatives correctant coloring agent pH-controlling agents antioxidants

13. 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 Solubilizer

14. polarity

15. 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

16. 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 benbarbitalConcentration 501000 ethanol 90

17. Preservatives are substances which are added to prevent microbial growth Preservatives parabens benzioc acid and sodium benzoate sorbic acid benzalkonium bromid others

18. sweeting agents flavoring agent mucilage effervescent Correctant natural pigment synthetized pigment edible pigment external application pigment Coloring agent

19. Section 3 Solutions

20. 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

21. Preparation of Solutions Weigh the sample Dissolve the sample filtrate quality test package Water Solutions A solution is formed in water as a solvent

22. 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

23. Section 4 Suspensions

24. 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

25. Physical stability and influencing factors flocculation and deflocculation sedimentation crystal growth and polymorphism

26. 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

27. Sedimentation behavior is induced by gravitation. Srokes’ law r―particle radius d―particle diameter ρ 1 ― the density of the particle ρ 2 ― the density of dispersion medium g ―acceleration caused by gravity η ― the viscosity of the medium sedimentation In order to enhance the stability of suspensions a)particle size reduction b)increasing the viscosity of the continuous phase

28. 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 crystal growth and polymorphism

29. 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.

30. Stabilizers for suspentions  suspending agents  wetting agents  flocculating agents and deflocculating agents  pH-controlling agents  others

31. Preparation method for suspensions dispersion method coacervation Methods of evaluating suspensions detection of the particle size detection of sedimentation volume ratio Where V u is the equilibrium volume of sediment, V 0 is the total volume of the suspension.

32. 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: detection of ζ potential reconstitution

33. 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.

34. Section 5 Emulsions

35. Contents of this section  Type, constitution, characteristic  Emulsifying agents  Additives  Preparation method  Phsical stability  Quanlity control

36. dispersion B phase A phaseEmulsion 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.

37. Fig.1 Mineral oil in water emulsion

38. Type, constitution, characteristic water phase （ W ） preservatives, correctants oil phase （ O ） emulsifier/emulsifying agent Based constitution others

39. O/W W/O Types of emulsions W/O/W O/W/O Internal phase External phase oil-in-waterwater-in-oil Water in- oil-in-water Oil-in-water- in-oil Internal phase External phase Basic types multiple

40. O/WW/O appearanceivory whitegreasy phase dilution testdiluted with waterdiluted 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 Methods to determine type of emulsions

41. classificationclassification 1 emulsion — 1~100  m 。 2 Submicroemulsion — 0.1~1.0  m 3 millimicroemulsion— 10~100 nm 4 multiple emulsions — <50  m

42. The basic requirements for emulsifier Types of emulsifier Emulsifying mechanism emulsifier

43. Mechanism of emulsion forming Surface-tension theory interfacial-film theory

44. Type of emusifier 1. high molecular compound 2. surfactants 3. solid powder

45. 1. high molecular compound acacia tragacanth gelatin lecithin almond cholesterol others

46. 2. surfactants ⑴ anionic surfactants polarity hydrophilic Nonpolarity hydrophobic Na + - Active part （ - ） General topical used emulsions ！

47. 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 ， ⑵ nonionic surfactants

48. Charateristic of nonionic surfactant ： for oral use ： nontoxic IV administration toxic( haemocytolysis ） Pluronic F 68 ： with the potential possibility of IV administration

49. Finely divided solids ， can be aggregated at surface between oil and water to form solid particle membrane Finely divided solids ， can be aggregated at surface 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 emulsions contact 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

50. 1. coemulsifier 2 ． preservatives 3 ． antioxidants 4. sweeting agent Additives of emulsions

51. Methods of emulsion preparation Prescription laying for emulsions Drug addition Preparation method emulsification facilities The influcing factors on emulsification examples

52. 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

53. 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. Physical stability of emulsions

54. phase inversion O/W type W/O type W/O O /W The reason for phase inversion ： property of emulsifier ： phase volume ratio ： W/O type——ф50%~60% O/W type——ф90%

55. 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 irreversible

56. antioxidants preservatives light 、 heat 、 air microorganisms spoilage Effective measure to protect emulsions acidification

57. 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