20120503-1-liquid-preparation3 OK

1. Liquid pharmaceuticalPreparations Murat Kizaibek Apr 22, 2012

2. 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

3. 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

4. colloid solution emulsion suspension

5. 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

6. 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

7. 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.

8. 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

9. Solvents for liquid preparations Aqueous solvent • – Distilled water Non-aqueous solvents • – Alcohol • – Glycerin • – Propylene glycol • – Polyethylene glycol (PEG) • – Dimethyl sulfoxide (DMSO) • – Fatty oils

10. water

11. 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

12. Ethanol (ethyl alcohol)

13. 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.

14. Glycerin (USP: glycerol)

15. 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.

16. Propylene glycol

17. 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.

18. Polyethylene glycol (PEG)

19. 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.

20. 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).

21. 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.

22. 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.

23. Excipients in liquid formulations • Solubilizer surfactant • Hydrotropy agent • Cosolvent • Preservatives • Flavours • Colours

24. 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.

25. 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).

26. 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+]X- Notes: 1. toxic, used only as antiseptics; 2. incompatible with anionic surfactants and polyvalent anions ; 3. unstable at high pH

27. 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 .

28. 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.

29. Structure of a phosphatidylcholine, a type of phospholipid in lecithin

30. 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.

31. Non-ionic surfactants • Polyhydric alcohol:Tween, Span • Polyoxyethylene • Pluronic (Poloxamer) • Sucrose esters (SE) 85 80 60 85 80 60 Tweens Spans

32. 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.

33. 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)

34. 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 water- soluble 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.

35. 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.

36. Properties of surfactants • Critical micelle concentration (CMC) • HLB

37. 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.

38. micell

40. 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

41. 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). . HLB 0 10 20 lipophilic hydrophilic

42. 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

43. 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

44. The mechanism for solubilization Solubilization is the process of incorporation of the solubilizate into or onto the micelles.

45. 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%

46. 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

47. Cosolvency Cosolvency • Definition: The solubility of weak electrolytes and nonpolar molecules can be increased by the addition of water-miscible 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

48. Solubility of phenobarbital in different concentrated alcohols

49. Preservatives • A preservative is a substance that is added to products such as foods, pharmaceuticals, cosmetics, etc. to prevent microbial contamination.

50. 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….