Surfactant

surfactant

1. SURFACTANT, SOLUBILIZER AND STABILIZER 1 Guided By:- Dr. (Mrs.) Aparna Palshetkar Prepared By :- SNEHA A. CHAVAN Department Of Pharmaceutics M-Pharmacy 1 st Year, I Semester

2. Solubilizer The agents which help in dissolving or increase the drug solubility into the formulation are known as solubilizing agents . 2

3. The solubility of weak electrolytes and nonpolar molecules can be increased by the addition of water-miscible solvents. This process is known as co-solvency and the solvents used in combination to increase the solubility of the solute are called co-solvents . Co-solvents : ethanol, propylene glycol, glycerin, sorbitol and polyethylene glycol. 3 Co-solvent

4. Surfactant Surfactants: are substances that absorb to surfaces or interfaces, causing a marked decrease in the interfacial tension. 4

5. Surfactant Structure 5

6. Surfactant Classification 6

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9. Properties O f Surfactants 9

10. Critical micelle concentration (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 10 Critical Micelle Concentration (CMC).

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12. HLB 12 HLB Scale

13. 13 Cetrimide Sodium Lauryl Sulfate (SLS) Sorbitan Esters (Sorbitan Fatty Acid Esters) Nonproprietary Names BP: Cetrimide PhEur: Cetrimide BP: Sodium Lauryl Sulphate JP: Sodium Lauryl Sulfate PhEur: Sodium Laurilsulfate USP-NF: Sodium Lauryl Sulfate BP, PhEur :- Sorbitan Laurate Sorbitan Oleate Sorbitan Palmitate Sorbitan Stearate Sorbitan Trioleate USP-NF: Sorbitan Monooleate Sorbitan Monopalmitate Sorbitan Monostearate Sorbitan Sesquioleate Sorbitan Triol Synonyms Cetab, Cetavlon, Cetraol, Morphans; Quammonium; Sucticide Dodecyl alcohol hydrogen sulfate, sodium salt Elfan 240 , natrii laurilsulfas, sodium laurilsulfate, sodium monododecyl sulfate, SDS Functional Category cationic surfactant Anionic surfactant Nonionic surfactant

14. 14 Cetrimide Sodium Lauryl Sulfate (SLS) Sorbitan Esters (Sorbitan Fatty Acid Esters) Handling Precautions solutions are irritant; avoid inhalation, ingestion, and skin and eye contact. Eye protection, gloves, and a respirator are recommended Inhalation and contact with the skin and eyes should be avoided; eye protection, gloves, and other protective clothing, are recommended. Adequate ventilation should be provided SLS emits toxic fumes on combustion Eye protection and gloves are Recommended Incompatibilities Incompatible with soaps, anionic surfactants, high concentrations of nonionic surfactants. Aqueous solutions react with metals Reacts with cationic surfactants, causing loss of activity even in concentrations too low to cause precipitation. SLS is incompatible with salts of polyvalent metal ions (Al, Pb, Zn) , and precipitates with potassium salts. Solutions of SLS (pH 9.5–10.0) are mildly corrosive to mild steel, copper, brass, bronze, and aluminum.

15. 15 Cetrimide Sodium Lauryl Sulfate (SLS) Sorbitan Esters (Sorbitan Fatty Acid Esters) Stability and Storage Condition chemically stable in the dry state, and also in aqueous solution at ambient temperatures. The bulk material should be stored in a well-closed container in a cool, dry place stable under normal storage conditions. However, in solution, under extreme conditions, i.e. pH 2.5 or below , it undergoes hydrolysis to lauryl alcohol and sodium bisulfate. The bulk material should be stored in a well-closed container away from strong oxidizing agents in a cool, dry place. Gradual soap formation occurs with strong acids or bases; sorbitan esters are stable in weak acids or bases. Sorbitan esters should be stored in a well-closed container in a cool, dry place.

16. 16 Cetrimide Sodium Lauryl Sulfate (SLS) Sorbitan Esters (Sorbitan Fatty Acid Esters) Safety If ingested orally, cetrimide and other quaternary ammonium compounds can cause nausea, vomiting, muscle paralysis, CNS depression, and hypotension; concentrated solutions may cause esophageal damage and necrosis . used topically – concentrated solution - cause burns. irritation to the skin, eyes, mucous membranes, upper respiratory tract, and stomach. prolonged exposure to dilute solutions - drying and cracking of the skin, contact dermatitis may develop. not used in iv preparations for humans. nontoxic and nonirritant materials. When heated to decomposition, the sorbitan esters emit acrid smoke and irritating fumes. Very mildly toxic by ingestion.

17. 17 Cetrimide Sodium Lauryl Sulfate (SLS) Sorbitan Esters (Sorbitan Fatty Acid Esters) Regulatory Status Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients . Included in list of ‘Existing Active Substances’ on the market in the Europe, and is registered according to REACH regulation. Cetrimide is not present in any approved product in the USA. Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients . Included in the FDA Inactive Ingredients Database (dental preparations; oral capsules, suspensions, and tablets; topical and vaginal preparations Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients. Included in the FDA Inactive Ingredients Database (inhalations; IM injections; ophthalmic, oral, topical, and vaginal preparations). Certain sorbitan esters are accepted as food additives in the UK.

18. Lecithin Nonproprietary Names :- USP-NF : Lecithin Synonyms:- E322 ; egg lecithin; LSC 5050; LSC 6040; mixed soybean phosphatides ; ovolecithin ; Phosal 53 MCT; Phospholipon 100 H; ProKote LSC; soybean lecithin; soybean phospholipids; Sternpur ; vegetable lecithin Functional Category :- Emollient ; emulsifying agent; solubilizing agent. Applications in Pharmaceutical Formulation or Technology:- Also included in IM and IV injections, parenteral nutrition formulations , and topical products such as creams and ointments. Lecithins are also used in suppository bases , to reduce the brittleness of suppositories, and have been investigated for their absorption-enhancing properties in an intranasal insulin formulation . Other studies have indicated that lecithin can protect against alcohol cirrhosis of the liver, lower serum cholesterol levels, and improve mental and physical performance. Used in membranous bilayer of liposome. Therapeutically , lecithin and derivatives have been used as a pulmonary surfactant in the treatment of neonatal respiratory distress syndrome 18

19. Cont… Stability and Storage Conditions :- Lecithins decompose at extreme pH. They are also hygroscopic and subject to microbial degradation. When heated, Lecithins oxidize, darken , and decompose. Temperatures of 160–180 º C will cause degradation within 24 hours. Fluid or waxy lecithin grades should be stored at room temperature or above; temperatures below 10 º C may cause separation. All lecithin grades should be stored in well-closed containers protected from light and oxidation. Purified solid L ecithins should be stored in tightly closed containers at subfreezing temperatures. Incompatibilities :- Incompatible with esterases owing to hydrolysis . Handling Precautions :- Lecithins may be irritant to the eyes; eye protection and gloves are recommended. 19

20. Cont… Safety :- excessive consumption may be harmful, it is highly biocompatible and oral doses of up to 80 g daily have been used therapeutically in the treatment of tardive dyskinesia . When used in topical formulations, lecithin is generally regarded as a nonirritant and non sensitizing material. The Cosmetic Ingredients Review Expert Panel (CIR ) has reviewed lecithin and issued a tentative report revising the safe concentration of the material from 1.95% to 15.0% in rinse-off and leave-in products. Regulatory Status Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations; IM and IV injections; otic preparations; oral capsules, suspensions and tablets ; rectal, topical, and vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 20

21. Poloxamer Nonproprietary Names BP, PhEur, USP-NF : Poloxamers Synonyms :- Lutrol ; Monolan ; Pluronic ; poloxalkol ; poloxamera ; polyethylene– propylene glycol copolymer; polyoxyethylene–polyoxypropylene block copolymer ; Supronic ; Synperonic . Functional Category :- Dispersing agent; emulsifying agent; solubilizing agent; tablet lubricant; wetting agent . Stability and Storage Conditions Poloxamers are stable materials. Aqueous solutions are stable in the presence of acids, alkalis, and metal ions. However, aqueous solutions support mold growth. The bulk material should be stored in a well-closed container in a cool, dry place. Incompatibilities :- Depending on the relative concentrations, poloxamer 188 is incompatible with phenols and parabens 21

22. Cont… Applications in Pharmaceutical Formulation or Technology The polyoxyethylene segment is hydrophilic while the polyoxypropylene segment is hydrophobic. All of the poloxamers are chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture. Therapeutically , poloxamer 188 stool lubricant in the treatment of constipation; it is usually used in combination with a laxative such as danthron. Used in the treatment of kidney stones, and as skin-wound cleansers. Poloxamer 338 and 407 are used in solutions for contact lens care . Handling Precautions :- Eye protection and gloves are recommended . Safety generally regarded as nontoxic and nonirritant materials. Poloxamers are not metabolized in the body. No hemolysis of human blood cells was observed over 18 hours at 25°C, with 0.001–10% w/v poloxamer solutions. Acute animal toxicity data for poloxamer 188 Regulatory Status:- Included in the FDA Inactive Ingredients Database (IV injections; inhalations, ophthalmic preparations; oral powders, solutions, suspensions, and syrups; topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 22

23. Stabilizer 23

24. 1. Anti-microbial agent 24 EXCIPIENTS RANGE EXAMPLE Benzalkonium Chloride 0.02 % w/v Celestone, Soluspan Benzethonium Chloride 0.01% Benadryl Benzyl alcohol 0.75-5 % Dimenhydrinate Injection, USP Chlorobutanol 0.25-0.5 % Codine phosphate m-Cresol 0.1-0.315% Humalog Myristyl gamma picolinium Chloride 0.0195-0.169 % Depo-Provera Paraben methyl 0.05-0.18% Inapsine Paraben propyl 0.005-0.1% Xylocaine Phenol 0.15-0.5% Calcimar 2-Penoxyethanol 0.50% Havrix Phenyl mercuric nitrate 0.001% Antivenin Thimerosal 0.003-0.012% Atgam

25. Benzalkonium Chloride Nonproprietary Names BP, JP, PhEur, USP-NF : Benzalkonium Chloride Synonyms :- Alkylbenzyldimethylammonium chloride; alkyl dimethyl benzyl ammonium chloride; benzalkonii chloridum ; BKC; Hyamine 3500; Pentonium ; Zephiran . Functional Category :- Antimicrobial preservative; antiseptic; disinfectant; solubilizing agent ; wetting agent . Stability and Storage Conditions Benzalkonium chloride is hygroscopic and may be affected by light, air , and metals. Solutions are stable over a wide pH and temperature range. Dilute solutions stored in polyvinyl chloride or polyurethane foam containers may lose antimicrobial activity. The bulk material should be stored in an airtight container, protected from light and contact with metals, in a cool, dry place. 25

26. Cont… Incompatibilities Incompatible with aluminum, anionic surfactants, citrates, cotton, fluorescein , hydrogen peroxide, hypromellose , iodides, kaolin, lanolin , nitrates, nonionic surfactants in high concentration, permanganates , protein, salicylates, silver salts, soaps, sulfonamides, tartrates , zinc oxide, zinc sulfate, some rubber mixes, and some plastic mixes. Benzalkonium chloride has been shown to be adsorbed to various filtering membranes, especially those that are hydrophobic or anionic Handling Precautions Benzalkonium chloride is irritant to the skin and eyes and repeated exposure to the skin may cause hypersensitivity . Concentrated Benzalkonium chloride solutions accidentally spilled on the skin may produce corrosive skin lesions with deep necrosis and scarring, and should be washed immediately with water, followed by soap solutions applied freely. Gloves, eye protection , and suitable protective clothing should be worn. Regulatory Status Included in the FDA Inactive Ingredients Database (inhalations, IM injections , nasal, ophthalmic, otic, and topical preparations). 26

27. Cont… Safety usually nonirritating, nonsensitizing , and is well tolerated in the dilutions normally employed on the skin and mucous membranes. Ototoxicity can occur when benzalkonium chloride is applied to the ear and prolonged contact with the skin can occasionally cause irritation and hypersensitivity. Benzalkonium chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions . Toxicity experiments with rabbits have shown benzalkonium chloride to be harmful to the eye in concentrations higher than that normally used as a preservative. However, the human eye appears to be less affected than the rabbit eye and many ophthalmic products have been formulated with benzalkonium chloride 0.01% w/v as the preservative. Benzalkonium chloride is not suitable for use as a preservative in solutions used for storing and washing hydrophilic soft contact lenses , as the benzalkonium chloride can bind to the lenses and may later produce ocular toxicity when the lenses are worn . Solutions stronger than 0.03% w/v concentration entering the eye require prompt medical attention . 27

28. Chlorobutanol Nonproprietary Names BP, JP, USP-NF : Chlorobutanol PhEur : Chlorobutanol, Anhydrous Synonyms:- Acetone chloroform; anhydrous chlorbutol ; chlorbutanol ; chlorobutanolum anhydricum ; chlorbutol ; chloretone ; Coliquifilm ; Methaform ; Sedaform ; trichloro - tert -butanol; b,b,b-trichloro-tertbutyl alcohol ; trichloro -t-butyl alcohol . Functional Category:- Antimicrobial preservative; plasticizer . Handling Precautions Chlorobutanol may be irritant to the skin, eyes, and mucous membranes. Eye protection and gloves are recommended along with a respirator in poorly ventilated environments. There is a slight fire hazard on exposure to heat or flame 28

29. Cont… Stability:- Chlorobutanol is volatile and readily sublimes. In aqueous solution, degradation to carbon monoxide, acetone and chloride ion is catalyzed by hydroxide ions. Losses of chlorobutanol also occur owing to its volatility, with appreciable amounts being lost during autoclaving; at pH 5 about 30 % of chlorobutanol is lost . Porous containers result in losses from solutions, and polyethylene containers result in rapid loss. Losses of chlorobutanol during autoclaving in polyethylene containers may be reduced by pre-autoclaving the containers in a solution of chlorobutanol ; the containers should then be used immediately. There is also appreciable loss of chlorobutanol through stoppers in parenteral vials. The bulk material should be stored in an airtight container at a temperature of 8–15°C . 29

30. Cont… Incompatibilities Owing to problems associated with sorption, chlorobutanol is incompatible with plastic vials, rubber stoppers, bentonite, magnesium trisilicate , polyethylene, and polyhydroxyethylmethacrylate , which has been used in soft contact lenses . To a lesser extent , carboxymethylcellulose and polysorbate 80 reduce antimicrobial activity by sorption or complex formation . Regulatory Status Included in the FDA Inactive Ingredients Database (IM, IV, and SC injection; inhalations; nasal, otic, ophthalmic, and topical preparations). Labeling must state ‘contains chlorobutanol up to 0.5%.’ Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. In the UK, the maximum concentration of chlorobutanol permitted for use in cosmetics, other than foams, is 0.5%. It is not suitable for use in aerosols. 30

31. Antioxidants Concentration (%w/w) Ascorbic acid 0.02-0.1 Sodium bisulfite 0.1-0.15 Sodium meta bisulfite 0.1-0.15 Sodium formaldehyde sulfoxylate 0.1-0.15 Thiourea 0.005 31 Ascorbic acid ester 0.01-0.15 Butylated hydroxy toluene (BHT) 0.005-0.02 Tocopherols 0.05-0.075 Antioxidants (oil soluble). 2. Anti-Oxidizing agent

32. Alpha Tocopherol Synonym :- Antisterility factor, alpha Tocopherol, fat soluble vitamin. Vitamin E is a generic term used for a group of chemically-similar compounds sharing the tocopherol and tocotrienol structures, which are lipid-soluble; hence, vitamin E is known as a fat-soluble vitamin . Functional Category :- Vitamin E supplement, Antioxidant. Stability :- oxidized by atmospheric oxygen and rapidly by ferric and silver salt. Tocopherol ester are more stable to oxidation than the free tocopherol but are in consequence less effective antioxidant. Storage :- stored under an inert gas, in an air tight container in a cool, dry place and protected from light. 32

33. Incompatibility :- incompatible with peroxide and metal ions, especially iron, copper, silver. It may be absorbed into plastic. Safety :- Tocopherol are well tolerated, although excessive oral intake may cross headache, fatigue, weakness, digestive disturbance and nausea. Prolonged and intensive skin contact may lead to erythema and contact dermatitis. The WHO has set an acceptable daily intake of tocopherol used as an antioxidant at 0.15-2.0 mg/kg body weight Application in Pharmaceutical Formulation:- α Tocopherol Recognized as source of Vitamin. β , δ , γ Tocopherol - more effective as antioxidant. α Tocopherol may be used as efficient plasticizer . d- α Tocopherol used as a non ionic surfactant in oral and injectable formulation 33 Cont…

34. Butylated Hydroxytoluene (BHT) Nonproprietary Names BP: Butylated Hydroxytoluene PhEur: Butylhydroxytoluene USP-NF: Butylated Hydroxytoluene Stability:- Exposure to light, moisture, and heat causes discoloration and a loss of activity Incompatibilities:- I ncompatible with strong oxidizing agents such as peroxides and permanganates. Contact with oxidizing agents may cause spontaneous combustion. Iron salts cause discoloration with loss of activity. Heating with catalytic amounts of acids causes rapid decomposition with the release of the flammable gas isobutene. 34

35. Applications in Pharmaceutical Formulation or Technology BHT has some antiviral activity and has been used therapeutically to treat herpes simplex labialis . Safety BHT is readily absorbed from the git and is metabolized and excreted in the urine mainly as glucuronide conjugates of oxidation products. Although there have been some isolated reports of adverse skin reactions, BHT is generally regarded as nonirritant and non asensitizing at the levels employed as an antioxidant. 35 Cont…

36. Storage :- stored under an inert gas, in an air tight container in a cool, dry place and protected from light Handling Precautions:- Irritant to the eyes and skin and on inhalation. handled in a well-ventilated environment; gloves and eye protection are recommended . Closed containers may explode owing to pressure build-up when exposed to extreme heat. Regulatory Status Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IM and IV injections, nasal sprays , oral capsules and tablets, rectal, topical, and vaginal preparations ). Included in non parenteral medicines licensed in the UK . Included in the Canadian List of Acceptable Non-medicinal Ingredients . 36 For Both Antioxidant

37. 3. Anti-Foaming Agents 37 The formation of foams during manufacturing processes or when reconstituting liquid dosage forms can be undesirable and disruptive. Anti-foaming agents are effective at discouraging the formation of stable foams by lowering surface tension and cohesive binding of the liquid phase . A typical example is Simethicone (polydimethylsiloxane-silicon dioxide), which is used at levels of 1-50ppm.

38. S IMETHICONE Nonproprietary Names BP, PhEur : Simeticone USP: Simethicone Synonyms :- Dow Corning Q7-2243 LVA; Dow Corning Q7-2587; polydimethylsiloxane– silicon dioxide mixture; Sentry Simethicone; simeticonum . Functional category :- Antifoaming agent, water repelling agent, tablet and capsule diluent Stability and storage condition :-simethicone product have tendency for silicone dioxide to settle slightly and containers of simethicone should therefore be shaken thoroughly to ensure uniformity of content before sampling or use. should be stored in cool and dry place away from oxidizing agent. Simethicone can be sterilized by dry heating or autoclaving, with dry heating a minimum 4 hr for 160°C is required. 38

39. Incompatibility :- Not generally compatible with aqueous system and will float like an oil on formulation unless it is first emulsified. Not used in formulation that are very acidic and highly alkaline. Since these condition may have tendency to break the polydimethylsiloxane polymer. Incompatible with oxidizing agent. Handling precaution :- Eye protectant and gloves are recommended Description:- The PhEur 6.0 and USP 32 describe simethicone as a mixture of fully methylated linear siloxane polymers containing repeating units of the formula [–(CH3)2SiO–]n, stabilized with trimethylsiloxy end blocking. units of the formula [(CH3)3 SiO –], and silicon dioxide. 39 Cont…

40. Applications in Pharmaceutical Formulation or Technology Therapeutically , simethicone is included in a number of oral pharmaceutical formulations as an anti flatulent . It is also included in antacid products such as tablets or capsules. In the USA, up to 10 ppm of simethicone may be used in food products. Regulatory Status :- GRAS listed. Included in the FDA Inactive Ingredients Database (oral emulsions, powders, solutions, suspensions, tablets; and rectal and topical preparations). Included in nonparenteral medicines licensed in the UK 40 Cont…

41. 4. Thickening Agents ( Viscosity imparting agents ) Viscosity imparting agents are of two types: a) Viscosity modifier- Viscosity modifiers decrease the viscosity of a liquid to improve pour ability and make it more palatable. b) Viscosity enhancer- Viscosity enhancers increase the viscosity of a liquid to improve pour ability and make it more palatable. Most commonly used viscosity imparting agents are : Hydroxyethyl cellulose, HPMC,MC, PVA, PVP 41

42. Carbomer Nonproprietary Names BP, PhEur : Carbomers USP-NF : Carbomer Note that the USP32–NF27 contains several individual carbomer monographs Synonyms Acrypol; Acritamer; acrylic acid polymer; carbomera; Carbopol; carboxy polymethylene; polyacrylic acid; carboxyvinyl polymer; Pemulen ; Tego Carbomer Functional Category:- Bioadhesive material; controlled-release agent; emulsifying agent; emulsion stabilizer; rheology modifier; stabilizing agent; suspending agent ; tablet binder. Carbomer 951 used as a viscosity-increasing aid in the preparation of multiple emulsion 42

43. Cont… Carbomer having low residuals of ethyl acetate, such as Carbopol 971P NF or Carbopol 974P NF, may be used in oral preparations, in suspensions, capsules or tablets Uses of carbomers Use Concentration (%) Emulsifying agent 0.1–0.5 Gelling agent 0.5–2.0 Suspending agent 0.5–1.0 Tablet binder 0.75–3.0 Controlled-release agent 5.0–30.0 Safety :- carbomer 934P has a low oral toxicity, nontoxic and nonirritant materials, no evidence in humans of hypersensitivity reactions to carbomers Incompatibilities :- Carbomers are discolored by resorcinol and are incompatible with phenol, cationic polymers, strong acids, and high levels of electrolytes, antimicrobial adjuvants, Trace levels of iron and other transition metals can catalytically degrade carbomer dispersions. Carbomers also form pH-dependent complexes with certain polymeric excipients. Adjustment of pH and/or solubility parameter can also work in this situation. 43

44. Stability and Storage Conditions Carbomers are stable, hygroscopic materials that may be heated at temperatures below 104°C for up to 2 hours without affecting their thickening efficiency. However, exposure to excessive temperatures can result in discoloration and reduced stability. Complete decomposition occurs with heating for 30 minutes at 260°C . Dry powder forms of carbomer do not support the growth of molds and fungi . In contrast, microorganisms grow well in unpreserved aqueous dispersions, and therefore an antimicrobial preservative such as 0.1% w/v chlorocresol, 0.18% w/v methyl paraben–0.02% w/v propyl paraben , or 0.1% w/v thimerosal should be added. The addition of certain antimicrobials, such as Benzalkonium chloride or sodium benzoate, in high concentrations (0.1% w/v) can cause cloudiness and a reduction in viscosity of carbomer dispersions. Aqueous gels may be sterilized by autoclaving with minimal changes in viscosity or pH, provided care is taken to exclude oxygen from the system, or by gamma irradiation, although this technique may increase the viscosity of the formulation. At room temperature , carbomer dispersions maintain their viscosity during storage for prolonged periods. Exposure to light causes oxidation that is reflected in a decrease in dispersion viscosity. Stability to light may be improved by the addition of 0.05–0.1% w/v of a water-soluble UV absorber such as benzophenone-2 or benzophenone-4 in combination with 0.05–0.1% w/v edetic acid. Carbomer powder should be stored in an airtight, corrosion resistant container and protected from moisture. The use of glass, plastic , or resin-lined containers is recommended for the storage of formulations containing carbomer. 44

45. Cont… Handling Precautions Excessive dust generation should be minimized to avoid the risk of explosion. Carbomer dust is irritating to the eyes, mucous membranes, and respiratory tract. In the event of eye contact with carbomer dust, saline should be used for irrigation purposes . Gloves, eye protection, and a dust respirator are recommended during handling. A solution of electrolytes (sodium chloride) is recommended for cleaning equipment after processing carbomers. Regulatory Acceptance Included in the FDA Inactive Ingredients Database (oral suspensions, tablets ; ophthalmic, rectal, topical, transdermal preparations; vaginal suppositories). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Nonmedicinal Ingredients . 45

46. Methylcellulose Nonproprietary Names :- BP, JP, PhEur, USP: Methylcellulose Synonyms ;- Benecel ; Cellacol; Culminal MC; E461; Mapolose; Methocel; methylcellulosum ; Metolose ; Tylose ; Viscol . Functional Category:- Coating agent; emulsifying agent; suspending agent; tablet and capsule disintegrant ; tablet binder; viscosity-increasing agent . Handling Precautions Dust may be irritant to the eyes and eye protection should be worn. Use in a well-ventilated area. Excessive dust generation should be avoided to minimize the risk of explosion. Methylcellulose is combustible. Spills of the dry powder or solution should be cleaned up immediately, as the slippery film that forms can be dangerous. 46

47. Cont… Stability and Storage Conditions P owder is stable, although slightly hygroscopic. The bulk material should be stored in an airtight container in a cool, dry place. Solutions of methylcellulose are stable to alkalis and dilute acids at pH 3–11, at RT. At pH > 3, acid-catalyzed hydrolysis of the glucose–glucose linkages occurs and the viscosity of MC solutions is reduced . On heating, solution viscosity is reduced until gel formation occurs at approximately 50 º C. MC solutions are liable to microbial spoilage and antimicrobial preservatives should therefore be used. Solutions may also be sterilized by autoclaving, although this process can decrease the viscosity of a solution. The change in viscosity after autoclaving is related to solution pH. Solutions at pH > 4 had viscosities reduced by more than 20% subsequent to autoclaving . Incompatibilities Complexation of methylcellulose occurs with highly surface-active compounds such as tetracaine and dibutoline sulfate. High concentrations of electrolytes increase the viscosity of methylcellulose mucilages owing to the ‘salting out’ of methylcellulose. With very high concentrations of electrolytes, the methylcellulose may be completely precipitated in the form of a discrete or continuous gel. Methylcellulose is incompatible with strong oxidizing agents. 47

48. Cont… Safety regarded as a nontoxic, non allergenic , and nonirritant material. Following oral consumption, MC is not digested or absorbed and is therefore a non caloric material. Ingestion of excessive amounts of methylcellulose may temporarily increase flatulence and gastrointestinal distension. In the normal individual, oral consumption of large amounts of MC has a laxative action and medium- or high-viscosity grades are therefore used as bulk laxatives. Esophageal obstruction may occur if MC is swallowed with an insufficient quantity of liquid. Consumption of large quantities of MC may additionally interfere with the normal absorption of some minerals. MC is considered to be toxic by the intraperitoneal route of administration . Regulatory Status GRAS listed. Accepted as a food additive in the USA, Europe and Japan. Included in the FDA Inactive Ingredients Database (sublingual tablets; IM injections; intrasynovial injections; nasal preparations; ophthalmic preparations; oral capsules, oral suspensions, and oral tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients. Reportedin the EPA TSCA inventory. 48

49. Quality Control Test 49

50. EMULSIFYING POWER OF SURFACTANTS The emulsifying power measures the ability of a product to help the formation of an emulsion Common method :- The emulsifying power is measured via the production of a standard emulsion and the study of its stability through visual observation. For R&D tests, the concentration and the nature of the surfactant are the only parameters to change. In quality control, the formulation remains the same but the production batch of the surfactant varies. The efficiency of the surfactant corresponds to the measurement of the stability of the emulsion compared to a reference emulsion. The test takes more time if the surfactant is efficient as the emulsion is more stable than the reference. Stability tests are generally accelerated by storing the emulsions at high temperature (40 to 50°C) but they can take a couple of days. The quality control of a production of surfactant can therefore take a few days, holding back the distribution of the batches. 50

51. FOAMABILITY OF SURFACTANTS The foamability measures the ability of a product to form foam. Common method : Various methods exist to determine the quantity of foam formed by a surfactant. Among them is the Ross-Miles method, which consists of a given surfactant solution falling from a set height into the same surfactant solution, hence creating foam. The height and the stability of the foam over time are visually assessed. In the case of surfactant with a low foamability or anti-foam products, the recommended method is the agitation of the surfactant solution with a turbine agitator during a set time and the measurement of the amount of foam created after pouring the solution in a volumetric cylinder. In both cases the measurements are visual. The stability tests of the foam are done by measuring the foam at set times. The control of the foamability is done through visual methods that are tedious and quite subjective. 51

52. DISPERSING POWER OF SURFACTANTS The dispersing power measures the ability of a product to help the formation of a dispersion. Common method : The dispersing power is measured by controlling and comparing the stability of a suspension depending on the concentration and the nature of the surfactant, as for emulsions. This test is usually done by a visual observation of the sedimentation of the product analysed , which can get tricky depending on the opacity of the system. Moreover, particle size measurements, which are commonly used, can lead to artefacts due to the high dilution taken place during the analysis. The control of the dispersing efficiency is often left to visual inspection and comparison with a reference dispersion. This test takes even more time if the surfactant is efficient. 52

53. Reference Handbook of Pharmaceutical Excipients, sixth edition, edited by Raymond C Rowe, Paul J Sheskey and M arian E. Quinn http ://www.titanex.com.tw/webc/images/pdf/AND-TLab-surfactant.pdf 53

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