Ascorbic Acid — 1 Nonproprietary Names BP: Ascorbic acid JP: Ascorbic acid PhEur: Acidum ascorbicum USP: Ascorbic acid 2 Synonyms C-97; cevitamic acid; 2,3-didehydro-L-threo-hexono-1,4-lac- tone; E300; 3-oxo-t-gulofuranolactone, enol form; vitamin C. 3 Chemical Name and CAS Registry Number Lt }-Ascorbic acid [50-81-7] 4 Empirical Formula and Molecular Weight CoHsOg 176.13 5 Structural Formula Ho HO" ‘OH 6 Functional Category Antioxidant; therapeutic agent. 7 Applications in Pharmaceutical Formulation or Technology Ascorbic acid is used as an antioxidant in aqueous pharma- ceutical formulations at a concentration of 0.01-0.1% wiv. Ascorbic acid has been used to adjust the pH of solutions for injection, and as an adjunct for oral liquids. Iris also widely used in foods as an antioxidant. Ascorbic acid has also proven useful as a stabilizing agent in mixed micelles containing, tetrazepam.(") 8 Description Ascorbic acid occurs as a white to light-yellow-colored, nonhygroscopic, adorless, crystalline powder or colorless crystals with a sharp, acidic caste. It gradually darkens in color upon exposure to light. 9 Pharmacopeiel Specifications See Table 1. Table I: Pharmacopeial specifications for ascorbic acid. See oe eee Test JP 2001 PhEwr 2005 USP 28 identification + + + Characters = + = Specific olotion +20.5"to 20.510 +205 (10% w/v solaion) 4 21.5° 421.5" +215: Residue enignition <0.10% — — <0.1% pH 2225 21-26 = Sulfted ash = <0.1% - Copper 7 <5ppm = Hoavy metals <20ppm << 10pm =< 0.002% loss on drying §—<0.20% — - ron = <2ppm = Oral acid - + - Appearance of + + - tolation Organic volaile — — - + ior 99.0% 99.0-100.5% 99.0-100.5% 10 Typical Properties Acidity/alkalinity: pH = 2.1-2.6 (5% w/v aqueous solution) Density (bulk): 0,7-0.9 gem: for crystalline material; 0.5-0.7 pfem for powder, Density (particle): 1.65 g/cm? Density (tapped): 1.0-1.2gfem: for crystalline materials 0.9-1.1 plem’ for powder. Density (true): 1.688 g/cm? Dissociation constant: PK yi = 4.175 Melting point: 190°C (with decomposition) Moisture content: 0.1% w/w Solubility: see Table Il. Table It: Solubility of ascorbie acid Solvent Solubility at 20°C Chloroform Practically insoluble Ethancl Vin 50 Ethanol (95%) Vin 25 Ether Practically insoluble Fixed oils Practically insoluble Giycerin Vin 1000 Propylene glycol Vin 20 Woler Vin 3.5suman diet, with 40™E ca ha hie Mf ieawever, these, figures. 3° ‘controversi 1 tos. oan 130 or 2s0.me dal ee ehough such ring doses ne inv bo bon SHEET red to Be potently adroit i hen sued Pe daly ere nom , ee ty abowe soome of ascorbic 2d SAN abso ahowt ie kelnys: are fy cam vediney exceed BY f ree wth any excess ammed ine her exsroitesting) gs) sei een report 8 8 Se ac ore ene anon ae WHO has sean eee ty ate, as antioxidants if Orhan 0 Ot Prod, at up to 1S e/g naturally present in food. oats! na LD (mouse, IV: 3.37 eke so (mouse, oral LD ( me Dee (eat, oral) 11 to ifingested in large quantities and Ascorbic acdmay ben Observe normal Precautions may be imraning ireumstances and quantity of, mare aporoprite f° Pecuon and ruber of plastic gloves #6 recommended. 16 Regulatory Status . ‘Accepted for use as a food additive in Europe. feed redients Guide (inhlations, Inde in the FDA Iacive Ingredients Gu vans, ofal capsules, suspensions, tablets, topical prepars- tons and ippostores- Included in medicines licensed in the Ug" tncluded’ in the Canadian List of Acceptable Non- medicinal Ingredients. 17. Related Substances “Ascorbyl palmitate; erythorbic acid; sodium ascorbate. 18 Comments Many dosage forms for ascorbic acid have been developed for its administration to patients, including. ‘microencapsulation.("”” 'A specification for ascorbic acid is contained in the Food Chemicals Codex (FCC). The EINECS number for ascorbic acid is 200-066-2, 19 Specific References 1. Haramad MA, Muller BW, Solubility and stability of tetrazepar in ined mitelles. Eur Pharm Sai 1998; 7-49-55. 0 + Haamala BR Sablty of ascorbic acid. STP Pharma 1985; } Touitow E, Gilhar D, Alhaique F, et al. Ascorbic acid in solution: bathochromic shift in dilation lations Int J eiotat: in dilution and degradation, Int J tha SA, Lotter AP du Preez JFL. DSC screening for d / , . 3 drug-d irons in plpharmaceaicalinendd for the alleviation of the symptoms of colds and fu, Drag Dev Ind Pharm 1987; 13: Mura R Berinets GP, Faucei a2 p Fauci MT, et al. Differential rimetry in companibility testing of picotamide with pharmas cipiems. Thermochim Acta 1998; 321: §9-65, angled ae varMmaccur, 6 Krishnan aS hengenine hyde mac 1320.29 oes fo fe epee ae of the panel 2, te ca age Stipe Reb Be eee to roost ices the tenth edition of the 8 Sabor poned Commianion LI races, Net necommended Dietary ATS" a eae Pr fv cn, min thesaPY Mog; 27: 148-170- 0 St Eppes nd Lon ee ei a tablets: | A” exicological evaluation of cxf iin. additives 13 FRONT ae Pe 1 principles and ‘of specifications, it em report of ERONUHIO expert commie on food World Health Organ Tech ee lt epee final en, 14 ea Sy gh 20 a ned ‘3002; 242: 329-334. 20 General References ramovici B, Molard F, Seguin By fee ableabiiy diferent grades of Pharma 1987; 3: 16~ Ne Faencing the stability of ascorbic acid in tor bg ici nuevoon oreo J Clin Hose Pharm 19849: 75-43 rene a Bl Correlation between the dsinteraion in 9-242. vi Moist, London: Royal Society of Chemistry, 1991, Hu f Wang Hi, Wa X. Effects of different adhesives on the stability Figure buccal tablets. Zhejiang Yike Daxue Xuebao 19975: RDAs, Food ang National Researeh, 104k eda. Washing Gromenil JC. Comparative study of in C [in French], STP Almassian. B. Development of @ parent ‘stigational anticancer drug, 3-amino semicarbazone. Pharm Dev Tec 0. Krishna G, Mao J, formulation of an inves jine-2-carboxaldehyde thio: 1999; 4: 71-80. ‘Nebuloni M, Pifferi G, Munna E. studies of a lyophilized form of an antibiotic. 135: 94-100. Pinsuwan S, Alvarez-Nunez FA, et al. Degradation kinetics dedimethylamino sancycline, a new anti-tumor agent, in aq solutions. Int J Pharm 1999; 181: 31-40. Saleh SI, Stamm A. Evaluation of some directly compressible L-as acid forms. STP Pharma 1988; 4: 10-14. Saleh $1, Stamm A, Contribution to the preparation of a ¢ ‘compressible ascorbic acid granular form: comparison of g prepared by three granulation methods and evaluation « corresponding tablets. STP Pharma 1988; 4: 182-187. Seta Y, Higuchi F, Otsuka T,, et al. Preparation and pharmac evaluation of Captopril sustained-release dosage forms us semisolid matrix. Int J Pharm 1988; 41: 255-262, ‘Thermal analysis in preformuls Boll Chim Farm | 21° Authors AH Kibbe, 22. Date of Revision 12 August 2005,Nein eet Properties Aciditylkalinitys yyy : = 4 7.0 For 3 10% wiv aqu 'PFeSSion char “es ary, deeastSTstics and the degree o j Pending upon the parts ice ity (bulk: 0.445 Density (tapped); Density (true): 1 Flowability: fags Particle size and praracteFs tend t0 be pad Btade of sors depending upon the Doon fo TROT aed Fen, On : ler grades ry us + While gran: ‘ranular grades have good Heat of solution valar Melting points |! Ws (26.5 cag) Anhydrous form: Gamma polymosphe os t2:C "morph: Metastable form 33 Table tt: Tost Identification z Characters . + : Acidity or alkalinity + - pH 2 - = Appearance of solution : asz0 Arsenic 1.39pm — Chloride 0.005% — es Sofote 0.008% — store fectilty — 20)Sem+ = Ghose : <20)Sem! — Hoavy metals = ead - - = uecre 400-80 0% = - t Wiiieced 40.2505 — aa = katie oc o-15.0% 5 5 Folmileic acid — 292.0% 4H Sime 70% > ” shox 7m - Woosoon e608 ~ S80. tnlonic ocd = . 850% Undecocid 3.0% - <4.0% ‘able IK: Typical properties of selected polysorbotes. Potrero WB vlve Specie gravity Viscosity oe o25.C faPas) Polyorboie20 «67 400 Popeboe 21 «133k 500 Pelee 40-1560 1.08 500 Fohorboe 60149 VN 00 Polysorbate 619.6 108 Soh Peyvoioees «10S 1.05 Sod PeaoricteBO «1501.08, rs Folperbate 81100 — 450 Felco 85 «1101.00 300 Polysorbate 120 14.9 7 Table X: Soils of slated polysotbotes in various solvents ‘Sum lth conten of panied sare acids 40.0% 10 Typical Properties Acid value: see Table VIIL. Acidity/alkalinity: pH = 6.0-8.0 for solution. Flash point: 149°C HLB value: see Table IX. Hydroxyl value: see Table VII. Moisture content: see Table vill. Saponification value: see Table VIIL Solubility: see Table X. Specific gravity: see Table IX. ‘Surface tension: for 0.1% wiy solutions, see Viscosity (dynamic): see Table IX. ‘Table XL. Table Vil: Typicol properties of selected palysorbotes Hydroxy! ‘Soponifcaion valve Moisture content Polysorbate 20 2.0 we 5 30 Polysorbate 21 3.0 2 105 30 Pelorbete 40-20 agg 3.0 Polysorbate 60 2.0 oy 200 3.0 Polysorbate 61 2.0 ego 30 Polysorbate 65 2.0 j5-90 3° Polysorbate 80 2.0 134-150 3° Polysorbate 81-20. 0 Polysorbate 85 2.0 Polysorbate 120 2.0 5% wily aqueous Pobysorbote Polyorbote20 St an os ot Polysorbate 40S ' Polyorboe60 = SI Polysorbate 61S Polysorbate 65 SW SW ow Polysorbate 80S Polyorboe 8} = SS st Polysorbate 85S Polysorbaie 120 S woowsoree” fl ‘p daprse =e Sse, =, W = on worm oble Xi Surtoce tension of related polyorbates, Polysorbate Surface tension ot 20 C (mN/en) Polysorbate 21 347 Polysorbate 40 as Polysorbate 60 425 Polysorbate 61 45 Polysorbate 80 425 Polysorbate 85 410 11 Stability and Storage Conditions Polysorhates are stable co clstrlytes and weak acs of Forder gradual saponification occurs with strons acids an aees BThe olkic acid esters are sensitive © oxidation Feieeorbates are hygroscopic and should be examined f water content prior fo use lana dried if necessary. Al. seareon with other polyoxyettylene suriaetants soa ean ead to te formation of peroxides. prolineSod; Sodium Hyaluronate 1 Nonproprietary Nam, BP: Sodium hyaluronate PhEur: Natri hyaluronss 2 Synonyms Hyaluronan hyaluronate sodium; RITA Ha c A Cac, 4 Empirical Formula and Molecular (CiaHlzoNO11Na), ‘Weight (401.3)n 5 Structural Formula “~ a 6 Functional Category Humectant; lubricant; matrix for sustained release, 7 Applications in Pharmaceutical Formulation or Technology Sodium hyaluronate is the predominant form of hyaluronic acid at physiological pH. The name hyaluronan is uss} Wit the polysaccharide is mentioned in general ferms) an liternture the terms hyaluronic acid and sodium hyalu are used interchangeably. caitiake Hyal aed therapeutically co teat ostcoarthens arama aeerive ean fr artic a Crosslinked hyaluronan a systems.'*) _— Fiyaiuroman is the most come tr and is knows y minoglycan in the Bum anions roche er a where hyaluronan solutions ha , » hncing the Seluar gptake of complexes Ts wet gee ates . ty and eerention ime useful fr he attache ra, whi Pe engneting ad GT ln? for use in issue mon negatively charged systems" i also has important applications in the fields of vascosurgery and vascosupplementation.*” 8 Description ‘The PhEur 2005 describes sodium hyaluronate as the sodium sale of hyaluronic acid, a glyeosaminoglyean consisting of 0: slucuronic acid and N-aceryl-o-glucosamine disaccharide units Sodium hyaluronate aceurs as white to off-white powder oF sramules. Tes very hygroscopic. 9 Pharmacopeial Specifications See Table I. Table i: Phormocopeicl specification for sodium hyaluroncle. Test PhEur 2005 CChoraciers . Identification + ‘Appoarance of solution + oH 50-85 Inne viscosity + Sulloied gleoraminoglycons = 1% ‘Nude acids <05 Proiin <0.3%0" Chlvidos <05% Iron <80 ppm oss on drying <20.0% ‘Microbiol contamination <10°/g Baceral endotoxins £0.051U/mg® Assoy 95.0-105.0% 501 poet ange ems £0 5/na for pa beg om 10 Typical Properties Acidity/alkalinity: pH = 5.0-8.5 (0.5% wiv aqueous solution Solubility: soluble in water, although speed of dissolutior depends upon molecular weight (higher molecular weight are slower to dissolve, although this process can be increase by gentle agitation. Slightly soluble in mixtures of orgari solvents with water” 11 Stability and Storage Conditions Sodium hyaluronate should he stored in a cook, dry place tightly sealed containers. The powder is stable for three years Stored in unopened containers. 12 Incompatibilities302 Glycerin 10 Typical Properties Boiling point: 290°C (with decomposition) Density: 1.2656 plem? at 15°C 1.2636 gem? at 20°C 12620 gem? at 25°C Flach point: 176°C (open cup) Freezing point: see Table I Hygroscopicity: hygroscopi Melting point: 17.8°C Osmolarity: a 2.6% viv aqueous solution is isoosmotic with Refractive index: ali = 1.4758; were = 1.4730. ity: see Table IV. ity: see Table V. 3.4 mN/m (63.4 dynesiem) at 20°C, 3.17 Gir = 1) Viscosity (dynamic: see Table VI. Table Il; Freezing points of aqueous glycerin solutions Concentration of aqueous Freezing pint () lycerin solution [w/w] 100 “16 200 48 30.0 95 400 “15.4 50.0 2 60.0 “347 667 ~465 80.0 -20.3 90.0 -16 Table IV: Soluilly of glycerin. Solvent Solubility at 20°C Acetone Slighily soluble Benzene Practcaly insoluble Chloroform Proctcolly insoluble Ethanol (95%) Soluble Ehhor Vin 500 Ethyl ocetote Vin Methanol Soluble Oiis Practically insoluble Woter Soluble aS Table Vi Specific growiy of aycern, Concentration of aqueous Specific gravity at 20°C lycern solution [% w/w) 10 1.024 20 1049 30 1.075 40 1103 50 1.128 60 1.156 ss Table Vi: _ Viscosity (dynamic) of aqueous alcerin solutions, Liaweoed Viscosity ot 20°C Ime 3) lycorin solution Oa w/w) - 5 ~ 1143 ‘ vit 3 2.095 3 6.05 7 10.96 4 22.94 no m0 83 a 11 Stability and Storage Conditions ic Pure glycerin is not prone to oxidation, ‘Jer ordinary storage conditions but it ‘with the evolution of toxic acrolein, ethanol (95%), and propylene Glycerin is hygroscopi by the atmosphere un decomposes on heating, Mixtures of glycerin with water, co are chemically stable. eer ny ersalze i stored 3 low temperatures; the cexystals do not melt until warmed to 20°C Glycerin should be stored in an airtight container, in a cool, dry place. 12 Incompatibilities i may € mixed with strong oxidizing agents SST ania londe pera chlorate, or petssiom permanganate. In dilute solution, the reaction proceeds at a Slower rate with several oxidation products being formed. Black discoloration of glycerin occurs in the presence of light, or on contact with zinc oxide or basic bismuth nitrate, ‘An iron contaminant in glycerin is responsible for the darkening in color of mixtures containing phenols, salicylates, and tannin, Glycerin forms a boric acid complex, glyceroboric acid, that is a stronger acid than boric acid. 13. Method of Manufacture Glycerin is mainly obtained from oils and fats as a by-product in the manufacture of soaps and fatty acids. It may also be obtained from natural sources by fermentation of, for example, sugar beet molasses in the presence of large quantities of sodium sulfite. Synthetically, glycerin may be prepared by the chlorination and saponification of propylene. 14. Safety Glycerin is used in a fide variet wide variety of pharmaceutical formulations including oral, ophthalmic, parenteral nal Iphical Preparations. Adverse effects are manly de wo che dehydrating properties of gycerin Oral doses are demulcent and mild Psi lent ang ly laxative in action arte loses may produce headache, thiee wee are e lycemia. The therapeutic Parenteral administration of e ee glycerin doses, 70-80 g over 30-60 minutes in adults ‘oral ill Pressure, may induce hemolysie, herwsalaty nuria, and renal. failure.!®! ‘dministration has a lu administration ha: SlowerIsopropyl Myristate 1 Nonproprietary Names BP: Isopropyl myristate PhEur: Isopropylis myristas USPNF: Isopropyl myristate 2 Synonyms Crodamol IPM; Estol 1PM: Kessco IPM 95; Lexol IPM-NF. Rita IPM; Stepan IPM; Tegosoft Mi rmethylethyl ester; Waglino! 6014. isopropyl ester of myristic acid myristic acid isopropyl ester; tetradecanoic acid, 1 3° Chemical Nome and CAS Registry Number 1-Methylethy! tetradecanoate [1 10-27-0] 4 Empirical Formula and Molecular Weight CisHyO2 2705 5 Structural Formula r DE _ ry 6 Functional Category Emollient; oleaginous vehicle; skin penetrant; solvent. 7 Applications in Pharmaceutical Formulation or Technology that is absorbed myristate is a nongreasy emollient semisolid bases Isopropyl ‘a component of realy by the skin. tis used 2 ial cs solvent for many substances, applied topically: Applications in topical pharmaceutical and cosmetic formuls carn pclade hath oil; make-up: hair and nal care products ss loions lip products; shaving products; skin lubricants Jecdosnnts; otic suspensions; and vaginal creams sce Table | For cramp, isopropyl myristate is 2 self emulsifying compo: reraea propane cold cream formulas which is suitable for rertye a vehicle for drugs or dermatological actives; it is also eee gumetcaly in stable mixtutes of water and glycerol Thopropyl myristate is used as a penetration enhancer for rranclermal formulations and has been used iq, conjunction oe therapeutic ultrasound and iontophoresis.” It has been sae ae qateroil gel profonges-telease emulsion and in tc inictoemufsions opeopsl mistae has aso been wsed aaraam ahcre, and sigaiicanty increased the release of dru rant etoposide loaded microspheres Teble Uses of iopropyl mitt Concentration (%) Use eee Derergent — 0,003-0.03 One pension 2024 Pasfumes Ce ions 2.02 ‘ 20-98 Topical eros 200 8 Description Isopropyl myristate is liquid of low viscosity that. cesrersof propan-2-0l and satura Sede, principally myristi acid. ‘clear, colorless, practically odorless congeats at about $C. Itconsists of ed high molecular weight fey 9 Pharmacopeial Specifications ‘See Table It emocopeial specications fr isopropyl myrsoe Table i: Ph Test PhEur 2005 ——_USPNF 29 dontfcation + + A of solution + 2 Speclc gravity - 0.846-0.854 Relative density ~0,953 0.846-0.854 Refractive index 16434-1437 1.432-1.436 Residue on ignition <0.1% <0.1% Acid value 51.0 <1.0 Sopenifcaion volve 202-212 202-212 lodine v 1.0 <10 ‘Appearance of solution + - Viscosity S-6mPos = Water 0.1% = Organic voloile impurities Assay (os Ci2Hs40r) 390.0% 10. Typical Properties Boiling point: 140.2°C at 266 Pa (2 mmblg) Flash point: 153.5°C (closed cup) Freezing point: =5°C Solubility: soluble in acetone, chloroform, ethanol (98%) ethyt acetate, fats fatty alcohols, fixed ols, liquid hydrocarbons tle, and was, isles many wanes, hoa 0” _ lanolin. Practically insole in glycerin, glycols and wate vase jnamereoapas (esata 11 Stability and Storage Conditions Isopropyl myristate i nt to oxic: mie i resistant to oxidation and hydrolysis 3m des nor bscome rancid I shouldbe stored in "wel csed ince in a cool, dry place and protected from light.1 Nonproprietary Names BP: Sorbitol IP. DSorbitol PhEur: Sorbitolum LUSPNF: Sorbitol 2 Synonyms C*PharmSorbidex; £420; 1,2,3,4,5,6-hexanehexol; Liponic 70-NC; Liponie 76-NC; Meritol; Neosorb; sorbite; D-sorbitol; Sorbitol Instant; Sorbogem. 3 Chemical Name and CAS Registry Number D-Ghucitol {50-70-4] 4 Empirical Formula and Molecular Weight CoHisOg 182.17 5 Structural Formula 6 Functional Category Humectants plasticizer; sweetening, agent; tablet and capsule diluent. 7 Applications in Pharmaceutical Formulation ‘or Technology Sorbitol is widely used as an excipient in pharmaceutical formulations. It is also used extensively in cosmetics and food products; see Table I. Sorbitol is used as a diluent in tablet formulations pre- pared by cither wet granulation or direct compression.('~" It is particularly useful in chewable tablets owing co its pleasant, sweet taste and cooling sensation. In capsule formulations itis used as a plasticizer for gelatin. Sorbitol has been used as a plasticizer in film formulations." In liquid preparations” sorbitol is used asa vehicle in sugar- fece formulations and as a stabilizer for drug,” viramin,!!°=" and antacid suspensions. Ithas also been shown to be a suitable carrier to enhance the in vitro dissolution rate of indometa- cin." In syrups it is effective in preventing crystallization round the cap of bottles. Sorbitol is additionally used in injectable''*! and topical preparations and therapeutically as an ‘osmotic laxative. Sorbitol may also be used analytically as a marker for assessing liver blood flow." es of sorbitol teblek_Ussse Concentration (3 on ~ - as Homectoo! 15, IM injocions| . toa ‘Moisture control agent in table 310, ‘Oral salons % Oral suspensions 2 iar for gelatin ond calulove . an of cop locking’ in syrups ond shrine 15-30 Substitute for glycerin and propylene glyco 3530 Tablet binder ond filer Toothpastes 20-0 Topical emulsions Topical emulsions 8 Description Sorbitol is p-glucitol. It is a hexahydric alcohol related to mannose and is isomeric with mannitol. Sorbital occurs as an odorless, white or almost colorless, ‘crystalline, hygroscopic powder. Four crystalline polymorphs ‘and one amorphous form of sorbitol have been identified that have slightly different physical properties, et, melting point.” Sorbitol is available in a wide range of grades and polymorphic forms such as granules, flakes, or pellets that tend to cake less than the powdered form and have more desirable compression characteristics. Sorbitol has a pleasant, cooling, sweet taste and has approximately 50-60% of the sweetness of sucrose, SEM: 1 Excipient: Sorbitol ‘Manufacturer: SPL Pharma Lot Nos 522468 ‘Manifieation; 100% 9 Pharmacopeial Specifications See Table I,Propylene Glycol a 1 Nonproprietary Names BP: Propylene glycol ropylene glycol PhEue: Propylenglycolum USP: Propylene glycol 2° Synonyms 1,2-Dihydroxypropane; E1520; 2-hydroxypropanal; methy theme glyco methyl glycol: propane-12-diok " 3. Chemical Name ond CAS Registry Number 1,2-Propanediol [57-556] (“r1,2-Propanediol (4254-14-2] [4141,2-Propanediol (4254-15-3] 4 Empirical Formula and Molecular Weight CHO; 76.09 5) Structural Formula 6 Functional Category Antimicrobial preservative; disinfectants humecta Solvent; stabilizer for vitamins, water-miscible coso 7 Applications in Pharmaceutical Formulation or Technology Propylene glycol has become widely used as a. solvent, extractant, and preservative in a variety of parenteral and fronparenteral pharmaccutical formulations. It is beer general solvent than glycerin and dissolves a wide variety of ‘uch as corticosteroids, phenols, sulfa drugs, ing (A-and D), most alkaloids, and many focal anesthe ‘Asan antise is similar c0 glyce ethanol. Propylene glycol is aqueous film-coating formulation Propylene glycol is also used industry as-a carrice for emulsifiers and as 2 vehi in preference to ethan, since its lack of volaih nore uniform flavor. See Table l icit is simitar to ethanol, and against molds it and only slighcly less effective than mmonly used as a plasticizer in casmeties and in the food ¢ for flavors y provides 2 hows Dosage form __ mot «pico farette Shon, ons ry coxoven! Aerosol slulions Sanne Ora soltions Poronterls Tepicols _ & Description Propylene glycol is a clear, colorless, viscous, practically eee iqued with 3 sweet, slighily acrid taste resembling that of glycerin. 9 Pharmacopeial Specifications ‘See Table Il ‘ble lie Phormacopeiel specification for propylene glycol. ot Phéur 2005 USP 28 ‘Wenticaron + + + Appaoronce - + - Specie gravy —-1.035-1.040 1.035-1.040 1.035-1.097 Aedity + + + Woler 505% <02% = <07% Residue on ignition <0,005% — — <35n9 Sulfoted ash - 500% Chloride <0.007% = 0.007% Sue 0.002% — <0,008% Heowy moiol eSppm 20g/day in adults) should therefor i Sorti ly fermented by oral microorganisms and has litle effect on dental plague pli; hence, its generally considered to be noncariogenie. Sorbitol is generally considered to be more irritating than mannitol. LDso (mouse, IV): 9.48 pkg {Dso (mouse, oral: 17.8 ghkg LD so (rat, IV}: 7.1 pike LDes (rat, SC): 29.6 ghkg 15 Handling Precautions Sorbitol may be harmful be irritant to the eyes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye Protection, gloves, and a dust mask or respirator ate Fecommended. if ingested in great quantities. [t may 16 Regulatory Status GRAS listed. Accepted for use as a food additive in Europe. {Included in the FDA Inactive Ingredients Guide (intra-articular and IM injections; nasal; oral capsules, solutions, suspensions, otaps and tablets; rectal, topical, and vaginal preparations), Included in parenteral and nonparenteral medicines licensed the UK. Included in the Canadian List of Acceptable Nom medicinal Ingeedients 17 Related Substances Maltitol solution; mannitol; sorbitol solution 70%; Sorbitol solution 70% Synonyms: sorbitol liquid; Sorbo. Appearance: a clear, colorless and odorless, xylitol, viscous liquid, olution #8 AM AqUEOLS solution 4, Comments: sorbitol ua Ihydrolyzed starch. For physic sis of serial in wate sltions ai a ore imPas) at index aint ( ¢) 2 Toe e 107s 213838 2 wa 28 1490-130 2 iss 4a ae 1g 0 119791 tale 60 50 Vz 5000 MSZ = 60 1293 110.0 Vase > 2 1330 900.0 1478 18 Comments Sorbitol may be substituted for sucrose to prepare 70-90% wjy net: ant grades of sorbitol, with different poly. sever tricks sie, and er physical characteristics sre tommercially available, e-8-, Neosorb (Roquette Frese), Tyron free grades are also available from some supplies, eoreeerecifeation for sorbitol is contained in the Food Chemieats Codex (FCC). The EINECS number for sorbiel 200-061-5 19 Specific References folokhia AM, Moustafa MA, Gouda MY. Effect of storage * eudsons on the hardness, dednepeon and drug rican eo, some tablet bases. Drug Dev Ind Pharms 1982; 8: 283-292. 2 Bolton S, Atari R. Crystalline sorbitol tablets effect of mixing time and lubricants on manufacturing. Drug Cosmet Ind 194%, 135(3} 44, 46,47, 46,50. 3 DuRoss JW. Modification of the erystalline structure of sorbitol and its cffcts on tableting characteristics, Pharm Technol 138 8(9): 42-53, f 4 Basedow AM, Moschl GA. Sorbitol instant ~ an excipient with unique tablesing properties. Drug Dev Ind Pharm 1986; 12-2061. 2089. 5 Schmidt PC, Vorssch W. Influence of manufacturing method of fillers and binders on their tableting properties: comparison of 8 Sommercially available sorbitols fin German). Pharm Ind 1987; 49: 495-503, © Keogars K, Heinaemacki J, Karjalainen M, etal, Developmentand 20g/day in adults) should therefore be avoided. Sorbitol is not readily fermented by oral microorganisms and bas litle effect on dental plague pH; hence, itis generally considered to be noncariogenic." Sorbitol is generally considered to be more it mannitol LDso (mouse, IV): 9.48 g/kg? LDeo (mouse, oral): 17.8 gikg [Dao (ea, IV): 7.1 ekg [Deo (rar, SC): 29.6 eke, ring than 15 Handling Precautions Sorbitol may be harmful if ingested in great quantities. It may be iritanc 10 the eyes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask or respirator ate recommended. 16 Regulatory Status GRAS listed, Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (intra-articular and IM injections; nasal oral capsules, solutions, suspensions, syrups and tablets; rectal, topical, and vaginal preparations) Included in parenteral and aonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients. 17 Related Substances ‘Malttol solution; mannitol; sorbitol solution 70%; xylitol Sorbitol solution 70% Synonyms: sorbitol liquid; Sorbo. “Appearance: a clear, colorless and odorless, viscous liquid, ion is an aqueous solution hydrolyzed. starch, For phys, sorbitol solv Comments: $01 a ated, partly re cal prope of obi nwo aun dole IV: Physi - oveetroon ot (nPaslat pit at lafe A i ———7ou 12 1348-14 10 az 1365-38 20 nas 1383-80 30 1155 44 1.400 -13.0 ® Mss td 288 50 yo 280 1437S 4 \309=«N0.0 1.458 = x \ ooo tae ee 18 Comments Sorbitol may be substituted for sucrose to prepare 70-90% ii pet al different grades of sorbitol, with different poly. ne tt Se ander phys chrcen mrerFommecially available, eg., Neosorb (Roquerte Freres), Hprogen-fre grades are also available fom some supple, Aeepeciiation. for sorbitol is contained in the Food ‘Chemicals Codex {FCC). The EINECS number for sorbitol is 200-061-5. 19 Specific References Mobthin AM, Moustafa MA, Gouda MW. Ele of sap 1 Metin onthe horas, dsneration and drug reas fey Some tablet bases, Drag Dev ted Pharm: 1982; 8: 283-292, 2 Bree Atanas Chat sorte ele eof ming oon 5 beans on manefactring. Drug Comme nd 198 135(5}: 44, 46, 47, 48, 50. 2 Dalles J. odienion ofthe ceysaline sroctare of sri sateen elctingchraciedos, Phar Teel 18% so, a2-83, 4 Bata AM, Mosel GA, Sorbitol instant ~ an excipient tmgue ableung propre: Dr De ad Phar 138612 206 a8 5. Sehmidt PC, Vorisch W. Influence of manufacturing mahod of filers nd binders on the eeing proper: omparssn of § ommercaly availble sorbitan Germany, Pharm Ind 1987 95505 6 Koga Ky Heinennek J, Kayjohinen M, eal Devopestad charscerztion of aueousamylosech sae arch daperate fain fraton Ear] Pharm Bopbamn 203,362) 215 7 Carvers ME Hoiimdk, J, Krogrs Kye a Solid steal mechanical properties of aqueous chitosan-amylose starch films dloticud with polyols. AAPS Phorm Sa’ Tech 304, (0) 15 8 Daowse RG, Lynch Ml Soritl in phamaceuel qu. Dg Game nd 1962 96 889-091, 13 ct 7,79, 8-8 9 Sahai GR, Guleeh J) Fomulaon ofa sable sod pls oralsapensin of prose penklin 6. Am Phare Ase Pt harm) 1956, 17. BOG-808 10 Bandini ]V Te sabi of ascorbic acid insti Batid med Jie Pharr Asc i 98S 24-258 11 arth BD, Loren IV. Aare stabi sey of a0 ot muliviamsn gid preparation, Ding Standards 198,26 St Mande H, Nobody raha Ne eta. Pysuoci characterization of solid dispersions of indometacin with PEG 6000, Ny 5 none sorb, den sal Eo REI Drug Dev ed Pharm 300% 3003} 308317,PhEur: Sorbitotum USPNF: Sorbitol 2 Synonyms C*PharmSorbidex; E420; 1,2,3,4,5,6-hexanchexol, Lipori 70-NC; Liponic 76-NC; Mertol; Neosortx sorbite; 0-sorbitok: Sorbitol instant; Sorbogem. 3. Chemical Name and CAS Registry Number -Glucitol {50-70-4] 4 Empirical Formula and Molecular Weight CHisO, 18217 5) Structural Formula 6 Functional Category plasticizer; sweetening agent; tablet and capsule 7 Applications in Pharmaceutical Formulation ‘or Technology Sorbitol is widely used as an excipient in pharmaceutical formulations. Ic is also used extensively in cosmetics and food products; see Table L Sorbitol is used as a diluent in tablet formulations, pre- pared by either wet granulation oF direct compression." It is, Particularly useful in chewable tablets owing to its pleasant, Sweet taste and cooling sensation. In capsule formulations i is used as a plasticizer for gelatin, Sorbitol has been used as a plasticizer in film formulations.°"" In liquid preparations” sorbitol is used asa vehicle in sugar free formulations and as a stabilizer for drug,®” vitamin"! and antacid suspensions. Ithas also been shown to be a suitable to enhance the it vitro dissolution rate of indometa- In syrups ic is effective in preventing crystallization around the cap of boules. Sorbitol is additionally used in injectable" and topical preparations and therapeutically as an osmotic laxative Sorbitol may also be used analytically as a marker for assessing liver blood flow." te User of obi — Toe anc cj ae fumecion! 3.15 tena 5. injections to Newt cone 20, ‘Oro oltion® x Pica er glin and collose S20, ri cop locking’ in syrups ond aiis 15°30 Petar yetin ond propyene heal 25-90 {let binder and filer 25-90 Teokhpasies 20. Topical emlsions Topic emlsions 8 Description Sorbitol is Degluctol. It is a hexahydric alcohol elated to mannose and is isomeric with mannitol. ‘Sorbitol occurs a8 an Lee white or almost cles, valline, hygroscopic powder. Four crystalline polymorphs Sarina Form of sorbitol have been identified tht have slightly different physical properties, eg, melting point!” Sorbitol is available in a wide range of grades and polymorphic Torms such as granules, flakes, oF pellets that tend to cake les than the powdered form and have more desirable compression characteristics, Sorbitol has a pleasant, cooling, sweet taste and has approximately 50-60% of the sweetness of sucrose. SEM: Excipient: Sorbicol Manufacturer: SPL Phaera Lot Now 522478 ‘Maguification: 100% 9 Pharmacopeial Specifications See TabletSEM: 1 Esciprent: Ascorbic aid USP (fine powder) Manufacturer: her Ved lat Nos 9A:NG92040-C0 146 Mupifcaton: 120% Voltage: 202V SEM: 2 Exciptent: Ascorbic acid USP (ine powder) Manufacture: Pier Led Lot No. 94-30G92040-CO 146 Mageificaton: 600% Voltage: 20kV Ascorbic Acid 49 SEM: 3 Excopint: Aronbc acd USP (fine granular] Manufacturers Per Ld Lot Ning 94-2640] 280-CO 148 Magnification: 120% olage: 20k 11. Stability and Storage Conditions In powder form, ascorbic acid is relatively stable in ar In the absence of oxygen and other oxidizing agents itis also heat stable. Ascorbic acd is unstable in solution, especially alkaline solution, readily undergoing oxidation on exposure to the ait” The oxidation process is accelerated by light and heat and is catalyzed by traces of copper and iron. Ascorbic acid Solutions exhibit maximom stability at about pH 5.4 Solutions may be sterilized by filtration. “The bulk material should be stored in a wellclosed ‘nonmetallic container, protected from light, in cool, dy place. 12. Incompatibilities Incompatible with alkalis, heavy metal ions, especially copper aand_iron, oxidiing materials, methenamine, phenylephrine hydrochloride, pyriamine maleate, salicylamide, sodium nitcte, sodium salicylate, theobromine salicylate, and picot- amide.” Additionally, ascorbic acid has beca found 0 interfere with certain colorimetric assays by reducing the intensity of the color produced." 13° Methed of Manufacture Ascorbic acid is prepared synthetically or extracted from various vegetable sources in which it occurs naturally, such as ‘ose hips, blackcurrant, che juice of citrus fruits, andthe ripe fruit of Capsicum annuum L. A common synthetic procedure involves the hydrogenation of D-glucose to b-sorbito, followed by oxidation using Acetobacter suboxydans to form L-sorbose. A-carboxyl group is then added at Ci by air oxidation of the diacetone derivative of t-sorbose and the resulting diacetone-2 keto-t-gulonic acid is converted to L-ascorbic acid by heating with hydrochloric acid.shaema RG. ation wae, Shane; Sharma RC. Patna wy tienen eit ORGS asta serge eis Soar Rta 7 Bape tn tae tence los tft oy spline ned Met helt fa rep ae A Sil Ss 81 Si rion of the RDAS, Food a a Hdeomimice on the tenn edition of te RDA Feed ang Come sie Allawances, 10s ed. Washi a a pon, 20 ln tate Pharmaceutical Press, 2001: 227-233. art ign bent Assoc PAS IOT 253-256. Sect rr fe Te Rap iota Ne 14 ee aR ed. Sax's Dangerous Properties of Industrial Mater, ith edn. New York: Wiley, 2004: SOS solbsheas 20 General References Gromenil JC. Comparative study of ramovici B, Molard F, Seguin B, t seetbleesblity of diferenc grades of vitamin C [in French), Srp Pharma 1987; 3: 16-22. " lw actors influencing the stability of ascorbic acid in to nice entre ish arg ee reattIN, Wolkof{ BI. Correlation between the disintegration in Bhagat he bicavalbiliy ‘of vitamin C tablets. Pharm Res 1993; 1 239-242. Davies MB, Austin J, Partridge DA. Vitamin C—Its Chemistry a ‘Biochemistry. London: Royal Society of Chemistry, 1991. Ho F Wang fi, Wo X. Effects of different adhesives onthe stability vitamin C buccal tablets. Zhejiang Yike Daxue Xuebao 1997, 108-110. Krishna G, Mao J, Almassian B. Development of a paren formulation of an investigational anticancer drug, 3-amino idine-2-carboxaldehyde thiosemicarbazone. Pharm Dev Tec 1999, 4: 71-80. ‘Nebuloni M, Pifferi G, Munna E. Thermal analysis in preformul studies of a lyophilized form of an antibiotic. Boll Chim Farm ' 135: 94-100. insuwan S, Alvarez-Nunez FA, et al. Degradation kinetics dedimethylamino sancycline, a new anti-tumor agent, in a solutions. Int J Pharm 1999; 181: 31-40. Saleh SI, Stamm A. Evaluation of some directly compressible t-a acid forms. STP Pharma 1988; 4: 10-14. Saleh SI, Stamm A. Contribution to the preparation of a compressible Lascorbic acid granular form: comparison of prepared by three granulation methods and evaluation __ corresponding tablets. STP Pharma 1988; 4: 182-187. seta Y, Higuchi F, Otsuka T, et al. Preparation and pharma evaluation of Captopril sustained-release dosage forms \ semisolid matrix. Int J Pharm 1988; 41: 255-262, 21 Authors \H Kibbe. Date of Revision 2 August 2005.1 Nonproprietary Names BP: Ascorbic acid JP: Ascorbic acid PhEur: Acidum ascorbicum USP: Ascorbic acid 2 Synonyms C97; cevitamic acid; 2,3-didehydro-L-threo-hexono-I,4-lac- cone; E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C. 3° Chemical Name and CAS Registry Number L-(+)-Ascorbic acid (50-81-71 4 Empirical Formula and Molecular Weight CoHs06 176.13 5 Structural Formula HO" oH 6 Functional Category Antioxidant; therapeutic agent. 7 Applications in Pharmaceutical Formulation or Technology Ascorbic acid is used as an antioxidant in aqueous pharma- ceutical formulations at a concentration of 0.01-0.1% wiv. Ascorbic acid has been used to adjust the pH of solutions for injection, and as an adjunct for oral liquids. It is also widely used in foods as an antioxidant. Ascorbic acid has also proven useful as a_scabilizing agent in mixed micelles containing tetrazepam." 8 Description Ascorbic acid occurs as a white to light-yellow-colored, nonhygroscopic, odorless, crystalline powder or colorless crystals with a sharp, acidic taste. It gradually darkens in color upon exposure to light. 9 Pharmacopeial Specifications See Table I. oble |: Pharmacopeial specifications for ascorbic acid, Test WP 2001 PhEur 2005 USP 28 {denificaion + + + Characters = + - Specific rotation + 20.5°to +205 = +20.5'y (10% w/v solution) +2157 +21.5° +215 Residue on ignition <0.10% 0.1% pH 22-25 - Sulfoted osh - = Copper - <5 ppm - Heavy metals <20ppm —< 10 ppm <0.002% lossondrying << 0.20% «0 — - Iron - <2ppm = Oxolic acid = + - Appearance of + + - solution Organic volatile — - + impurities Assay 2 10 Typical Properties pH = 2.1-2.6 (5% wiv aqueous solutio Density (bulk) 0.7-0.9 g/cm? for crystalline material; 0.5-0.7 g/cm? for powder, Density (particle): 1.65 g/cm? Density (tapped): 1.0-1.2.g/em! for crystalline material; 0.9-1.1 g/cm? for powder. Density (true): 1.688 gic’? Dissociation constant: pKa 5 pKy2 = 11.57. Melting point: 190°C (with decomposition) ‘Moisture content: 0.1% wiw Solubility: see Table Il. Table It Solubility of ascorbic acid. Solvent Solubility at 20°C Chloroform Practically insoluble Ethanol Vin 50 Ethanol (95%) Vin 25 Ether Practically insoluble Fixed oils Practically insoluble Glycerin Vin 1000 Propylene glycol 1 in 20 Water Tin 3.5Propylene Glycol 1 Nonproprietary Names BP: Propylene glycol JP: Propylene glycol PhEue: Propylenglycolum USP: Propylene glycol 2 Synonyms 1.2-Dihydroxypropane; £1520; 2shydroxypropanol, methyl ethylene glycol; methyl glycol propane-1 2d 3° Chemical Name ond CAS Registry Number 1,2-Propanedio (57-55-6] 2-Propanediol [4254-14.2] t (4-1,2-Propanediol [4254-15-3] 4 Empirical Formula and Molecular Weight CHO, 76.09 5) Structural Formula Hon l | a an hoon nH 6 Functional Cotegory Antimicrobial preservative; disinfectant; humectan; plasticizer; solvent; stabilizer for vitamins; warer-miscible cosolvent. 7 Applications in Pharmaceutical Formulation ‘or Technology Propylene glycol has become widely used as 2 solvent uractant, and preservatwe in 2 varetyof parencera and tonpareneal phormaceutiesl formulations, Te it a beter fencral solvent than elyerin and dislves a wide vary of frateals, such a5 coricoseoids pheno, silt drs, Parbiturtes,stamins (A and D), mose alkaloids, and many local anesthetics ‘Acanansepdc its smart ethanol, aad agaist molds it is similar co glycerin and only shy less effective than sihanol. Propylene lye is commonly used as a plasczer in agus i oating formulations Propylene yeas aso we in cosmetics and inthe food industri for enulsiirs and ay archi fr favors rriptceence eo ethanol since it lack of volatility provides a vruge union favor, Se Tbe Tela _Usovcl propre ghee _—__—__ i Deepa _ Coen woaaoy SCR 5 fare Solon, semisolids 15-30 Solvent ot casolvent Asrotol solutions 10-30 Siziew 02s Rawr [O80 on x ee 8 Description Propylene glycol is a clear, colorless, viscous, pracicaly that of glycerin. 9 Pharmacopeial Specifications ‘See Table Il ee e001 _—Per2005 _ UsPZ8 Ldeifcation| + + + peeves : i Speiegeiy — LOR5-1.040 1035-1040 1 0n8107 sey + : : ‘weer “osu komm ozs Randie mignon <0008% — * $3500 Siowek = xoom = Ghenie <0 <0.001% <10ppm <5 pom 96% total colrin exten Identification: maximum in cyclohe Saitseed ache oa ‘yelohexane at 453-456 nm. Subsidiary coloring mater: carce carotene, <3.0% of total eolorh purity USE eens ‘Arsenic: <3 ppm Assay: 96-101% Lead: < 10 ppm Residue on ignition: <0.2% ol on Sym <0.2% Solubility: soluble 1 in 30 parts of chlo ine ethanol, glycerin, and rvs Incompatibilites: generally incompatible with oxidizi ‘ron Ruane ipatible with oxidizing agents; Subility: beta-carotene is very susceptible to oxidation an antioxidants such as ascorbic ak ote cen te tocopherols should be added. Store protected {com light ata low temperature (~20°C) in containers sealed under nitto- en. Method of manufacture: al industrial —— Carotenoids are based on Peionone, The mae eae oe ‘obtained by total synthesis from acetone and acetylene vie dehydrolinalol. The commercially available material i usually “extended” on a matrix such as acacia or maltodex: trin, These extended forms of beta-carotene are dispersible in aqueous systems. Beta-carowene is also available a5 micronized crystals suspended in an edible oll such as peanut oil Comments: beta-carotene is capable of producing colors ‘varying from pale yellow to dark orange. Ie can be used as a color for sugarcoated tablets prepared by the ladle process, However, beta-carotene is very unstable o ight and tig and products containing this material should be securely packaged to minimize degradation. Betacarotene is part- ularly unstable when used in spray-coating, processes, probaly owing to ames on aac el dispersed spray droplets. ‘Because of ts poor water solubility, beta-carotene cannot be used to color clear aqueous systems, and cosolvens such as ethanol must be used. ; Suppostoris have ben sel clered wth bo in approximately 0.1% concentrati 1B matters expressed as beta- noids other than beta- matters. Fm, practically Indigo carmine Empirical formula: CygHsN2Na20sS2 Molecular weight: 466.37 CAS number: (860-22-0] Synonyms: 2-(1,3-dihydr 2,3-dihydro-3-oxo-1H1 disodium 5,5'-indigotin indigotine; sodium indig‘ blue. .§-sulfo-2H-indol-2-ylidene)- oat alone acid disodium sal; Mfsulfonate; £132; FD&C blue #2; vin disulfonate; soluble indigo Coloring Agents 197 Structure: | Appearance: dak blue powder. Aqueous soltions ae blue oF ae parpe Absorption smaximium: 608nm Color index Nos C173015 Prey (EU: ‘Arent <3 ppm Land: <10ppmn Mercury: €1 ppm Crdmium: <1 ppm Heavy metals: £40 pm Etherexractable matter: <0.2% under neutral conditions Accessory colorings < 1.0% Teatin-Sslfonic ads < 1.0% 1-<03% Assay: 585% total coloring maners, calculated a5 the sodium sk Dist <18%. Waterinsluble mate: <02%, Subsidiary coloring maners: excluding provsion above, “1.0% Organic compounds other than coloring mates: <0.5% Unslfonated primary aromatic amines: <0.01%, av anine Purity (US) ‘Arsenic: <3 ppm 2-1 Dibydro--oxo-2H indol2-yidene) 2,3- 85% Volatile mates, chlorides and sulfates (calculated as the sodium salts: <15.0% at 135°C Waterinsoluble mancr: <04% Solubility se Table VI 3,3'-dioxo-2,2'-biindoylidene-5,7’-disulfonate: ‘Table Vi; Solubility of indigo carmine. Solvent Solubility at 20°C unless otherwise stated Acetone Proctically insoluble Ethanol (75%) Vin 1430 Glycerin Vin 100 Propylene glycol Yin 1000 Propylene glycol (50%) Vin 167 Woler Vin 125 ot 2°C Vin 63 01 25°C Vin 45 a1 60°Csnip a A YORE dour pay SauepmesIsopropyl Myristate 1. Nonproprictary Names BP: Isopropyl myristate PhEur: Isopropslis myristas USPNF: Isopropyl myristate 2 Synonyms Crodamol IPM; Estol IPM; isopropyl ester of Kessco IPM 95; Lexol [PM-NF; myristic acid iso Rita IPM; Stepan IPM; Tegosoft M; tetradec imethylethyl ester; Waglinol 6014 3 Chemical Name and CAS Registry Number 1-Methylthy!teicadecanoate [110-27-0] 4 Empirical Formula and Molecular Weight CirHtOy 270.5 5° Structural Formula x DIU Ke 0 0 6 Functional Category Enmollien;oleaginous vehicles skin peneteant; solvent, 7 Applications in Pharmaceutical Formulation or Technology riscate is a nongeeasy emollient that is absorbed Teis used asa component of semisolid bases X for many substances applied topically. ‘Applications in ropical pharmaceutical and cosmetic formula tions include bath ol; make-up: hair and nail care products “reams; Totions lip products; shaving products skin lubricants; Jeodorants otc Suspensions; and vaginal creams see Table For example, sopcopy! myristate isa self-ermulsifying compo hhentof a propose cold cream forrnila," whic issuable for Thee a vehicle for drugs or dermatological actives; itis aso used coumeiallyn stable mixtures of water and glycerol? isopropyl myristate is used as a. penetration enhancer for crondGinelformalatons and bas been used conjunction Ai therapeutic ultrasound and iontophoresis! Ie has been TAD ina wateroil gel prolonged-rlease emulsion and in teh uemicroemusions. bopropyl myristate has also been used sronpcres, and significantly increased the release of drug from etoposide-ioaded microspheres." Isopropyl reaslily bythe sk and_as a sol i: canon Deere 0,003-0.08, supension 02a fetune os-20 Microamulions «50 Soop 003-03 Topical ones, 20-980 Topical crams ond lions 1,0-109 Tepiecleroms ondlefens re 8 Description Ieopropy! myristate is 2 clear, colorless, practically odorless csi ths congeals at aout 3° consis eae of propan-2-ol and sacurated high molecular weigh fatty Seids, principally myristc acid. 9 Pharmacopeial Specifications See Table I Toble Phormacopeicl specifications for isopropyl myrtle ies PhEor 2005 USPNF 23 ldeniaion . + ‘Appearance of ohtion + ~ Specie geity 7 o8de-0.8s4 Relative density =0853 0.846-0.854 fective index 1ABde1437 1492-1496 Reside on ignition <0.1% 20.1% Acid valve £10 <10 Soponifiction valve 202-212 202-212 iodine value 10 <10 Appeorance of slvion + as Viconiy 5-6 nos - Wor 0.1% - Crgarc vlatie impurities - + Assay [0s CrsH Oa) 290.0% 390.0% 10 Typical Properties Boiling point: 140.2°C at 2661 (2 mmHg) Flash point: 153.5°C (closed cup) Freezing point: =5°C Solubility: soluble in acetone, chloroform, ethanol (95%), ethyl acetate, fats, fatty alcohols, fixed oils, liquid hydrocarbons, tle and wanes, isoves many axe, cols or wl, Practically insoluble in glycerin, glycols, and watee. coy janie Pfs 6-90 a 38 6 11 Stability and Storage Conditions Isopropyl myristate is resistant to oxidation and hydrolysis and doesnot become rancid. I should be stored in welbcoxed ‘container in a cool, dry place and protected from light.a ia. tncomparibiliios a opropyl myst comes into contac with rl weno acon with concomitant Sa ioe £2 feof the eb: comact wh pais avatend silent, results in swelling. Isopropyl myristate is pobaile with hard paraffin, producing a granular mixture. sca incompasbe with song oxidizing agents. i 13. Method of Manufacture nyt myssace maybe prepared ithe by the eseifiaton homer acd. with propan-2-l or by the reaction of of toy chloride and propan-2o with the aid of a suitable satifochocnating agent. A high-purity material i ako eho avalable, produced by enzymaci eserifiaion sotpe emnperaure. ’ 14 Safety sopropyl myristate i widely used in cosmeties and ropial Loe euical formulations and js generally cegarded a8 a haps and eonieritant material.°-”? by regarded LDso (mouse, oral}: 49.7 ¢/kg® LDso (rabbit, skin): 5 e/g 15 Handling Precautions ‘fserve normal precautions appropriate to the circurstar Oe guantity of material handled. circumstances 16 Regulatory Status Included in the FDA Inactive Ingredients Guide (otic, topical, rrensdermal, and vaginal preparations). Used in nonparenteral reedsines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Isopropyl palmitate. Isopropyl Myrisiote 375 18 Comments “The EINECS number for isopropy! myristare is 203-7514. 19 Specific References sno, CMI, Sls Fores E Proposal and ical study of modern dermo-pharmmcites! uch) chon Form 1996 138: 364 373; i een G. Stability estimation of emulsions oF Ses of water and glycerol. J Cosmet Sci 2 a ‘Ropropyl mysitate in de aren radema omontcst of Pan OE Ae Ch, {Tung YB. Transdermal iontopheresis Fe Narr oe elit combined eflec of peteatment PY saa vo aancers, dnt J Phare 19973 149: 183-195 Faery caret I Effect of topropy] myritic acid ester om the ae eet gs and bv er clase of eropenide from Fee caetacres, AAPS Pharm TechSei 2000; M8): 32 Sage Pipi E.Lack of toxiity and carcinogenicity of some Stenbic SPanancous agents. Toxicol Appl Pharmacol 1974: 3017-13. 6 File DL. Monographs on fragganes raw materials, Food Chater Toxicol 19765 144 307-338. re Tx Sns Me, Calle J, Safer evaluation of cosmetic ee nen] Soe Cosmet Chem: 1977; 28: 377-393. eee Lee Damgeroms Properties of Industrial Materials, Vithvede, New York: Wile, 2004: 2164 20 General References Fingerald JE, Kurtz SM, Schardein JL, Kaump DH, Cutancous ang erated stodis with vehicles containing isopropy! myristate and Pegnut oil Taxicol Appl Pharmacol 1968; 13: 448-453. Nallhare §, Vyas SP Prolonged release of rifampicin from internal phase of tink war emulion yen Inndian J Pharm Sei 19953 57: 21 Authors AK Taylor. 22 Date of Revision 16 August 2005.Hyaluronan; hyaluronate sodiy © * hyaluronate sodium; RITA Ha s RITA 1 3 Chemical a Name and CAS Registry Ny lumber Sodium hyaluronate [9067-32 4 Empirical Formula and Motecula (CuHoNONa}, (401.3) 5 Structural Formula CO:Na 6 Functional Category 7} Weight Humectant; lubricant; matrix for sustained release. 7 Applications in Pharmaceutical Formulation or Technology Sodium hyaluronate is the predominant form of hyaluranic sod ar physiological pH. The name hyaluronan is used when the polysaccharide is mentioned literature the terms hyaluronic are used interchangeably. ‘Hyaluronan is used therapeutical the knee, and is an effective trean Crosslinked hyaluronan gels systems.” Hyaluronan is the most glycosaminoglycan in to interact with polymeric and where hyaluronan solutions fa cellular uptake of complexes: availability and rerention time o It is immunoneutral, whi of biomaterials for use in tissue fhe human vitreous makes ics are used ‘common liposomal fF drugs 2 engineeti Ily to teat osteoarthet sment for arthritic pain been shown (0 deer HS ies useful for enhancing the rdministered to the eye fal for the attachment general cerms, and in the ‘acid and sodium hyaluronate ‘as drug delivery negatively charged humor, and is known DNA complexes,” we the ig and drug delivery systems: i also has imporeat applcaions in the fick of ascosurgery and yascosupplementation."” 8 Description ‘The PhEur 2005 describes sodium hyaluronate as the sodium Sat of hyaluronic acids a glyosamioglyan consi of 2 elicuronte acd and N-acetyl Deghacosamine disaccharide units Sodium hyaluronate oceurs as white to offavhite powder oF tranules, eis very hygroscopic. 9 Pharmacopeial Specifications See Table L Table: Pharmacopeial specification for sodium hyaluronate ee PhEur 2005 Chorecers —_ dentition 3 Appeoranee ef sltion + aH 5085 Inns viscosity Silloled gheorominaghycars <1" Nude ects <05 Protein <0.3%"" Chlorides 205% tron <80ppm lesson drying £2000% ‘Microbial contamination <10°/g Bacteal endotoxins 20.0510/mg Assay 95.0-105.0% oer prl dog ams 0.5 ng br prenel dosage rm 10 Typical Properties Acidity/alkalinity: pH = 5.0-8.5 (0.5% wiv aqueous solutio Solubility: soluble in water, although speed of dissolui depends upon molecular weight (higher molecular wei ate slower to dissolve, although this process can be incre by gentle agitation). Slightly soluble in mixtures of orga solvents with water, 11 Stability and Storage Conditions Sodium hyaluronate should be stored in a cool, dry plac tightly sealed containers. The powsler is stable for three yes stored in unopened containers 12. Incompatibiliti