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19 Specific References 8 Japan Pharmaceutical Council. Japanese Pharmaceutical Excipients 2004. Tokyo: Yakuji Nippo, 2004; 102–103. 1 Rowe RC. Opacity of tablet film coatings. J Pharm Pharmacol 1984; 9 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical 36: 569–572. Excipients 2004. Tokyo: Yakuji Nippo, 2004; 746–747. 2 Rowe RC. Synthetic iron oxides: ideal for pharmaceutical colorants. 10 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Pharm Int 1984; 5: 221–224. Excipients 2004. Tokyo: Yakuji Nippo, 2004; 939. 3 Ceschel GC, Gibellini M. Use of iron oxides in the film coating of tablets. Farmaco Ed Prat 1980; 35: 553–563. 4 Buxbaum G. Industrial Inorganic Pigments, 2nd edn. Weinheim. Wiley- 20 General References VCH, 1998; 89–91. — 5 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2111–2112. 6 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. 21 Authors Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ C Egger, D Schoneker, S Tiwari. coshh/table1.pdf (accessed 5 February 2009). 7 Joint FAO/WHO Expert committee on Food Additives (2008). Iron oxides. http://www.fao.org/ag/agn/jecfa-additives/details.html?id=893 22 Date of Revision (accessed 5 February 2009). 5 February 2009.

I Isomalt

1 Nonproprietary Names 5 Structural Formula BP: Isomalt PhEur: Isomalt USP-NF: Isomalt

2 Synonyms C*PharmIsoMaltidex; E953; galenIQ; hydrogenated isomaltulose; hydrogenated palatinose; IsoMaltidex 16500; isomaltum; Palatinit.

3 Chemical Name and CAS Registry Number Isomalt [64519-82-0] Isomalt is a mixture of two stereoisomers: 6-O-a-D-glucopyranosyl-D- (1,6-GPS) [534-73-6] 1-O-a-D-glucopyranosyl-D- dihydrate (1,1-GPM) [20942- 99-8]

Generally, isomalt comprises a mixture of 1,6-GPS and 1,1-GPM. 1,6-GPS crystallizes without water and is more soluble than 1,1- GPM. By shifting the ratio of the two components, the solubility and crystal water content can be adjusted; see Section 10. galenIQ 4 Empirical Formula and Molecular Weight 720 has a GPM : GPS ratio of 1 : 1; galenIQ 721 has a GPM : GPS ratio of 1 : 3. C12H24O11 344.32 (for anhydrous) C12H24O112H2O 380.32 (for dihydrate) Isomalt 343

6 Functional Category SEM 3: : galenIQ 810; manufacturer: BENEO-Palatinit GmbH; magnification: 65; voltage: 10 kV. Coating agent; granulation aid; medicated confectionary base; sweetening agent; tablet and capsule diluent.

7 Applications in Pharmaceutical Formulation or Technology Isomalt is a noncariogenic excipient used in a variety of pharmaceutical preparations including tablets or capsules, coatings, sachets, and suspensions, and in effervescent tablets. It can also be used in direct compression and wet granulation.(1) In buccal applications such as chewable tablets it is commonly used because of its negligible negative heat of solution, mild , and ‘mouth feel’.(2,3) It is also used widely in lozenges, -free , and hard-boiled , and as a sweetening agent in confectionery for diabetics. See also Section 18.

8 Description I Isomalt is a sugar () that occurs as a white or almost SEM 4: Excipent: galenIQ 981; manufacturer: BENEO-Palatinit GmbH; white powder or granular or crystalline substance. It has a pleasant magnification: 90; voltage: 5 kV. sugarlike with a mild sweetness approximately 50–60% of that of .(2–4)

SEM 1: Excipient: galenIQ 720; manufacturer: BENEO-Palatinit GmbH; magnification: 400; voltage: 5 kV.

SEM 5: Excipent: galenIQ 990; manufacturer: BENEO-Palatinit GmbH; magnification: 130; voltage: 10 kV.

SEM 2: Excipient: galenIQ 721; manufacturer: BENEO-Palatinit GmbH; magnification: 400; voltage: 5 kV.

9 Pharmacopeial Specifications See Table I. 344 Isomalt

Table I: Pharmacopoeial specifications for isomalt. 350 Test PhEur 6.0 USP32–NF27 300 Identification þþ 250 þ Characters — 200 Related products þþ Conductivity 420 mScm–1 420 mScm-1 150 Reducing 40.3% 40.3% 100 Lead 40.5 ppm — Heavy metals — 410 mg/g 50 Nickel 41 ppm 41 mg/g Water 47.0% 47.0% 0 Tablet crushing strength (N) 01234567 Assay 98.0–102.0% 98.0–102.0% Compression force (kN)

Figure 1: Tablet crushing strength of isomalt (galenIQ 720, BENEO- 10 Typical Properties Palatinit GmbH). Angle of repose see Table II. Formulation: 99.5% isomalt, 0.5% magnesium stearate Compressibility Compression characteristics may vary, depend- Tablet weight: 240 mg ing on the grade of isomalt used; see Figure 1. Diameter: 8 mm Density (bulk) see Table II. Press: Fette P1200 Punch: concave Density (tapped) see Table II. I Density (true) 1.52 g/cm3 for 1,6-GPS; 1.47 g/cm3 for 1,1-GPM. Flowability Powder is cohesive; granules are free flowing.(2) 14 Glass transition temperature 12 638C for a 1 : 3 mixture of 1,1-GPM and 1,6-GPS; 688C for 1,1-GPM; 10 598C for 1,6-GPS.(2) 8 Heat of combustion 0.017 kJ/kg(5) þ Heat of solution 14.6 kJ/mol for an equimolar mixture of 1,1- 6 GPM and 1,6-GPS.(2) Hygroscopicity Not hygroscopic until 85% RH, at 258C.(2) See 4

also Figure 2. Water content (%) Melting point 2 8 141–161 C for a 1 : 3 mixture of 1,1-GPM and 1,6-GPS; 0 166–1688C for 1,6-GPS; 0 20 40 60 80 100 168–1718C for 1,1-GPM.(2) Relative humidity (%) Minimum ignition temperature >4608C Moisture content see Figure 2. Adsorption galenlQ 720 Particle size distribution Desorption galenlQ 720 Approximately 90% >100 mm for galenIQ 720; Crystal water galenlQ 720 approximately 58% >20 mm for galenIQ 800; Adsorption galenlQ 721 approximately 99% >200 mm for galenIQ 960. Desorption galenlQ 721 (3) pH 3–10 Crystal water galenlQ 721 Solubility see Figure 3.

Figure 2: Sorption isotherms of isomalt DC types (galenIQ, BENEO- Table II: Typical physical properties of selected commercially available Palatinit GmbH). isomalt grades, galenIQ (BENEO-Palatinit GmbH). Measured using Dynamic Vapor Sorption, Su¨dzucker AG. Grade Angle of repose Density (bulk) Density 1,6-GPS occurs without crystal water and 1,1-GPM crystallizes with 2 (8) (g/cm3) (tapped) mol crystal water (the initial water content in commercial forms, see (g/cm3) Section 18. The starting point of the curves depends on the water content. The content of free water in the product is typically 0.1–0.5%. galenIQ 720 38 0.43 0.48 galenIQ 721 37 0.42 0.45 galenIQ 800 — 0.50 0.65 galenIQ 810 — 0.59 0.70 galenIQ 960 33 0.82 — exhibits considerable resistance to acids and microbial influences.(1) galenIQ 980 — 0.82 — Isomalt is non-hygroscopic, and at 258C does not significantly galenIQ 981 — 0.78 — galenIQ 990 — 0.85 — absorb additional water up to a relative humidity (RH) of 85%; paracetamol (acetaminophen) tablets based on isomalt were stored for 6 months at 85% RH at 208C and retained their physical aspect.(1) 11 Stability and Storage Conditions If stored under normal ambient conditions, isomalt is chemically Isomalt has very good thermal and chemical stability. When it is stable for many years. When it is stored in an unopened container at melted, no changes in the molecular structure are observed. It 208C and 60% RH, a re-evaluation after 3 years is recommended. Isomalt 345

90 18 Comments 80 Compression of isomalt without lubrication is difficult, and 70 problems such as die wall sticking, capping, and lamination have been observed. The addition of a lubricant such as magnesium 60 stearate will reduce die wall adhesion. Co-extrusion of isomalt with 50 paracetamol (acetaminophen) significantly improved the tableting 40 properties of the mixtures, compared to physical mixtures of drug and isomalt.(18) Direct molding is also a potentially suitable 30 (18) Solubility (%) technique for producing isomalt-based tablets. 20 galenlQ 720 A variety of different grades of isomalt are commercially galenlQ 721 10 available that have different applications, e.g. galenIQ 720 and 721 are used in direct compression, galenIQ 810 is used in wet 0 0 20 40 60 80 100 120 granulation, galenIQ 981 is used in coatings, and galenIQ 990 is Temperature (°C) used in boilings. 19 Specific References Figure 3: Solubility of isomalt types in water (galenIQ, BENEO-Palatinit GmbH).(2) 1 Ndindayino F et al. Characterization and evaluation of isomalt performance in direct compression. Int J Pharm 1999; 189: 113–124. 2 BENEO-Palatinit GmbH. Technical literature: Isomalt, galenIQ, 2007. Isomalt does not undergo browning reactions; it has no reducing 3 Cargill. Technical literature: C*PharmIsoMaltidex, 2007. groups, and therefore it does not react with other ingredients in a 4 Schiweck H. Palatinit—Production, technological characteristics and formulation (e.g. with amines in Maillard reactions). analytical study of foods containing Palatinit. Alimenta 1980; (19): 5– 16. I 5 Livesey G. The energy values of dietary fibre and sugar for 12 Incompatibilities man. Nutr Res Rev 1992; (5): 61–84. — 6 Waalkens-Berendsen DH et al. Embryotoxicity/teratogenicity of isomalt in rats and rabbits. Food Chem Toxicol 1990; 28(1): 1–9. 7 Smits-Van Prooije AE et al. Chronic toxicity and carcinogenicity study 13 Method of Manufacture of isomalt in rats and mice. Food Chem Toxicol 1990; 28(4): 243–251. 8 Waalkens-Berendsen DH et al. Multigeneration reproduction study of Isomalt is produced from food-grade sucrose in a two-stage process. isomalt in rats. Food Chem Toxicol 1990; 28(1): 11–19. Beet sugar is converted by enzymatic transglucosidation into the 9 Waalkens-Berendsen DH et al. Developmental toxicity of isomalt in reducing isomaltulose. This undergoes catalytical rats. Food Chem Toxicol 1989; 27(10): 631–637. to produce isomalt. 10 Pometta D et al. Effects of a 12 week administration of isomalt on metabolic control in type-II-diabetics. Akt Erna¨hrung 1985; 10: 174– 177. 14 Safety 11 FAO/WHO. Toxicological evaluation of certain food additives and contaminants.. Twentieth report of the joint FAO/WHO expert Isomalt is used in oral pharmaceutical formulations, confectionery, committee on food additives. World Health Organ Tech Rep Ser and food products. It is generally regarded as a nontoxic, 1987; No. 539. nonallergenic, and nonirritant material. 12 Livesey G. Tolerance of low-digestible : a general view. Br Toxicological and metabolic studies on isomalt(5–10) have been J Nutr 2001; 85(Suppl. 1): S7–S16. summarized in a WHO report prepared by the FAO/WHO Expert 13 Paige DM et al. Palatinit digestibility in children. Nutr Res 1992; 12: Committee (JECFA), resulting in an acceptable daily intake of ‘not 27–37. ’ (11) 14 Storey DM et al. The comparative gastrointestinal response of young specified . children to the ingestion of 25 g sweets containing sucrose or isomalt. Br The glycosidic linkage between the mannitol or sorbitol moiety J Nutr 2002; 87(4): 291–297. and the moiety is very stable, limiting the and 15 Featherstone DB. Effect of isomalt sweetener on the caries process: A absorption of isomalt in the . There is no significant review. J Clin Dent 1995; 5: 82–85. increase in the blood glucose level after oral intake, and glycemic 16 Van der Hoeven JS. Influence of disaccharide alcohols on the oral response is very low, making isomalt suitable for diabetics. The microflora. Caries Res 1979; 13(6): 301–306. 17 Gehring F, Karle EJ. The Palatinit with special emphasis majority of isomalt is fermented in the large intestine. In general, on microbial and caries-preventing aspects. Z Erna¨rung 1981; 20: 96– isomalt is tolerated very well, although excessive consumption may 106. (12–14) result in laxative effects. 18 Ndindayino F. Direct compression and moulding properties of co- Isomalt is not fermented by bacteria present in the mouth; extruded isomalt/drug mixtures. Int J Pharm 2002; 235(1–2): 159–168. therefore no significant amount of organic acid is produced that attacks tooth enamel.(15–17) 20 General References Bauer KH et al. Coated Pharmaceutical Dosage Forms: Fundamentals, 15 Handling Precautions Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials. Stuttgart: Medpharm Scientific Publications, 1998; Observe normal precautions appropriate to the circumstances and 280. quantity of material handled. Eye protection, gloves, and a dust BENEO-Palatinit GmbH http://www.beneo-palatinit.com/en/Homepage/ mask or respirator are recommended. (accessed 16 January 2009). Do¨ rr T, Willibald-Ettle I. Evaluation of the kinetics of dissolution of tablets and lozenges consisting of saccharides and sugar substitutes. Pharm Ind 16 Regulatory Status 1996; 58: 947–952. Fritzsching B, Schmidt T. A survey of isomalt as a sugar free excipient for GRAS listed. Accepted as a food additive in Europe. nutraceuticals.. Pharmaceutical Manufacturing and Packing Sourcer 2000(Sept); 70–72. 17 Related Substances Iida K et al. Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS). J Pharm Soc Jpn 2000; — 120(1): 113–119. 346

Ndindayino F et al. Direct compression properties of melt-extruded isomalt. 21 Authors Int J Pharm 2002; 235(1–2): 149–157. B Fritzsching, O Luhn, A Schoch. Ndindayino F et al. Bioavailability of hydrochlorothiazide from isomalt- based moulded tablets. Int J Pharm 2002; 246: 199–202. O’Brien Nabors L, ed. Alternative Sweeteners: An Overview, 3rd edn. New 22 Date of Revision York: Marcel Dekker, 2001; 553. 16 January 2009.

Isopropyl Alcohol

1 Nonproprietary Names 8 Description BP: Isopropyl Alcohol Isopropyl alcohol is a clear, colorless, mobile, volatile, flammable JP: Isopropanol liquid with a characteristic, spirituous odor resembling that of a mixture of and acetone; it has a slightly bitter taste. I PhEur: Isopropyl Alcohol USP: Isopropyl Alcohol 9 Pharmacopeial Specifications See Table I. 2 Synonyms Alcohol isopropylicus; dimethyl carbinol; IPA; isopropanol; petro- Table I: Pharmacopeial specifications for isopropyl alcohol. hol; 2-propanol; sec-propyl alcohol; rubbing alcohol. Test JP XV PhEur 6.0 USP 32 3 Chemical Name and CAS Registry Number Identification þþþ Appearance of þþ— Propan-2-ol [67-63-0] solution Absorbance — þ — 4 Empirical Formula and Molecular Weight Characters — þ — Specific gravity 0.785–0.788 0.785–0.789 0.783–0.787 C3H8O 60.1 Refractive index — 1.376–1.379 1.376–1.378 Acidity or alkalinity þþþ 4 4 5 Structural Formula Water 0.75% 0.5% — Nonvolatile residue 41.0 mg 420 ppm 40.005% Distillation range 81–838C— — Benzene — þ — Peroxides — þ — Assay — — 599.0%

10 Typical Properties Antimicrobial activity Isopropyl alcohol is bactericidal; at con- 6 Functional Category centrations greater than 70% v/v it is a more effective Disinfectant; solvent. antibacterial preservative than ethanol (95%). The bactericidal effect of aqueous solutions increases steadily as the concentra- 7 Applications in Pharmaceutical Formulation or tion approaches 100% v/v. Isopropyl alcohol is ineffective against bacterial spores. Technology Autoignition temperature 4258C Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharma- Boiling point 82.48C ceutical formulations, primarily as a solvent in topical formula- Dielectric constant D20 = 18.62 tions.(1) It is not recommended for oral use owing to its toxicity; see Explosive limits 2.5–12.0% v/v in air Section 14. Flammability Flammable. Although it is used in lotions, the marked degreasing properties Flash point 11.78C (closed cup); 138C (open cup). The water of isopropyl alcohol may limit its usefulness in preparations used azeotrope has a flash point of 168C. repeatedly. Isopropyl alcohol is also used as a solvent both for tablet Freezing point 89.58C film-coating and for tablet granulation,(2) where the isopropyl Melting point 88.58C alcohol is subsequently removed by evaporation. It has also been Moisture content 0.1–13% w/w for commercial grades (13% w/w shown to significantly increase the skin permeability of nimesulide corresponds to the water azeotrope). from carbomer 934.(3) Refractive index 20 Isopropyl alcohol has some antimicrobial activity (see Section nD = 1.3776; 25 10) and a 70% v/v aqueous solution is used as a topical disinfectant. nD = 1.3749. Therapeutically, isopropyl alcohol has been investigated for the Solubility Miscible with benzene, chloroform, ethanol (95%), treatment of postoperative nausea or vomiting.(4) ether, glycerin, and water. Soluble in acetone; insoluble in salt