kywods

(a) The titration method in JPE is only capable of monitoring the total free acid amount, which is here termed free succinic acid. It has been demonstrated that the total free acids consists of free acetic and succinic acids.(15)

A new accurate and robust analytical method based on liquid chromatography has been developed for the analysis of free organic acids, and acetyl and succinoyl substitutions in hypromellose acetate succinate.(15) It provides efficient separa- tion and sensitive quantitation of free acetic and succinic acids. Another new analytical method based on liquid chromato- graphy has also been developed for the analysis of methoxyl and 2-hydroxypropoxyl substitutions in hypromellose acetate succinate.(28)

Specific References

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 1993. Tokyo: Yakuji Nippo, 1994: 182–187.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 1998. Tokyo: Yakuji Nippo, 1998: 95.

New monograph for Hypromellose Acetate Succinate (In-Process Revision). Pharmaceutical Forum 2003; 29(1): 142–146.

Shin-Etsu Chemical Co. Ltd. Technical bulletin: Shin-Etsu AQOAT for aqueous enteric coating and aqueous sustained-release coating, 1998.

Hilton AK, Deasy PB. Use of hydroxypropyl methylcellulose acetate succinate in an enteric polymer matrix to design controlled- release tablets of amoxycillin trihydrate. J Pharm Sci 1993; 82: 737–743.

Streubel A, Siepmann J, Peppas NA, Bodmeier R. Bimodal drug release achieved with multi-layer tablets: transport mechanisms and device design. J Control Release 2000; 69: 455–468.

Tezuka Y, Imai K, Oshima M, Ito K. 13C-NMR structural study on an enteric pharmaceutical coating cellulose derivative having ether and ester substituents. Carbohyd Res 1991; 222: 255–259

Anderson NR, Oren PL, Ogura T, Fujii T. United States Patent No. 5,508,276; 1996.

Nagai T, Obara S, Kokubo H, Hoshi N. Application of HPMC and HPMCAS to aqueous film coating of pharmaceutical dosage forms. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel Dekker, 1997: 177–225.

Jeong YI, Ohno T, Hu Z, et al. Evaluation of an intestinal pressure- controlled colon delivery capsule prepared by dipping method. J Control Release 2001; 71: 175–182.

Nakamichi K, Izumi S, Yasuura H. Method of manufacturing solid dispersion. United States Patent No. 5,456,923; 1994.

Miyajima M, Yamaguchi Y, Tsunematsu T, Toshihisa O. Pharma- ceutical composition of dihydropyridine compound. United States Patent No. 4,983,593; 1989.

Hypromellose Acetate Succinate 353

Takeichi Y, Baba K, Kinouchi Y, et al. Combinative improving effect of increased solubility and the use of absorption enhancers on the rectal absorption of uracil in beagle dogs. Chem Pharm Bull 1990; 38: 2547–2551.

Baba K, Takeichi Y, Nakai Y. Molecular behavior and dissolution characteristics of uracil in ground mixtures. Chem Pharm Bull 1990; 38: 2542–2546.

Chen R, Sekulic S, Zelesky T. Development and validation of a cost-effective, efficient, and robust liquid chromatographic method for the simultaneous determination of the acetyl and succinoyl content in hydroxypropyl methylcellulose acetate succinate poly- mer. J AOAC Int 2002; 85(4): 824–831. Correction: 85(6), 125A.

Onda Y, Muto H, Maruyama K. Ether-ester derivatives of cellulose and their applications. United States Patent No. 4,226,981; 1980.

Final report on the safety assessment of hydroxyethylcellulose, methylcellulose, hydroxypropyl methylcellulose and cellulose gum. J Am Coll Toxicol 1986; 5: 1–59.

Informatics: GRAS (Generally Recognized as Safe) Food ingre- dients—cellulose and derivatives. For the FDA National Technical Information Service (NTIS). 1972, PB No. 22128.

Obara S, Muto H, Shigeno H, et al. A three month repeated oral administration study of a low viscosity grade of hydroxypropyl methylcellulose in rats. J Toxicol Sci 1999; 24: 33–43.

Frawley JP. Studies on the gastro-intestinal absorption of purified sodium carboxymethylcellulose. Food Cosmet Toxicol 1964; 2: 539–543.

Kitagawa H, Satoh T, Yokoshima T, Nanbo T. Absorption, distribution and excretion of hydroxypropyl methylcellulose phthalate in the rat. Pharmacometrics 1971; 5: 1–4.

Hoshi N, Ueno K, Yano H, Hirashima K, Kitagawa H. General pharmacological studies of hydroxypropylmethyl cellulose acetate succinate in experimental animals. J Toxicol Sci 1985; 10: 129– 146.

Hoshi N, Yano H, Hirashima K, Kitagawa H, Fukuda Y. Toxicological studies of hydroxypropylmethyl cellulose acetate succinate—Acute toxicity in rats and rabbits, and subchronic and chronic toxicities in rats. J Toxicol Sci 1985; 10: 147–185.

Hoshi N, Ueno K, Igarashi T, et al. Studies of hydroxypropyl- methyl cellulose acetate succinate on fertility in rats. J Toxicol Sci 1985; 10: 187–201.

Hoshi N, Ueno K, Igarashi T, et al. Teratological studies of hydroxypropylmethyl cellulose acetate succinate in rats. J Toxicol Sci 1985; 10: 203–226.

Hoshi N, Ueno K, Igarashi T, et al. Teratological study of hydroxypropylmethyl cellulose acetate succinate in rabbits. J Toxicol Sci 1985; 10: 227–234.

Hoshi N, Ueno K, Igarashi T, et al. Effects of offspring induced by oral administration of hydroxypropylmethyl cellulose acetate succinate to the female rats in peri and post natal periods. J Toxicol Sci 1985; 10: 235–255.

Rashan J, Chen R, Zelesky T, Sekulic S. Developing an alternative liquid chromatographic method for determining methoxyl and 2- hydroxypropoxyl content in cellulose ether derivatives. J AOAC Int 2003; 86(4): 694–702.

General References

Doelker E. Cellulose derivatives. In: Adv Polym Sci 1993; 107: 199– 265.

Tanno F, Nishiyama Y, Kokubo H, Obora S. Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions. Drug Dev Ind Pharm 2004; 30(1): 9–17.

Authors

R Chen, BC Hancock, RM Shanker.

Date of Revision

24 August 2005.

Hypromellose Phthalate

Nonproprietary Names

BP: Hypromellose phthalate

JP: Hydroxypropylmethylcellulose phthalate PhEur: Hypromellosi phthalas

USPNF: Hypromellose phthalate

Synonyms

Cellulose phthalate hydroxypropyl methyl ether; HPMCP; hydroxypropyl methylcellulose benzene-1,2-dicarboxylate; 2- hydroxypropyl methylcellulose phthalate; methylhydroxypro- pylcellulose phthalate.

Chemical Name and CAS Registry Number

Cellulose, hydrogen 1,2-benzenedicarboxylate, 2-hydroxypro- pyl methyl ether [9050-31-1]

Empirical Formula and Molecular Weight

Hypromellose phthalate is a cellulose in which some of the hydroxyl groups are replaced with methyl ethers, 2-hydro- xypropyl ethers, or phthalyl esters. Several different types of hypromellose phthalate are commercially available with molecular weights in the range 20 000–200 000. Typical

average values are 80 000–130 000.(1)

Structural Formula

Functional Category

Coating agent.

Applications in Pharmaceutical Formulation or Technology

Hypromellose phthalate is widely used in oral pharmaceutical formulations as an enteric coating material for tablets or granules.(2–8) Hypromellose phthalate is insoluble in gastric fluid but will swell and dissolve rapidly in the upper intestine. Generally, concentrations of 5–10% of hypromellose phthalate are employed with the material being dissolved in either a dichloromethane : ethanol (50 : 50) or an ethanol : water (80 : 20) solvent mixture. Hypromellose phthalate can normally be applied to tablets and granules without the addition of a plasticizer or other film formers, using established coating techniques. However, the addition of a small amount of plasticizer or water can avoid film cracking problems; many commonly used plasticizers, such as diacetin, triacetin, diethyl and dibutyl phthalate, castor oil, acetyl monoglyceride, and polyethylene glycols, are compatible with hypromellose phtha- late. Tablets coated with hypromellose phthalate disintegrate more rapidly than tablets coated with cellulose acetate phthalate. Hypromellose phthalate can be applied to tablet surfaces using a dispersion of the micronized hypromellose phthalate powder in an aqueous dispersion of a suitable plasticizer such as triacetin, triethyl citrate, or diethyl tartrate along with a

wetting agent.(9)

Hypromellose phthalate may be used alone or in combina- tion with other soluble or insoluble binders in the preparation of granules with sustained drug-release properties; the release rate is pH-dependent. Since hypromellose phthalate is tasteless and insoluble in saliva, it can also be used as a coating to mask the unpleasant taste of some tablet formulations. Hypromellose phthalate has also been co-precipitated with a poorly soluble drug to improve dissolution characteristics.(10)

Description

Hypromellose phthalate occurs as white to slightly off-white, free-flowing flakes or as a granular powder. It is odorless or with a slightly acidic odor and has a barely detectable taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for hypromellose phthalate.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Water 45.0% 45.0% 45.0%

Viscosity (208C) + — +

Residue on ignition 40.20% 40.20% 40.20%

Chloride 40.07% 40.07% 40.07%

Heavy metals 410 ppm 410 ppm 40.001%

Free phthalic acid 41.0% 41.0% 41.0%

Organic volatile impurities — — +

Phthalyl content — 21.0–35.0% 21.0–35.0%

Type 200731 27.0–35.0% — —

Type 220824 21.0–27.0% — —

Hypromellose Phthalate 355

1.82 g/cm3 for HP-50;

1.65 g/cm3 for HP-55.(11)

Density (bulk):

0.278 g/cm3 for HP-50;

0.275 g/cm3 for HP-55;

0.239 g/cm3 for HP-55S.(11)

Density (tapped):

0.343 g/cm3 for HP-50;

0.306 g/cm3 for HP-55;

0.288 g/cm3 for HP-55S.(11)

Melting point: 1508C. Glass transition temperature is 1378C for HP-50 and 1338C for HP-55.(12)

Moisture content: hypromellose phthalate is hygroscopic; it takes up 2–5% of moisture at ambient temperature and humidity conditions. For the moisture sorption isotherm of HP-50 measured at 258C, see Figure 1.

Particle size distribution: see Figure 2.

Solubility: readily soluble in a mixture of acetone and methyl or ethyl alcohol (1 : 1), in a mixture of methyl alcohol and dichloromethane (1 : 1), and in aqueous alkali. Practically insoluble in water and dehydrated alcohol and very slightly soluble in acetone. The solubilities of the HP-50 and HP-55 grades, in various solvents and solvent mixtures, are shown in Table II.(11)

Viscosity: see Figures 3 and 4.

Table II: Solubility of hypromellose phthalate (HP-50 and HP-55, Shin- Etsu Chemical Co. Ltd.).

Solvent Solubility

HP-50 HP-55

Acetone S/I S

Acetone : dichloromethane S/I S

Acetone : ethanol S/S S

Acetone : methanol S S

Acetone : 2-propanol S/S S

Acetone : water (95 : 5) S S

Benzene : methanol S S

Dichloromethane S/I S/I

Dichloromethane : ethanol S S

Dichloromethane : methanol S S

Dichloromethane : 2-propanol S/S S

Dioxane S S

Ethanol (95%) S/I S/I

Ethyl acetate X S/I

Ethyl acetate : ethanol S/S S

Ethyl acetate : methanol S S

Ethyl acetate : 2-propanol S/I S

Methanol S/I S/I

Methyl ethyl ketone S/I S

Propan-2-ol X S/I

Note: solubilities are for the pure solvent, or a (1 : 1) solvent mixture, unless otherwise indicated. S = soluble, clear solution.

S/S = slightly soluble, cloudy solution. S/I = swells but insoluble.

X = insoluble.

SEM: 1

Excipient: Hypromellose phthalate (HP-55) Manufacturer: Shin-Etsu Chemical Co. Ltd. Magnification: 60×

SEM: 2

Excipient: Hypromellose phthalate (HP-55) Manufacturer: Shin-Etsu Chemical Co. Ltd. Magnification: 600×

Stability and Storage Conditions

Hypromellose phthalate is chemically and physically stable at ambient temperature for at least 3–4 years and for 2–3 months at 408C and 75% relative humidity.(11) It is stable on exposure to UV light for up to 3 months at 258C and 70% relative humidity. Drums stored in a cool, dry place should be brought to room temperature before opening to prevent condensation of moisture on inside surfaces. After 10 days at 608C and 100% relative humidity, 8–9% of carbyoxybenzoyl group were hydrolyzed. In general, hypromellose phthalate is more stable than cellulose acetate phthalate. At ambient storage conditions, hypromellose phthalate is not susceptible to microbial attack.

356 Hypromellose Phthalate

Figure 1: Equilibrium moisture content of hypromellose phthalate (Shin-Etsu Chemical Co. Ltd.) at 258C.(11)

⃝: HP-50

□: HP-55

Q: HP-55S

Figure 3: Dynamic viscosity of hypromellose phthalate (HP-50) (Shin- Etsu Chemical Co. Ltd.) in various solvent mixtures at 208C.(11)

⃝: Acetone : ethanol (1 : 1)

□: Dichloromethane : ethanol (1 : 1)

Q: Ethanol : water (1 : 1)

Figure 2: Particle size distribution of hypromellose phthalate (Shin- Etsu Chemical Co. Ltd).(11)

⃝: HP-50

□: HP-55

Q: HP-55S

Figure 4: Dynamic viscosity of hypromellose phthalate (HP-55) (Shin- Etsu Chemical Co. Ltd.) in various solvent mixtures at 208C.(11)

⃝: Acetone : ethanol (1 : 1)

□: Dichloromethane : ethanol (1 : 1)

Q: Ethanol : water (8 : 2)

Hypromellose Phthalate 357

Incompatibilities

Incompatible with strong oxidizing agents.

Splitting of film coatings has been reported rarely, most notably with coated tablets that contain microcrystalline cellulose and calcium carboxymethylcellulose. Film splitting has also occurred when a mixture of acetone : propan-2-ol or dichloromethane : propan-2-ol has been used as the coating

The number following ‘HP’ in each grade designation refers to the pH value (×10) at which the polymer dissolves in aqueous buffer solutions. The designation ‘S’ in HP-55S indicates a higher molecular weight grade, which produces films with a greater resistance to cracking.

Table III: Types of hypromellose phthalate available from Shin-Etsu Chemical Co. Ltd.

solvent, or when coatings have been applied in conditions of

low temperature and humidity. However, film splitting may be avoided by careful selection of formulation composition, including solvent, by use of a higher molecular weight grade of polymer, or by suitable selection of plasticizer.

The addition of more than about 10% titanium dioxide to a coating solution of hypromellose phthalate, which is used to produce a colored film coating, may result in coating with decreased elasticity and resistance to gastric fluid.(11)

Method of Manufacture

Hypromellose phthalate is prepared by the esterification of hypromellose with phthalic anhydride. The degree of alkyloxy and carboxybenzoyl substitution determines the properties of the polymer and in particular the pH at which it dissolves in aqueous media.

Safety

Hypromellose phthalate is widely used, primarily as an enteric coating agent, in oral pharmaceutical formulations. Chronic and acute animal feeding studies on several different species have shown no evidence of teratogenicity or toxicity associated with hypromellose phthalate.(13–17) Hypromellose phthalate is generally regarded as a nonirritant and nontoxic material.

LD50 (rat, oral): >15 g/kg(13)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Although no threshold limit value has been set for hypromellose phthalate, it should be handled in a well- ventilated environment and the generation of dust should be minimized.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Cellulose acetate phthalate; hypromellose.

Comments

Various grades of hypromellose phthalate are available with differing degrees of substitution and physical properties, e.g., grades HP-50, HP-55, and HP-55S (Shin-Etsu Chemical Co Ltd). See Table III.

Property Grade of hypromellose phthalate

HP-50 HP-55 HP-55S

Substitution type 220824 200731 200731

Hydroxypropoxy content 6–10% 5–9% 5–9%

Methoxy content 20–24% 18–22% 18–22%

Phthalyl content 21–27% 27–35% 27–35%

Molecular weight 84 000 78 000 132 000

In the USA, the substitution type is indicated by a six digit number: the first two digits represent the approximate percentage content of methoxy groups; the next two digits represent the approximate percentage content of hydroxypro- poxy groups; and the final two digits represent the approximate percentage content of phthalyl groups.

To dissolve hypromellose phthalate in acetone : ethanol (95%) or dichloromethane : alcohol solvent systems, the hypromellose phthalate should first be well dispersed in alcohol before adding acetone or dichloromethane. When using acetone : dichloromethane, hypromellose phthalate should be first dispersed in the dichloromethane and then the acetone added to the system. A specification for hypromellose phthalate is contained in the Food Chemicals Codex (FCC).

Specific References

Rowe RC. Molecular weight studies on hydroxypropyl methyl- cellulose phthalate (HP55). Acta Pharm Technol 1982; 28(2): 127–130.

Ehrhardt L, Patt L, Schindler E. Optimization of film coating systems [in German]. Pharm Ind 1973; 35: 719–722.

Delporte JP, Jaminet F. Influence of formulation of enteric coated tablets on the bioavailability of the drug [in French]. J Pharm Belg 1976; 31: 263–276.

Patt L, Hartmann V. Solvent residues in film forming agents [in German]. Pharm Ind 1976; 38: 902–906.

Stafford JW. Enteric film coating using completely aqueous dissolved hydroxypropyl methyl cellulose phthalate spray solu- tions. Drug Dev Ind Pharm 1982; 8: 513–530.

Thoma K, Heckenmu¨ ller H, Oschmann R. Resistance and disintegration behaviour of gastric juice resistant drugs [in German]. Pharmazie 1987; 42: 832–836.

Thoma K, Heckenmu¨ ller H. Impact of film formers and plasticizers on stability of resistance and disintegration behaviour [in Ger- man]. Pharmazie 1987; 42: 837–841.

Takada K, Oh-Hashi M, Furuya Y, et al. Enteric solid dispersion of ciclosporin A (CiA) having potential to deliver CiA into lymphatics. Chem Pharm Bull 1989; 37: 471–474.

Muhammad NA, Boisvert W, Harris MR, Weiss J. Evaluation of hydroxypropyl methylcellulose phthalate 50 as film forming polymer from aqueous dispersion systems. Drug Dev Ind Pharm 1992; 18: 1787–1797.

Sertsou G, Butler J, Hempenstall J, Rades T. Solvent change co- precipitation with hydroxypropyl methylcellulose phthalate to improve dissolution characteristics of a poorly water-soluble drug. J Pharm Pharmacol 2002; 54(8): 1041–1047.

Shin-Etsu Chemical Co. Ltd. Technical literature: Hydroxypropyl methylcellulose phthalate, 1993.

358 Hypromellose Phthalate

Sakellariou P, Rowe RC, White EFT. The thermomechanical properties and glass transition temperature of some cellulose derivatives used in film coating. Int J Pharm 1985; 27: 267–277.

Kitagawa H, Kawana H, Satoh T, Fukuda Y. Acute and subacute toxicities of hydroxypropyl methylcellulose phthalate. Pharmaco- metrics 1970; 4(6): 1017–1025.

Kitagawa H, Satoh T, Yokoshima T, Nanbo T. Absorption, distribution and excretion of hydroxypropyl methylcellulose phthalate in the rat. Pharmacometrics 1971; 5(1): 1–4.

Ito R, Toida S. Studies on the teratogenicity of a new enteric coating material, hydroxypropyl methylcellulose phthalate (HPMCP) in rats and mice. J Med Soc Toho-Univ 1972; 19(5): 453–461.

Kitagawa H, Yano H, Fukuda Y. Chronic toxicity of hydro- xypropylmethylcellulose phthalate in rats. Pharmacometrics 1973; 7(5): 689–701.

Kitagawa H, Yokoshima T, Nanbo T, Hasegawa M. Absorption, distribution, excretion and metabolism of 14C-hydroxypropyl methylcellulose phthalate. Pharmacometrics 1974; 8(8): 1123–

1132.

General References

Deasy PB, O’Connell MJM. Correlation of surface characteristics with ease of production and in vitro release of sodium salicylate from various enteric coated microcapsules prepared by pan coating. J Micoencapsul 1984; 1(3): 217–227.

Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199–265. Rowe RC. Materials used in the film coating of oral dosage forms. In: Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6.

Oxford: Blackwell Scientific, 1984: 1–36.

Biopure 100; Germall 115; imidazolidinyl urea; methanebis[N,N' (5-ureido-2,4-diketotetrahydroimidazole)- N,N-dimethylol]; 1,1'-methylenebis{3-[3-(hydroxymethyl)- 2,5-dioxo-4-imidazolidinyl]urea}; Tri-Stat IU.

Chemical Name and CAS Registry Number

N, N''-Methylenebis{N'-[3-(hydroxymethyl)-2,5-dioxo-4-imi- dazolidinyl]urea} [39236-46-9]

Empirical Formula and Molecular Weight

C11H16N8O8 388.29 (for anhydrous) C11H16N8O8.H2O 406.33 (for monohydrate)

Structural Formula

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Imidurea is a broad-spectrum antimicrobial preservative used in cosmetics and topical pharmaceutical formulations; typical concentrations used are 0.03–0.5% w/w. It is effective between pH 3–9 and is reported to have synergistic effects when used with parabens; see Section 10.

Description

Imidurea is a white, free-flowing odorless powder.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for imidurea.

Test USPNF 23

Identification +

Color and clarity of solution +

pH (1% w/v solution) 6.0–7.5

Loss on drying 43.0%

Residue on ignition 43.0%

Heavy metals 40.001%

Organic volatile impurities +

Nitrogen content (dried basis) 26.0–28.0%

Typical Properties

Acidity/alkalinity: pH = 6.0–7.5 (1% w/v aqueous solution).

Antimicrobial activity: predominantly an antibacterial preser- vative, imidurea also has some selective antifungal proper- ties. Used at concentrations between 0.03–0.5% w/w it is effective between pH 3–9, although preservative efficacy is best seen in slightly acidic solutions. Synergistic effects have been reported and preservative activity is considerably enhanced, particularly against fungi, when used in combi- nation with parabens.(1,2) A cosmetic formulation contain- ing 0.5% imidurea, 0.2% methylparaben, and 0.1% propylparaben was effectively preserved against various Pseudomonas species.(3) For reported minimum inhibitory concentrations (MICs), see Table II.(4)

kywods

728x90

468x60.

mob

mercredi 6 novembre 2024

Aucun commentaire:

Enregistrer un commentaire

pop

slder

redect

push