Croscarmellose sodium is a crosslinked polymer used as a tablet and capsule disintegrant. It occurs as a white or grayish-white powder and functions to break up tablets and capsules after ingestion, aiding dissolution. Croscarmellose sodium is produced by crosslinking carboxymethylcellulose sodium and is generally regarded as nontoxic when used within typical pharmaceutical concentrations of 0.5-5% as a disintegrant.
Croscarmellose sodium is a crosslinked polymer used as a tablet and capsule disintegrant. It occurs as a white or grayish-white powder and functions to break up tablets and capsules after ingestion, aiding dissolution. Croscarmellose sodium is produced by crosslinking carboxymethylcellulose sodium and is generally regarded as nontoxic when used within typical pharmaceutical concentrations of 0.5-5% as a disintegrant.
Croscarmellose sodium is a crosslinked polymer used as a tablet and capsule disintegrant. It occurs as a white or grayish-white powder and functions to break up tablets and capsules after ingestion, aiding dissolution. Croscarmellose sodium is produced by crosslinking carboxymethylcellulose sodium and is generally regarded as nontoxic when used within typical pharmaceutical concentrations of 0.5-5% as a disintegrant.
Croscarmellose sodium is a crosslinked polymer used as a tablet and capsule disintegrant. It occurs as a white or grayish-white powder and functions to break up tablets and capsules after ingestion, aiding dissolution. Croscarmellose sodium is produced by crosslinking carboxymethylcellulose sodium and is generally regarded as nontoxic when used within typical pharmaceutical concentrations of 0.5-5% as a disintegrant.
Croscarmellose sodium is a crosslinked polymer of carboxymethyl- cellulose sodium. See Carboxymethylcellulose sodium.
5 Structural Formula SEM 2: Excipient: croscarmellose sodium (Ac-Di-Sol); manufacturer: FMC
See Carboxymethylcellulose sodium. Biopolymer; magnification: 1000.
6 Functional Category Tablet and capsule disintegrant.
7 Applications in Pharmaceutical Formulation or
Technology Croscarmellose sodium is used in oral pharmaceutical formulations as a disintegrant for capsules,(1,2) tablets,(3–13) and granules. In tablet formulations, croscarmellose sodium may be used in both direct-compression and wet-granulation processes. When used in wet granulations, the croscarmellose sodium should be added in both the wet and dry stages of the process (intra- and extra- granularly) so that the wicking and swelling ability of the disintegrant is best utilized.(11,12) Croscarmellose sodium at concentrations up to 5% w/w may be used as a tablet disintegrant, although normally 2% w/w is used in tablets prepared by direct compression and 3% w/w in tablets prepared by a wet-granulation process. See Table I.
Table I: Uses of croscarmellose sodium.
Use Concentration (%)
Disintegrant in capsules 10–25 9 Pharmacopeial Specifications Disintegrant in tablets 0.5–5.0 See Table II. See also Section 18.
10 Typical Properties Acidity/alkalinity pH = 5.0–7.0 in aqueous dispersions. 8 Description Bonding index 0.0456 Croscarmellose sodium occurs as an odorless, white or grayish- Brittle fracture index 0.1000 white powder. Density (bulk) 0.529 g/cm3 for Ac-Di-Sol
2 06 Croscarmellose Sodium 20 7 4.0 0.5
10000 × [2nd deriv. log(1/R)]
13 Method of Manufacture 1887 Alkali cellulose is prepared by steeping cellulose, obtained from 2404 wood pulp or cotton fibers, in sodium hydroxide solution. The 2239 alkali cellulose is then reacted with sodium monochloroacetate to 1388 2310 2017 obtain carboxymethylcellulose sodium. After the substitution
log(1/R) C reaction is completed and all of the sodium hydroxide has been 0.0 used, the excess sodium monochloroacetate slowly hydrolyzes to 2085 glycolic acid. The glycolic acid changes a few of the sodium 1430 2325 2361 carboxymethyl groups to the free acid and catalyzes the formation of crosslinks to produce croscarmellose sodium. The croscarmellose 2279 sodium is then extracted with aqueous alcohol and any remaining 1916 sodium chloride or sodium glycolate is removed. After purification, −4.0 −0.2 croscarmellose sodium of purity greater than 99.5% is obtained.(4) 1100 1300 1500 1700 1900 2100 2300 2500 The croscarmellose sodium may be milled to break the polymer Wavelength/nm fibers into shorter lengths and hence improve its flow properties.
Figure 1: Near-infrared spectrum of croscarmellose sodium measured by 14 Safety
reflectance. Croscarmellose sodium is mainly used as a disintegrant in oral pharmaceutical formulations and is generally regarded as an Table II: Pharmacopeial specifications for croscarmellose sodium. essentially nontoxic and nonirritant material. However, oral consumption of large amounts of croscarmellose sodium may Test JP XV PhEur 6.5 USP32–NF27 have a laxative effect, although the quantities used in solid dosage Identification þ þ þ formulations are unlikely to cause such problems. Characters þ þ — In the UK, croscarmellose sodium is accepted for use in dietary pH (1% w/v dispersion) 5.0–7.0 5.0–7.0 5.0–7.0 supplements. Loss on drying 410.0% 410.0% 410.0% The WHO has not specified an acceptable daily intake for the Heavy metals 410 ppm 420 ppm 40.001% Sodium chloride and 40.5% 40.5% 40.5% related substance carboxymethylcellulose sodium, used as a food sodium glycolate additive, since the levels necessary to achieve a desired effect were Sulfated ash — 14.0–28.0% — not considered sufficient to be a hazard to health.(14) Residue on ignition 14.0–28.0% — 14.0–28.0% See also Carboxymethylcellulose Sodium. Degree of substitution 0.60–0.85 0.60–0.85 0.60–0.85 Content of water-soluble 1.0–10% 410.0% 410.0% 15 Handling Precautions material Settling volume 10.0–30.0 mL 10.0–30.0 mL 10.0–30.0 mL Observe normal precautions appropriate to the circumstances and Microbial contamination — þ þ quantity of material handled. Croscarmellose sodium may be Aerobic — 103 cfu/g 103 cfu/g irritant to the eyes; eye protection is recommended. Fungi — 102 cfu/g 102 cfu/g 16 Regulatory Status Density (tapped) 0.819 g/cm3 for Ac-Di-Sol Included in the FDA Inactive Ingredients Database (oral capsules, Density (true) 1.543 g/cm3 for Ac-Di-Sol granules, sublingual tablets, and tablets). Included in nonparenteral NIR spectra see Figure 1. medicines licensed in the UK. Included in the Canadian List of Particle size distribution Acceptable Non-medicinal Ingredients. Ac-Di-Sol: not more than 2% retained on a #200 (73.7 mm) 17 Related Substances mesh and not more than 10% retained on a #325 (44.5 mm) mesh. Carboxymethylcellulose calcium; carboxymethylcellulose sodium. Solubility Insoluble in water, although croscarmellose sodium rapidly swells to 4–8 times its original volume on contact with 18 Comments water. Practically insoluble in acetone, ethanol and toluene. Croscarmellose sodium is one of the materials that have been Specific surface area 0.81–0.83 m2/g selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information 11 Stability and Storage Conditions Chapter <1196> in the USP32–NF27, the General Chapter 5.8 Croscarmellose sodium is a stable though hygroscopic material. in PhEur 6.0, along with the ‘State of Work’ document on the PhEur A model tablet formulation prepared by direct compression, EDQM website, and also the General Information Chapter 8 in the with croscarmellose sodium as a disintegrant, showed no significant JP XV. difference in drug dissolution after storage at 308C for 14 months.(9) Typically, the degree of substitution (DS) for croscarmellose Croscarmellose sodium should be stored in a well-closed sodium is 0.7. container in a cool, dry place. The EINECs number for croscarmellose sodium is 232-674-9.
12 Incompatibilities 19 Specific References
The efficacy of disintegrants, such as croscarmellose sodium, may 1 Botzolakis JE, Augsburger LL. Disintegrating agents in hard gelatin capsules. Part I: mechanism of action. Drug Dev Ind Pharm 1988; be slightly reduced in tablet formulations prepared by either the 14(1): 29–41. wet-granulation or direct-compression process that contain hygro- 2 Dahl TC et al. The influence of disintegrant level and capsule size on scopic excipients such as sorbitol.(10) dissolution of hard gelatin capsules stored in high humidity conditions. Croscarmellose sodium is not compatible with strong acids or Drug Dev Ind Pharm 1991; 17(7): 1001–1016. with soluble salts of iron and some other metals such as aluminum, 3 Gissinger D, Stamm A. A comparative evaluation of the properties of mercury, and zinc. some tablet disintegrants. Drug Dev Ind Pharm 1980; 6(5): 511–536. 2 08 Crospovidone
4 Shangraw R et al. A new era of tablet disintegrants. Pharm Technol 13 Ferrero C et al. Disintegrating efficiency of croscarmellose sodium in a 1980; 4(10): 49–57. direct compression formulation. Int J Pharm 1997; 147: 11–21. 5 Zhao N, Augsburger LI. The influence of product brand-to-brand 14 FAO/WHO. Evaluation of certain food additives and contaminants. variability on superdisintegrant performance. A case study with Thirty-fifth report of the joint FAO/WHO expert committee on food croscarmellose sodium. Pharm Dev Technol 2006; 11(2): 179–185. additives. World Health Organ Tech Rep Ser 1990; No. 789. 6 Zhao N, Augsburger LI. The influence of swelling capacity of
C superdisintegrants in different pH media on the dissolution of hydrochlorthiazide from directly compressed tablets. AAPS Pharm Sci 20 General References Tech 2005; 6(1): E120–E126. 7 Battu SK et al. Formulation and evaluation of rapidly disintegrating DMV-Frontera Excipients. Product literature: Primellose and Primojel, fenoverine tablets: effects of superdisintegrants. Drug Dev Ind Pharm August 2008. 2007; 33(11): 1225–1232. European Directorate for the Quality of Medicines and Healthcare 8 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopi- (EDQM). European Pharmacopoeia – State Of Work Of International city on disintegrant efficiency in direct compression tablets in terms of Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edq- dissolution. J Pharm Sci 1987; 76: 907–909. m.eu/site/-614.html (accessed 6 February 2009). 9 Gordon MS, Chowhan ZT. The effect of aging on disintegrant FMC Biopolymer. Material Safety Datasheet: Ac-Di-Sol, May 2008. efficiency in direct compression tablets with varied solubility and JRS Pharma. Product literature: Vivasol. http://www.jrspharma.de/Pharma/ hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 16: wEnglisch/produktinfo/productinfo_vivasol.shtml (accessed 6 February 437–447. 2009). 10 Johnson JR et al. Effect of formulation solubility and hygroscopicity on disintegrant efficiency in tablets prepared by wet granulation, in terms of dissolution. J Pharm Sci 1991; 80: 469–471. 21 Author 11 Gordon MS et al. Effect of the mode of super disintegrant incorporation on dissolution in wet granulated tablets. J Pharm Sci 1993; 82(2): 220– RT Guest. 226. 12 Khattab I et al. Effect of mode of incorporation of disintegrants on the 22 Date of Revision characteristics of fluid-bed wet-granulated tablets. J Pharm Pharmacol 1993; 45(8): 687–691. 6 February 2009.
Crospovidone
1 Nonproprietary Names 7 Applications in Pharmaceutical Formulation or
BP: Crospovidone Technology PhEur: Crospovidone Crospovidone is a water-insoluble tablet disintegrant and dissolu- USP-NF: Crospovidone tion agent used at 2–5% concentration in tablets prepared by direct- compression or wet- and dry-granulation methods.(1–6) It rapidly exhibits high capillary activity and pronounced hydration capacity, 2 Synonyms with little tendency to form gels. Studies suggest that the particle size Crospovidonum; Crospopharm; crosslinked povidone; E1202; of crospovidone strongly influences disintegration of analgesic Kollidon CL; Kollidon CL-M; Polyplasdone XL; Polyplasdone tablets.(7) Larger particles provide a faster disintegration than XL-10; polyvinylpolypyrrolidone; PVPP; 1-vinyl-2-pyrrolidinone smaller particles. Crospovidone can also be used as a solubility homopolymer. enhancer. With the technique of co-evaporation, crospovidone can be used to enhance the solubility of poorly soluble drugs. The drug is adsorbed on to crospovidone in the presence of a suitable solvent 3 Chemical Name and CAS Registry Number and the solvent is then evaporated. This technique results in faster 1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] dissolution rate.
4 Empirical Formula and Molecular Weight 8 Description
(C6H9NO)n >1 000 000 Crospovidone is a white to creamy-white, finely divided, free- The USP32–NF27 describes crospovidone as a water-insoluble flowing, practically tasteless, odorless or nearly odorless, hygro- synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. An scopic powder. exact determination of the molecular weight has not been established because of the insolubility of the material. 9 Pharmacopeial Specifications See Table I. See also Section 18. 5 Structural Formula See Povidone. 10 Typical Properties Acidity/alkalinity pH = 5.0–8.0 (1% w/v aqueous slurry) Density 1.22 g/cm3 6 Functional Category Density (bulk) see Table II. Tablet disintegrant. Density (tapped) see Table II.
