Formulation Development Forum

Excipient quality and performance are crucial factors in drug development and manufacturing. Excipient producers evaluate their products in given formulations to assess their utility compared with other excipients and functionality with specific active ingredients. International Specialty Products (ISP, Wayne, NJ), a producer of crospovidone, a commonly used superdisintegrant, recently launched a new ultra-pure grade of crospovidone to provide a crospovidone product with lower levels of peroxides, an important consideration in drug stability.

ISP manufactures standard pharmaceutical grades of crospovidone and launched an ultra-pure grade of crospovidone in November 2010. Crospovidone is a cross-linked homopolymer of N-vinyl-2-pyrrolidone. Peroxides result from the oxidation of crospovidone during production and storage, and their formation can be reduced by processing and packaging crospovidone under inert conditions. Although the United States Pharmacopeia does not specify peroxide limits for crospovidone, the European Pharmacopoeia does, with Type A having a limit of 400 ppm max, and the smaller particle size Type B having a limit of 1000 ppm max.

ISP's standard pharmaceutical grades of crospovidone have peroxide specification limits of 400 ppm max for both Type A and Type B products. Its new ultra-pure pharmaceutical crospovidone is available in two grades, with peroxide specifications of 30 ppm max and 50 ppm max for Type A and Type B respectively, explains Tim Bee, senior director of the global pharmaeutical technical operations at ISP.

ISP produces its ultra-pure grades of crospovidone (Polyplasdone Ultra and Ultra-10) at a new facility in Texas City, Texas, which is also one of two sites where the company manufactures its standard pharmaceutical grades of crospovidone (Polyplasdone XL and Polyplasdone XL-10). The ultra-pure grades of crospovidone are available in the same typical particle size ranges as the standard pharmaceutical grades. The ultra-purity grades have average particle sizes of 110–140 µm (Polyplasdone Ultra) and average particle sizes of 20-30 µm (Polyplasdone Ultra-10).

Bee explains that the lower levels of peroxides in the ultra-pure grades of crospovidone are achieved by manufacturing, drying, packing, and sealing the product under inert conditions (i.e., nitrogen) to limit peroxide formation. ISP has been manufacturing the standard pharmaceutical grades of crospovidone at its Texas City, facility since 2007, and began work on the high-purity grades in 2008. Following process improvements and optimization, the ultra-pure grades have been available on a commercial scale since November 2010. Bee explains that the ultra-pure grades of crospovidone would be beneficial for active ingredients that need the performance advantages offered by crospovidone, but may be susceptible to peroxides, which could affect drug stability and possible degradation of the drug substance.

The issue of peroxide contamination in crospovidone was recently underscored when the US Food and Drug Administration issued an advisory to manufacturers of drugs and dietary supplements to apprise them of a contaminated lot of crospovidone from a Chinese supplier (2). The peroxide level found by FDA in the lot was more than four times the maximum level of peroxide (400 ppm) allowed by global compendial monographs. FDA issued the advisory because it was "concerned that drug manufacturers using excipients containing high levels of peroxides will observe a loss of drug potency and the formation of excessive impurities during the product shelf life" (2). FDA advised manufacturers to use sound risk-management principles when working with a supplier of crospovidone to ensure the quality of the product.

In terms of functionality, commonly used superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate are effective at low concentration levels (2–5 w/w%) in tablet formulation by facilitating the rate and extent of tablet disintegration (3). Bee points out, however, that although these excipients are often comparable with respect to disintegration, there can be differences in dissolution. As a nonionic compound, crospovidone can be more effective with cationic active ingredients, an advantage compared with anionic disintegrants such as croscarmellose sodium and sodium starch glycolate, which would interact with the cationic actives and potentially retard dissolution. In one recent study, for example, ISP evaluated the respective effects of crospovidone, croscarmellose sodium, and sodium starch glycolate on the dissolution behavior of eight cationic drugs from a model direct-compression tablet formulation with 2% w/w superdisintegrant (3). Although no significant differences were observed in the disintegration times of the tablets, the study showed that actives formulated with crospovidone showed a more rapid dissolution rate than the same drugs formulated with other superdisintegrants for the cationic drugs studied, irrespective of the drug's aqueous solubility (3).

In a separate study, ISP evaluated the impact of the superdisintegrant on the dissolution of 13 poorly soluble drugs (4). Although no significant differences were observed in the disintegration times of the tablets, the study showed that actives formulated with crospovidone showed a more rapid dissolution rate than the same drugs formulated with other superdisintegrants for 12 of the 13 poorly soluble drugs studied.

Sources

1. Ph. Eur. 7.0 (Strasbourg, France), 1771–1773 (2011).

2. FDA, "Advisory to Drug and Dietary Supplement Manufacturers, Compounding Pharmacies and Distributors of Excipients and Dietary Ingredients—FDA Detects High Levels of Peroxide in Crospovidone" (Rockville, MD, Oct. 21, 2010).

3. J. Balasubramaniam et al., Dissolution Technol. 15 (2), 18–25 (2008).

4. J. Balasubramaniam and T. Bee, Pharm. Technol. 33 (4) supp. Excipient Performance for Solid Dosage Forms, s6–s14 (2009).