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Tim Bee is a senior director of pharmaceuticals at International Specialty Products, 1361 Alps Rd., Wayne, NJ 07470, tel. 973.628.4148.
Jagdish Balasubramaniam is a manager of pharmaceutical research and development at International Specialty Products India.
The addition of superdisintegrants to oral solid dosage forms can improve disintegration and, in turn, drug dissolution.
This article is an adaptation of an article published in Pharmaceutical Technology, April 2009. The full version can be accessed at: www.pharmtech.com/superdisintegrant.
Dissolution of a drug is essential for its absorption through the biological membranes into systemic circulation and, thus, for therapeutic efficacy. To aid dissolution, conventional tablet formulations generally require rapid disintegration, which can be facilitated by the addition of superdisintegrants. Commonly used superdisintegrants, such as crospovidone, croscarmellose sodium and sodium starch glycolate, are highly efficient at low concentration levels (2–5 w/w%) in tablet formulations at facilitating the rate and extent of tablet disintegration. However, the correlation between tablet disintegration and drug dissolution is not always observable.1–3
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More than 60% of new drugs in development — along with nearly half the drugs coming off patent in the next 10 years — are poorly soluble, and selecting formulation ingredients that enhance dissolution is increasingly important to achieve therapeutic efficacy. Once a tablet disintegrates, the solubility properties of the drug, either alone or assisted by other formulation ingredients, determine the drug's subsequent dissolution rate and extent of release.
The solubility properties of water-soluble drugs result in rapid and high-level drug release, but with poorly soluble drugs, other ingredients in the formulation, including the disintegrant, play a key role in determining the drug dissolution characteristics exhibited by the finished formulation.
With that in mind, a study was conducted to explore the impact of superdisintegrant selection on the dissolution rate of poorly soluble drugs.
Crospovidone, croscarmellose sodium and sodium starch glycolate are superdisintegrants widely used to accelerate the rate of disintegration in oral solid dosage forms. Although these materials are used to provide the same function within the formulation, they differ in their chemical structure, particle morphology and powder properties.
Croscarmellose sodium is the sodium salt of a cross linked, partly O (carboxymethylated) cellulose, while sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch or of a cross linked carboxymethyl ether of starch.4 Both are sodium salts and are anionic. In addition, their polymer backbones are composed mostly of glucose repeat units.
In contrast, crospovidone is an insoluble, cross-linked homopolymer of N vinyl 2 pyrrolidone and is nonionic. Chemically, the repeat structure of crospovidone is similar to N methylpyrrolidone (NMP), a water miscible, polar aprotic solvent with high interfacial activity used as a solubilizer in many applications.
When examined under a scanning electron microscope, croscarmellose sodium particles have a fibrous, nonporous structure; sodium starch glycolate particles are spherical and nonporous; and crospovidone particles (Type A and Type B) appear highly porous and granular (Table 1).
Table 1: Comparison of physical properties of common superdisintegrants.
As outlined in the European Pharmacopoeia, crospovidone is available in different particle sizes, with crospovidone Type B having a smaller average particle size than crospovidone Type A. Although they differ in particle size, both types have similar particle morphology. In Table 1, a comparison of typical average particle size and surface area, determined by a Malvern Mastersizer (Malvern Instruments, UK) and BET gas adsorption, respectively, of the superdisintegrants shows crospovidone Type B to have the smallest particle size with highest surface area. The high surface area further increases interfacial activity, which can aid drug dissolution. Thus, the unique, chemical structure and powder properties of crospovidone Type B may improve the dissolution of poorly soluble drugs.
Drug dissolution profiles are increasingly used to evaluate drug release characteristics of pharmaceutical products. The dissolution media adopted by the pharmacopoeias or recommended by the FDA for in vitro dissolution testing are designed to maximize drug release for a given drug. Thus, for a given marketed drug, the recommended medium becomes the quality control standard to assure batch to batch consistency, and ensure continuing product quality and performance are maintained should changes be made to the manufacturing process.
Although the recommended media for in vitro dissolution testing can be used to guide formulation development, it is typically nondiscriminatory between formulation ingredients, as drug release with a poorly soluble drug is usually driven more by the medium than by formulation ingredients.
Discriminatory dissolution profiles are highly desirable for distinguishing between products with differences in pharmaceutical attributes (formulation and/or manufacturing process differences).5
In the present study, dissolution testing was conducted in the recommended media for the drug (the US Pharmacopeia or FDA recommended medium), as well as in modified dissolution media designed to produce drug release profiles that discriminate between formulations with different superdisintegrants. The discriminating media were selected with at least one formulation achieving 80% drug release. The recommended and discriminating media for each drug tested are shown in Table 2.
Table 2: Dissolution media tested for drugs with varying degrees of aqueous solubility.
For a given drug, the formulations were produced using the same process, ingredients and ingredient levels. Tablets were prepared at the highest market dose using a direct compression or wet granulation process, as considered appropriate through a review of the ingredients listed in the Physician's Desk Reference and patent literature. In addition, tablets were compressed to equivalent tablet breaking force to minimize the impact of the tablet's physical properties on the dissolution results. Only the selection of superdisintegrant varied.
With the 13 poorly soluble drugs evaluated, no significant differences were observed in the breaking force and disintegration times of the tablets prepared using the various superdisintegrants for a given drug studied. The full results can be viewed by visiting: www.pharmtech.com/superdisintegrant.
The t80 results for all 13 drugs studied in both media are shown in Table 3. As examples, the dissolution profiles for the tablets with atorvastatin in the recommended and discriminating media are shown in Figures 1 and 2.
Table 3: T80 values of drugs tested in different dissolution media.
In the recommended media, crospovidone Type A and Type B provided the fastest t80 for 12 of the 13 drugs studied, while crospovidone Type B provided the fastest t80 for 10 of the 13 drugs studied.
Figure 1: Dissolution profile for 80 mg Atorvastatin tablets in recommended media.
In the discriminating media, crospovidone Type B provided the fastest release for 12 of 12 drugs — a discriminating medium for raloxifene HCl tablets was not developed as the recommended medium was sufficiently discriminating; hence only 12 drugs were evaluated in a discriminatory medium.
Figure 2: Dissolution profile for 80 mg Atorvastatin tablets in discriminating media.
The dissolution profiles indicate that the tablets with crospovidone Type B in both the recommended and discriminating media had the fastest rate of dissolution.
Even though the superdisintegrants gave similar disintegration results, the choice of superdisintegrant had a significant impact on drug dissolution.
As the discriminating media showed even greater differences in dissolution rate between the superdisintegrants studied, the discriminating media were highly effective at identifying differences between superdisintegrants selected.
For the most poorly soluble drugs, crospovidone Type B was often the only superdisintegrant to yield a formulation achieving 80% drug release in the discriminating media. Overall, the results suggest that crospovidone Type B, which has a solvent-like chemistry and a high surface area resulting in high interfacial activity, is more effective at enhancing the dissolution rate of poorly soluble drugs.
The author says...
At a time when formulators are faced with increasing numbers of poorly soluble drugs, it is very important to select superdisintegrants that maximize drug dissolution.
A comprehensive study conducted to evaluate the impact of crospovidone, croscarmellose sodium and sodium starch glycolate on the dissolution rates of poorly soluble drugs with varying aqueous solubility showed that crospovidone Type B provided the fastest rate of dissolution. The fact that tablet strength and disintegration times for the tablets containing each drug and all the superdisintegrants' studies were similar showed that tablet hardness and disintegration did not influence study results. Crospovidone Type B has unique chemistry, particle size and particle morphology that result in high interfacial activity, which significantly aid dissolution.
Jagdish Balasubramaniam is Manager, Pharmaceutical R&D, at International Specialty Products Pvt Ltd (India).
Tim Bee is Senior Director, Pharmaceuticals, at International Specialty Products (NJ, USA). Tel. +1 973 628 4148 TBee@ispcorp.com
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4. US Pharmacopeia, USP 31–NF 26 (2008).
5. S.A. Qureshi, Dissolution Technologies, 13(4), 18–23 (2006)