By Catherine Shaffer
Reliable binders made new again by clever modification
Twenty-first century science and technology move at the speed of light. There's barely time to accept one new medical breakthrough before another is announced, and if you don't take your computer out of the box fast enough, it's likely to be obsolete.
In an age when most people experience some form of future shock before their 21st birthday, there's something reassuring about a technology that is mature and consistent over time. Pharmaceutical excipients comprise one such field. These additives and ingredients have changed little since your Dad's formulations in the 1960s, and when it comes to holding a tablet together, old school gums, starches, cellulosic materials, and synthetic binders are still solid choices for almost any application.
Additionally, the regulatory process for introducing a novel excipient would be far too prohibitive for the modest cost savings that such a compound could yield. The new excipient entity would have three possible paths to approval: generally recognized as safe determination under 21 CFR parts 182, 184, and 186, new drug application approval for a specific drug product, or approval as a food additive under 21 CFR part 171.
While these processes are worth the expense for a potential new blockbuster cancer therapy, it’s hard to justify for something that is going to make your pills stick together better.
What has changed since the 1960s, however, is the nature of the drugs. An ironic side effect of the drug design pipeline is that it tends to produce poorly soluble compounds. What typically happens is that the chemist will start with a reasonably soluble compound that is a moderate inhibitor of the drug target. To improve the activity of the compound, the chemist adds functional groups to the original compound. The additional carbon molecules linking the new groups to the body of the compound increase the hydrophobic character of the new compound.
After several iterations, the chemist ends up with an incredibly powerful drug inhibitor that has the solubility of a ball of tar. Over 60% of drugs in development today are estimated to be poorly soluble, a challenge formulation chemistry may or may not look forward to with relish.
Made New Again
To meet this challenge, excipient manufacturers have found ingenious ways to get more performance out of standard compendial excipients. Emerson Resources Inc., (Norristown, Pa.) contracts with pharmaceutical companies in product development and has had a lot of success with the new multifunctional excipients.
Rob Tuohy, manager of scientific affairs for Emerson, said recently that no one “can afford to advance a new chemical entity unless it’s a drug. What you have is a lot of innovation in combining excipients...or getting enhanced properties through particle engineering.”
A few examples illustrate how these ‘old standby’ pharmaceutical binders are made new again by modern manufacturing processes or clever modification. Most of these binders are doing at least one additional job, reducing cost and streamlining the formulation.
Starch 1500, made by Colorcon, is a partially pregelatinized starch created by a manufacturing process, not a chemical modification. The process breaks a bond between the amylose and amylopectin molecules, which are normally bound together in a spherical crystal structure. This binder is useful for compressible granulation processes.
Starch acts as a disintegrant in a tablet formulation. Partially pregelatinized starch is an effective binder, disintegrant, flow aid, and lubricant. A fully pregelatinized starch can be used in wet granulated formulations, but it will not have the disintegration properties of the partially pregelatinized product. According to Colorcon's literature, Starch 1500 can serve as a superdisintegrant in some formulations as well.
Tests of a formulation of 85% acetominophen and 15% Starch 1500 yielded a tablet that disintegrated in less than one minute in dissolution tests and released 80% of its drug within five minutes. In a study of Starch 1500 in lamuvidine tablet formulations, the resulting tablets had improved hardness and friability compared with povidone-filled tablets.1 Disintegration and dissolution were also superior.
Silicified Microcrystalline Cellulose
Another manufacturing technique that can improve the properties of a binder involves coprocessing two excipients. JRS Pharma (Rosenburg, Germany) used this strategy to combine the properties of microcrystalline cellulose and colloidal silicon dioxide. The result is silicified microcrystalline cellulose, marketed under the trade name Prosolv.
The two excipients retain their intrinsic properties but also posess synergistic properties not originally present in either. In addition to functioning as a binder, Prosolv is a disintigrant and a lubricant, and it improves tablet compactibility and flow.
Isomalt is an older compendial excipient, typically used in syrups and lozenges, that was never considered exceptional. A better isomalt is made in a two-stage production process converting sucrose to isomaltulose and then isomaltulose to mannitol dihydrate (1,1-GPM dihydrate) and sorbitol (1,6-GPS). The resulting mixture, marketed under the trade name GalenIQ by BENEO-Palatinit (Mannheim, Germany), has a number of attractive excipient properties, including good compactibility, flow, and mixing properties, as well as enhanced binding properties.
“That's an example of an old left-for-dead excipient,” said Mr. Tuohy. “It's not a new chemical. You don't have to worry about FDA toxicity issues. They made it relevant again.… More and more of these excipient companies are going to go back and look at their old duds and look at how they can resurrect them. I think there's going to be a push for that,” he said.
Polyvinyl pyrrolidones (PVP) are a family of synthetic excipients used as binders. In the past, natural gums such as guar gum were commonly used in drug formulations. However, the natural products had variations betweeen batches that were difficult to predict.
These gums have largely been replaced by synthetic products such as PVP. Multifunctional PVPs are now available, and Plasdone S-630 Copovidone from International Specialty Products (ISP, Wayne, N.J.) is one. Plasdone S-630 Copovidone is created by adding vinyl acetate to the vinylpyrrolidone polymer. This reduces the hydrophilicity of the molecule and lowers its glass transition temperature. The resulting binder is tougher and able to form a flexible film. It forms a tough, compressible tablet and can offset properties of poor compression or, in some cases, poor solubility of the active pharmaceutical ingredient (API).
Timothy Bee, PhD, senior technical and business development director of pharmaceuticals at ISP, has studied the performance of PVP binders in acetominophen tablets. “Acetominophen is a high-dose drug that’s difficult to compress directly on its own. Granulation with povidone or PVP can help prepare a tablet in a size that’s small and relatively easy to swallow, something a consumer would tolerate.... If the formulation used something that wasn’t very efficient, you would end up with either a very large tablet or one with poor physical properties.”
Using Multifunctional Excipients
These are just a few examples of many newer multifunctional or high-functioning excipients. Methods used to engineer these products include modification of particle size distribution by milling, seiving, agglomerating, spray drying, or roller compacting; selection of certain crystal polymorphic forms; cocrystallization, isolation of the crystal portion of the cellulose chain; modifications of the cooking process; modifications of the drying process; and nanosize water dispersion.2
Using multifunctional excipients simplifies the formulation process. Cost savings are not necessarily realized in reducing the amount of excipient used, which is a very small fraction of the cost of the tablet, but in reducing the total number of ingredients. Simple formulations are more straightforward to prepare, and fewer ingredients reduce the odds of adverse drug-excipient or excipient-excipient interactions. Multifunctional excipients are especially valuable in the manufacture of generic drugs, where there are not as many resources to devote to developing unique drug formulations.
Another concern when sourcing binders and other pharmaceutical excipients is the quality of the material. Recent scandals resulting from inadequate sourcing of pharmaceutical or food products have led to questions about whether the chain of custody of a material is truly reliable. Suppliers may buy ingredients from sources that do not have a third party audit to verify good manufacturing practices (GMP).
A recent example was the heparin scandal in 2008. A misunderstanding arose when a Chinese supplier had not manufactured the product but had purchased it from another source and had not audited the manufacturing process to ensure that it met U.S. Food and Drug Administration guidelines. Fraudulently sourced pharmaceutical ingredients, whether API or excipient, can be a real hazard in a globalized economy. Using highly functional excipients carries an extra layer of insurance on many levels. First, they are proprietary formulas that are backed by reputable manufacturers. Second, with a shorter overall formulation ingredient list, it is much less likely that an inadequately or fraudulently sourced material will slip into the supply chain.
“Anyone can put a statement in a brochure that they're GMP, but until they have someone from an outside company conduct an audit, it doesn't mean anything,” Dr. Bee said. “If suppliers are buying ingredients without GMP verification through a third party audit, or if they don't do their own audit, they're taking a risk in terms of potential contamination, mislabeling, or poor quality of their product.”
Although the pipeline for new pharmaceutical binders is currently empty, that doesn't mean binders are boring. New technologies and manufacturing processes increase the functionality of binders and add new functionality. A single excipient can be a binder, a disintegrant, and a lubricant. In some cases, a successful drug tablet can be made with only an API and a single excipient serving all functions.
Synthetic and highly engineered materials have replaced natural products. Today's novel drugs are poorly soluble, on average, which means that disintegrant properties of excipients are more important than ever. Overall, a stable excipient compendium is not a stagnant one, and better binders are to be found among older products reinvented.
Shaffer is a freelance writer based in Ann Arbor, Mich. Reach her at firstname.lastname@example.org.
Rahman BM, Ibne-Wahed MI, Khondkar P, et al. Effect of starch 1500 as a binder and disintegrant in lamivudine tablets prepared by high shear wet granulation. Pak J Pharm Sci. 2008; 21(4):455-459. 2. Chang D, Chang RK. Review of current issues in pharmaceutical excipients. PharmTech Web site. May 2, 2007. Available at: http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=423551. Accessed February 19, 2010.