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Tablets & Capsules July 2019 17 Matrix tablets Multiparticulate capsules More common Less common Lower cost, simpler to manufacture More expensive to manufacture More difficult to adjust the dose and/or dissolution release profile without impacting other aspects of the product Easier to adjust the dose and/or dissolution release profile without impacting other aspects of the product Better for straightforward products • Commonly single API • Basic release pattern Better for complex products • Multiple APIs • Complicated release pattern Often easier to tech transfer Often more difficult to tech transfer Significant market competition Less competition due to greater differentiation Table 1 Tablets versus capsules for OCR formulations Solutions for drug-delivery conundrums While tablets are typically less costly and time-con- suming to manufacture, multiparticulate formulations are often the best—or the only—choice to achieve a specific dissolution profile. Formulators can combine immediate- and delayed-release granular components to achieve the desired performance. To illustrate, imagine a drug product with two APIs that must be dosed together. Each API tends to induce tolerance, a state in which the patient requires higher and higher doses to achieve a therapeutic effect. A typical slow-release formulation exposes cells to the drug contin- uously, causing progressive alterations in their ability to respond. In contrast, sequential administration of imme- diate- or short-release doses tends not to induce tolerance because the drug level in the patient's bloodstream dips between doses, allowing cell receptors to normalize before their next exposure to the drug. By mimicking this pattern that allows drug levels to drop periodically, for- mulators can create a once-a-day delivery system that maintains a therapeutic effect without inducing tolerance. This can be accomplished by combining immediate-re- lease and delayed-release bead populations for each API, delivering two to three separate pulses of each API from a single capsule. Delayed release is another means of achieving useful chronotherapeutic effects. This strategy can be used to delay release of an evening dose of the calcium channel blocker verapamil until early morning, the most frequent time for heart attacks, or release of an arthritis medication can be delayed until overnight to prevent the morning stiffness typical of that disease. Similarly, 12- to 24-hour, sustained-release pain medications can smooth out blood levels to diminish side effects and maintain efficacy. Summary The major differences between matrix tablets and mul- tiparticulate capsules for OCR formulations are listed in Table 1. Solid OCR drug product development is far from straightforward, which is why many companies look to an outsourcing partner with extensive experience in solid OCR formulation, especially for products with complex release patterns or multiple APIs. Such a partner can help streamline the process, eliminate missteps, shorten time- lines, and prevent unnecessary expenditures, ensuring the OCR development project's success. T&C Richard Sidwell is chief scientific officer at Recro Gainesville, Gainesville, GA (770 534 8239, www.recrogainesville.com). The company specializes in controlled-substance and modi- fied-release formulations and handles development and manu- facturing projects, from formulation and method development to manufacturing, packaging, and logistics. Patient-to-patient variation in gastric emptying rate is another important consideration. Differences are more likely to affect a tablet's performance, because the entire tablet moves as a unit. The API resides either in the stomach or beyond, unlike capsule beads that move gradually along the digestive tract. This continuous stomach emptying often results in lower patient-to-pa- tient pharmacokinetic variability. Manufacturing. Manufacturing monolithic-matrix tab- lets uses simple equipment and is relatively quick and inex- pensive. This uncomplicated process facilitates technology transfer and keeps in-process testing and cycle times to a minimum. A batch, which might weigh thousands of kilo- grams, can be produced in a few hours. If needed, a granu- lation step can improve the formulation's uniformity and flow for more efficient tablet compression. Newly avail- able excipients can ease manufacturing further, allowing faster batch production, better release, and lower cost. Manufacturing multiparticulate capsules, on the other hand, is more complicated and requires building a popu- lation of beads for each API by adding the API to a core, such as a sugar particle, and then coating it with a release-controlling polymer film. After the beads are formed, they must be mixed in the desired proportion and placed into the capsules. The less-common equip- ment and more complex processes required complicate technology transfer and scale-up. The multistep, labor-intensive processing required for multiparticulate capsules limits batch sizes to the hun- dreds of kilograms and takes up to 24 hours per coating step. As a result, multiparticulate OCR products are fre- quently more expensive and time-consuming to manufac- ture than tablets.