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The authors examine the use of a hypromellose-based product as an excipient in a controlled release formulation using direct-compression tableting.
Direct compression (DC) is becoming a preferred manufacturing method for tablets. This process is less complicated than dry- or wet-granulation processes and therefore offers shorter product-development timelines and reduced cost to manufacture through the elimination of granulation unit operations. In addition, DC can be used for heat- and/or moisture-sensitive active pharmaceutical ingredients (APIs) because it has a low heat history and does not require water during processing. Excipients used in DC processing, however, must have a combination of properties, including good flow, compressibility, minimal segregation tendency, and good physical and chemical compatibility—a combination not usually associated with controlled-release (CR) excipients. A new family of hypromellose (HPMC) products (Methocel cellulose ethers, Dow Chemical, Midland, MI) was developed that combines these properties with the ability to provide controlled-drug release.
HPMC products are widely used rate-controlling polymers in oral controlled-release drug-delivery applications. These excipients offer flexibility in formulation and function for preparation of oral solid-dosage forms. However, their application in DC tableting processes is limited in some cases and complicated in others because of their poor powder flow properties. Recent product development efforts have improved powder flow while maintaining suitable compressibility and CR performance and minimizing segregation.
DC and the use of CR excipients
DC is a tableting process in which a dry blend of ingredients is placed into a tablet hopper and compressed into tablets. It is a much simpler process than wet or dry granulation, eliminating several unit operations and resulting in a more straightforward manufacturing system (see Figure 1). This results in lower manufacturing costs and shorter development times for new formulations. DC has the added advantage of being less harsh on heat- and moisture-sensitive APIs.
The main parameters for an ideal DC excipient are flowability, compressibility, minimal tendency to segregate, and physical and chemical compatibility with APIs and other ingredients. Reliable flow of pharmaceutical mixtures out of tablet-press hoppers is particularly important for problem-free tablet-press operation and consistent tablet properties. Failure to ensure reliable flow can result in both considerable manual interventions for the tablet-press hopper and poor tablet physical properties, such as high tablet-to-tablet weight variability and tablet hardness.
Because HPMC has generally poor flow properties and is often present in formulations at high levels (up to 30%), it can have a serious effect on formulation flow in a DC process. As a result, preparing CR formulations with a DC process can be difficult, usually requiring compromises such as flow enhancers or slower production rates. Typically, CR formulations are processed using wet granulation to achieve adequate mixing and improved flow. If the flow properties of HPMC could be improved, the less costly DC process could be used.
Influence of material properties and environmental factors on powder flow
Powder flow can be a difficult property to quantify because it is influenced by so many factors. Material properties such as particle size and distribution, bulk density, particle shape, moisture content, and cohesiveness all have a role in determining powder flow (1). In addition, environmental factors such as humidity, particle-to-wall interactions, bin and hopper design and dimensions, consolidation time, and load affect powder processing. Measuring powder flow with conventional bench-scale tests can be deceptive because small-scale processes primarily show the effects of particle-to-particle cohesion. If two products have the same chemistry, the particle-to-particle cohesion will be similar. At a larger scale, however, more relevant to production processes, there is an increased influence of gas permeability of the bulk solid. If the gas permeability of the bulk solid is low, the flowing solid is unable to dilate in the conical section of the hopper, a phenomenon referred to as "limiting flow rate."
Development of DC-grade HPMC using limiting flow rate analysis
The three key measurements used to determine the limiting flow rate are cohesive strength, permeability, and compressibility. During development efforts to improve the flow of CR HPMC, cohesive strength was measured in a shear tester (model RST-01.pc, Dr.-Ing. Dietmar Schulze Schüttgutmesstechnik, Wolfenbüttel, Germany). Permeability and compressibility (bulk density as a function of load) were measured in custom-made equipment. These data were used in a program that solves a series of differential equations to determine the limiting flow rate (2). This technique was used to demonstrate improved flow of the new grades of HPMC for DC, CR applications. This improvement is not the result of decreased particle cohesion (as measured by ring-shear tests), but rather improved permeability of the material as influenced by particle size. Figure 2 shows photomicrographs of the DC-and CR-grade polymers obtained from the image analyzer (RapidVue, Beckman Coulter, Fullerton, CA). The mean particle size of the DC-grade HPMC is more than two times that of the CR-grade HPMC. The limiting flow rate for the DC-grade HPMC was calculated to be 2400 lb/h, while the limiting flow rate for the CR grade HPMC was calculated to be 100 lb/h. Table I compares the physical properties of low- and high-viscosity DC-grade HPMCs.
Performance of a formulation of metoprolol tartrate and DC HPMC
In studies involving a metoprolol tartrate formulation using DC- and CR-grades of HPMC (see Table II), improvement in flow using the DC grade of HPMC was visually evident at the tablet press (i.e., no manual intervention was required). This resulted in lower tablet-to-tablet weight and hardness variation compared with the CR grade (see Table III). Improved powder flow was also demonstrated via testing with an Aero-Flow powder analyzer (model 0-8030, Amherst Processing Instruments, Hadley, MA). The formulation based on the DC grade exhibited nearly 50% reduction in mean time to avalanche. Dissolution tests of the DC HPMC formulation (see Table II) suggest the same level of controlled-drug release with either DC or CR HPMC (see Figure 3).
Evaluation of additional formulations containing granular acetaminophen and naproxen sodium also yielded comparable drug-release profiles between DC and CR grades of HPMC (see Figure 4). These two APIs represent drugs with very different physical properties. Granular acetaminophen has poor compressibility and is only sparingly soluble. Its mean particle size is about 400 µ. Naproxen sodium is freely soluble with a mean particle size of 50 µ.
Further tests showed that 18 months storage of the DC- grade HPMC at room temperature and humidity did not affect controlled-release properties or tablet hardness for an acetaminophen-based formulation. The robustness of the DC HPMC particles was also studied in a V-blender. Experiments were performed by blending for 40 min at both 8-qt and 3-ft3 scales. Only a modest 5% reduction in the particle-size mean was observed.
DC of CR formulations is possible with the advent of DC-grade hypromellose with improved flow characteristics. After testing in formulations using a wide range of APIs, dissolution profiles and tablet properties of the DC HPMC formulations were shown to be comparable to those of CR-grade HPMC formulations.
Mark J. Hall,* is a lead application development specialist, Brian D. Koblinski is a market development manager, Harold W. Bernthal is an application laboratory supervisor, Karl V. Jacob is a research scientist, and Kacee B. Ender is an application development specialist, all at Dow Wolff Cellulosics R&D, The Dow Chemical Company, 1691 N. Swede Road, Larkin Laboratory, Midland, MI 48674, tel. 989.636.4202, fax 989.638.9836, email@example.com
*To whom all correspondence should be addressed.
1. G.E. Amidon, "Physical and Mechanical Property Characterization of Powders," in Physical Characterization of Pharmaceutical Solids, Vol 70, H. Britain Ed., (CRC Press, 1995) pp. 281-320.
2. D.A. Craig and R.J. Hossfeld, "Measuring Powder Flow Properties," Chemical Engineering, 109 (10), 41–46 (2002).