A New Hypromellose Excipient for Direct-Compression, Controlled-Release Applications - Pharmaceutical Technology

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A New Hypromellose Excipient for Direct-Compression, Controlled-Release Applications
The authors examine the use of a hypromellose-based product as an excipient in a controlled release formulation using direct-compression tableting.


Pharmaceutical Technology


Development of DC-grade HPMC using limiting flow rate analysis


Table I
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


Table II
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).


Table III
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.


Figure 3
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.

Conclusion


Figure 4
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,

*To whom all correspondence should be addressed.

References

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).


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