Facilitating direct compression of hydrophilic matrices with METHOCEL™ DC, Premium Direct Compression (DC) Grade Hypromellose Polymers

By Gus LaBella

In today’s pharmaceutical industry, formulation scientists have shorter timelines and fewer resources to develop products. The manufacture of products must be cost-effective and remain profitable. To achieve these goals, many companies look to utilize a direct compression (DC) process to manufacture tablets. This process involves combining all of the necessary raw materials in a blender to produce a uniform mixture and then compressing directly into tablets. By contrast, formulations that are produced by wet granulation or roller compaction, involve more processing steps resulting in additional equipment trains, labor, expertise, and space, and thus longer development and manufacturing times. Also, with wet granulation processes, there is an added risk of drug degradation due to exposure to moisture or heat from the process. However, two primary reasons for the granulation processes are to improve the flow properties to enable high speed tabletting and/ or to reduce the segregation potential for low dose drugs.

Hydrophilic matrix formulations are the most commonly used technology to achieve extended release (ER) oral dosage forms (3 - 6). For these ER formulations, flow problems are commonly seen due to high concentrations of the hydrophilic polymers needed to achieve the desired drug release profile. Wet granulation of these formulations may be challenging due to the hydrophilic and gel-forming nature of the polymer. One approach to avoid these challenges is to enable utilization of a direct compression process using DC grade excipients. New grades of METHOCEL^TM, premium cellulose ethers, (hypromellose) have been developed by Dow Wolff Cellulosics called METHOCEL^TM DC, which are agglomerated grades of hypromellose that retain the functionality of the METHOCEL^TM CR grade polymers for controlling drug release while offering improved flow properties to facilitate direct compression processes, see Figure 1. The functional properties of the METHOCEL^TM DC grade products are similar to their CR grade counterparts. Table 1 lists the properties of the METHOCEL^TM DC grades. Two differentiating properties are the particle size and the bulk density. Since particle size is important for flow properties, it is controlled through several sieve screen specifications. The agglomeration process also produces a lower bulk density as compared to the CR grade products. The DC grades are currently offered in the K chemistry (hypromellose 2208) series. Viscosities of, 4,000 and 100,000 mPa-sec allow the formulator to choose the proper grade based on API solubility or desired drug release profile. In addition, an experimental grade (XCS47113) with a viscosity of 100 mPa-sec is also available for sampling (7).

Figure 1 - Agglomerated METHOCEL^TM DC particles

Table 1 - METHOCEL^TM DC properties

Formulation development through laboratory scale is rarely troubled with the problems that are experienced at full scale by the production staff. Many times, problems do not become significant until the pilot scale is reached. It is difficult to reproduce these problems at the small scale so one technique, "limiting flow rate analysis", is used to determine flow rates of powders out of large scale hoppers or bins. In many cases, powders will have trouble flowing out of a hopper or bin due to the inability of the powder to "dilate" or reduce in density as it approaches the hopper outlet leading to flow rate limitations. Limiting flow rate analysis is a technique that utilizes the measured material properties of permeability, compressibility and cohesive strength in conjunction with a specified bin or hopper design to determine the rate of powder discharge from the bin (8 - 9). If we take a theoretical example of manufacturing a 500 mg tablet on a press running at 5,000 tablets per minute, the flow rate out of the bin would need to be 150 kg per hour. This analysis was performed for two different grades of METHOCEL^TM comparing the CR grade against the DC grade assuming a hopper with six inch diameter outlet. The results are shown in Table 2 (with support from Jenike & Johanson Inc.). The METHOCEL^TM DC had a significantly higher (>20 times) limiting flow rate compared to the METHOCEL^TM CR grade of comparable viscosity and substitution.

Table 2 - Limiting flow rate analysis for two METHOCEL^TM grades

A performance test was conducted with two formulations, using metoprolol tartrate as a model drug and METHOCEL^TM DC grade or METHOCEL^TM CR grade as the rate controlling polymer (Table 3) (10). The results of tablet characteristics of the two formulations, Table 4, clearly shows that the formulation containing METHOCEL^TM DC grade performed better in terms of tablet weight uniformity and content uniformity, while maintaining similar tablet hardness.

Table 3 - Hydrophilic matrix formulations

Table 4 - Tablet properties

Figure 2 shows dissolution profiles of the two formulations (Table 3) containing METHOCEL^TM K4M DC and K4M CR grades. The results clearly show that even with the agglomerated METHOCEL^TM DC improving flow and tablet properties, the dissolution profiles remained similar to the formulations containing METHOCEL^TM CR grade. Additional tests were conducted with model drugs with varying particle size, dose, and solubility and in each case, the f2 similarity factor values were 80 or greater when DC and CR grades were compared (10).

Figure 2 - Comparative dissolution profiles using two METHOCEL^TM grades

METHOCEL^TM DC grades offer formulators an option for using direct compression processes for their ER hydrophilic matrix formulation development and manufacture. The hypromellose products offer reliable, well characterized controlled drug release while facilitating flow properties of the formulation to achieve a successful direct compression process. METHOCEL^TM DC is supported worldwide by Colorcon and Dow Wolff Cellulosics technical expertise. Colorcon offers samples and start up formulation services through the HyperStart®, oral solid dose starting formulation service, available at www.colorcon.com.

References

1. McCormick, D. Evolutions in Direct Compression. Pharmaceutical Technology. 2005, April.
2. Parikh, D., [ed.]. Handbook of Pharmaceutical Granulation Technology. 2. New York : Taylor and Francis, 2005.
3. Alderman, D. A. A Review of Cellulose Ethers in Hydrophilic Matrices for Oral Controlled Release Dosage Forms. Int. J. Pharm. Tech. Prod. Mfr. 1984, Vol. 5, pp. 1-9.
4. Hogan, J. E. Hydroxypropylmethylcellulose Sustained Release Technology. Drug Dev. Ind. Pharm. 1989, Vol. 15, pp. 975-999.
5. Li, C. L., et al. The Use of Hypromellose in Oral Drug Delivery. J. Pharm. Pharmacol. 2005, Vol. 57, pp. 533-546.
6. Rajabi-Siahboomi, A. R. and Jordan, M. P. Slow Release HPMC Matrix Systems. Eur. Pharm. Rev. 2000, Vol. 5, pp. 21-23.
7. A New, Low Viscosity, Direct Compression Grade Hypromellose for Controlled Release Applications. Bernthal, H., et al. Los Angeles, California : AAPS, 2009.
8. Craig, D. A. and Hossfeld, R. J. Measuring Powder Flow Properties. Chemical Engineering. 2002, pp. 41-46.
9. Powder Flowability of a New Direct Compression Grade Hypromellose Using Limiting Flow Rate Analysis. Jacob, K., et al. Atlanta, Georgia : AAPS, 2008.
10. A New Hypromellose Excipient for Direct Compression Controlled Release Applications. Ender, K., et al. San Diego, California : AAPS, 2007.

METHOCEL^TM is a trademark of The Dow Chemical Company.