Using Polyethyline Oxide Blends to Assess the Effect of Excipient Variability - Pharmaceutical Technology

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Using Polyethyline Oxide Blends to Assess the Effect of Excipient Variability
The authors discuss a study that demonstrates the use of polyethylene oxide mixtures to investigate the effect of polymer viscosity on formulation robustness.


Pharmaceutical Technology
Volume 33, Issue 12


Figure 4: Drug dissolution for diltiazem hydrogen chloride (HCl) formulations containing polyethylene oxide compared with formulations containing polyethylene oxide blends. (FIGURE COURTESY OF THE AUTHORS)
Effect of blending on tablet hardness . Tables III and IV compare tablet hardness for PEO formulations containing theophylline and diltiazem HCl, respectively. Hardness was significantly higher (ANOVA, P < 0.05) for both theophylline and diltiazem HCl formulations containing PEO blends when compared to formulations using standard Polyox 1105 NF WSR products. The variation in tablet hardness was relatively small for theophylline formulations (0.5%) as opposed to diltiazem HCl formulations (13%) when comparing formulations with PEO blends to the formulations where standard Polyox 1105 NF WSR was used. The variation may be a result of particle-size effects in the PEO blends. Further investigation is required to understand the impact of particle properties on tablet-hardness properties in formulations containing PEO blends.


Figure 5: Rate of drug dissolution for theophylline formulations containing polyethylene oxide compared with formulations containing polyethylene oxide blends. (FIGURE COURTESY OF THE AUTHORS)
Effect of blending on drug dissolution. A comparison of drug dissolution profiles was made using the similarity factor, f2, which measures the closeness between two profiles (2, 3). The US Food and Drug Administration has set a public standard of f2 value between 50–100 to indicate similarity between two dissolution profiles. Drug-dissolution profiles for both theophylline (see Figure 3) and diltiazem HCl (see Figure 4) formulations showed acceptable similarity for all formulations (f2 > 75 and f2 > 82, respectively). This indicates that the viscosity of PEO, whether as an individual product or a blend, did not significantly affect drug dissolution within the range evaluated. The rate of drug dissolution for formulations with blended PEO showed more variation in the first several hours of dissolution with the formulation containing theophylline (see Figure 5) than with the formulation containing diltiazem HCl (see Figure 6), suggesting that viscosity of PEO blends is slightly sensitive to drug solubility.

Conclusions


Figure 6: Rate of drug dissolution for diltiazem hydrogen chloride formulations containing polyethylene oxide (PE0) compared with formulations containing PEO blends. (FIGURE COURTESY OF THE AUTHORS)
Blends of PEO polymers produced viscosities across the range of a standard PEO product specification and remained consistent with the typical PEO product to which it was compared. Molecular weight and polydispersity for PEO blends were consistent with standard PEO products, which showed a typical unimodal distribution. When formulated in a matrix tablet, the PEO blends showed good f2 similarity to typical PEO products when comparing drug-dissolution profiles. The rate of drug dissolution showed more variation in the first several hours of dissolution with theophylline for formulations containing PEO blends, suggesting that variability in the viscosity of PEO blends is slightly sensitive to drug solubility. This information demonstrates a reasonable approach to assess the impact of excipient variability in formulation development by blending standard products, and has practical implications in the design of robust extended-release, PEO-based formulations.

Acknowledgments

The authors would like to thank Ali Rajabi-Siahboomi, PhD, director of scientific affairs; Marina Levina, PhD, senior manager of product development; and Xiaguang (Guang) Wen, PhD, formulation technologies manager, all of Colorcon (West Point, PA) for their input during this joint project.

Jennifer L'Hote-Gaston* is an application development specialist at Dow Wolff Cellulosics for The Dow Chemical Company, Midland, MI 48642, tel. 989.638.0794, fax 989.638.9836,
. Robert Schmitt, PhD, is a scientist, and Cheryl Karas is a laboratory technologist, both at Dow Wolff Cellulosics. Yongfu Li is a senior analytical chemist in the analytical sciences laboratory at The Dow Chemical Company.

*To whom all correspondence should be addressed.

Submitted: July 8. 2009; Accepted Aug. 17, 2009.

References

1. P.J. Flory, Principles of Polymer Chemistry (Cornell University Press, Ithaca, NY), Chapter VII-4c, pp. 311–314 (1953).

2. J.W. Moore and H.H. Flanner, Pharm. Tech. 20 (6), 64–74 (1996).

3. V. Shah, Y. Tsong, and P. Sathe, Pharm. Res. 15 (6) 889–896 (1998).


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