Results
Propranolol hydrochloride ER model formulations. The results indicated that at 30% polymer concentration, all propranolol blends exhibited comparable bulk/tapped density and
powder flow. All matrix tablets had comparable hardness, tensile strength, and friability values. Similar results were observed
for all formulations with 15% w/w polymer concentration, indicating that the material attributes (i.e., percent HP, particle
size, and viscosity) of Methocel K15M CR had minimal or no influence on the physical properties of the formulated powder blends
or tablets. All matrices showed low friability (≤ 0.06%) and consistent content uniformity (97.8–101.5%).
Figure 1: Propranolol hydrochloride release profiles—effect of viscosity.
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Propranolol HCl release was slower when polymer concentration increased from 15% to 30% w/w (see Figures 1–3). At both 15% and 30%, drug-release profiles were similar (f
2
= 63 and 68, respectively) despite variations in Methocel viscosity (see Figure 1). Use of higher polymer concentration (30% w/w) resulted in lower tablet-to-tablet variability as indicated by the error
bars.
Figure 2: Propranolol hydrochloride release profiles—effect of percent hydroxypropoxyl
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The effect on drug release of the percent HP substitution of hypromellose on the drug-release profiles is shown in Figure
2. Here too, at both 15% and 30% polymer concentration, the drug-release profiles were similar (f
2
= 82 and 91, respectively) despite variations in percent HP content.
Figure 3: Propranolol hydrochloride release profiles—effect of particle size.
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The effect of Methocel particle size on the drug-release profiles is shown in Figure 3. At 30% polymer concentration, the drug-release profiles were very similar (f
2
= 95) despite variations in particle size. At 15% polymer concentration, however, the batch with the larger particle size
(low percentage through 230 mesh) gave a faster and dissimilar (f
2
= 46) drug-release profile compared with the batch with the finer particle size (high percentage through 230 mesh) of the
polymer. In addition, tablet-to-tablet variability was higher in the formulation containing the coarser particle size in comparison
to the center point and fine particle-size formulations. All formulations produced good results fitting to the Power Law equation
(R2 > 0.99). The release exponent (n) was in the range of 0.59–0.63 for 30% w/w polymer formulations and 0.48–0.56 for 15% w/w polymer formulations, indicating
drug release mainly by diffusion (11).
Higher polymer concentration may decrease sensitivity of the formulation to minor variations in raw materials or the manufacturing
process. The potential for particle-size variability to influence in vitro drug release was shown to be negated when higher concentration of Methocel K15M CR was used.
Theophylline ER model formulations. Study results indicated that comparable physical properties were obtained for theophylline powder blends and compressed
tablets at both 15% and 30% polymer concentration. All matrices showed low tablet-weight variation (1.0–1.9%), low friability
(≤ 0.14%), and consistent content uniformity (94.8–100.0%).
Figure 4: Theophylline release profiles–effect of particle size (n = 6; drug dissolution using USP
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Theophylline release rates were lower when polymer concentration was increased from 15% to 30% (w/w) as shown in Figure 4. At both 15% and 30% polymer concentrations, drug-release profiles were similar (f
2
> 50) despite variations in Methocel viscosity, percent HP substitution, and particles size. Results for all formulations
fit to the Power Law equation (R2 > 0.99). The release exponent (n) was in the range of 0.50–0.62 for 30% w/w polymer formulations and 0.39–0.48 for 15% w/w polymer formulations, indicating
that diffusion is the principal mechanism of drug release (13).
The linear-regression model also was applied to examine the relationship between drug-release response (i.e., release constant
(k), release exponent (n) or time for 80% drug release [T
80%])and predictor variables (i.e., viscosity, percent HP, and particle size measured by percent through 230 mesh). Results indicated
statistically an insignificant relationship (p value > 0.1).
Conclusion
The study demonstrated that evaluation of hypromellose materials-attribute variability on matrix formulation robustness can
be readily determined. It was shown that material-attribute-variability effects can be dependent upon the rate-controlling
polymer concentration. This observation has important implications for designing Methocel-based ER matrices.
Results indicate that the ranges studied for viscosity, percentag of HP, and particle size of Methocel K15M Premium CR had
no significant effect on the physical properties of propranolol HCl or theophylline formulation blends and tablets. This finding
is important for direct-compression processing because blend properties, such as flow and compactability, can impact CQA,
such as content uniformity for a matrix formulation.
For both model formulations, the drug-release profiles from Methocel matrices were slower when the polymer concentration was
increased from 15% to 30% w/w. At 30% polymer concentration, the drug-release profiles of propranolol HCl were similar (f
2
> 68) despite variations in viscosity, percent HP, and particle size. At 15% w/w polymer concentration, the drug-release
profiles of propranolol HCl were similar (f
2
> 63) despite variations in viscosity and percent HP substitution; therefore, for these case studies, both material attributes
were noncritical.
An early indication of risk associated with material-attribute variability is an important factor in formulation design and
the subsequent manufacturing-process selection. The formulator can develop an enhanced understanding by building quality into
its drug product by evaluating material attributes and "designing out" variability effects. Development of poorly designed
and understood products can lead to manufacturing and cost inefficiencies, including customized excipient specifications and
batch selection as well as producing out-of-specification drug products. The approach, presented in this study, provides a
useful starting point for identifying and managing excipient material-attribute criticality when developing drug products
through QbD strategies.
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