(788b) Prediction of Tablet Dissolution from API and Excipient Polymer Properties

Prediction of
Tablet Dissolution from API and Excipient Polymer Properties

Jaime L. Curtis-Fisk¹ (JLCurtisfisk@dow.com), True
L. Rogers¹ (TLRogers@Dow.com),
Karen M. Balwinski¹ (KMBalwinski@Dow.com),
Kathryn O. Hewlett¹ (KOHewlett@Dow.com),
Robert L. Schmitt² (SchmitRL@Dow.com),
Shrikant N. Khot¹ (SNKhot@Dow.com)
¹ The Dow Chemical Company, Midland, MI USA
² The Dow Chemical Company, Collegeville, PA USA

Purpose: Modified-release (MR) matrix tablets
are typically produced using hydroxypropyl methylcellulose (HPMC) as rate-modifying
polymer. HPMC effectively sustains release of a broad range of active
pharmaceutical ingredients (APIs), but specific dissolution behavior varies
depending on the API properties, excipient properties, and formulation. Recently,
a new line of HPMC, METHOCEL™ DC2 grades, have been introduced to facilitate
direct compression formulations given its enhanced flowability. The ability to
predict performance based on properties of components could streamline
formulation development and provide a more direct route to troubleshooting
challenging APIs. Combined such a capability with a direct compression
manufacturing technique would mean faster and less expensive development and
manufacturing.  The intent of this study was to identify the API and polymer
properties that most directly impacted dissolution performance, connect the
observed performance to fundamental API and polymer chemistry, and develop
predictability that connects this fundamental understanding to efficient
formulation design.

Methods: The impact of API and polymer
properties on dissolution was investigated by evaluating dissolution
performance of APIs covering a broad range of solubility, shown in Figure 1.
Tablets contained a standard formulation of 50% API, 30% METHOCEL DC2 HPMC, 19%
impalpable lactose, and 1% magnesium stearate. A standard formulation was
utilized for all APIs to make a direct comparison of the structure/activity
relationship between API properties and dissolution performance. Tablets were
prepared by hand-feeding powder formulations into the tablet press to remove
variability in die fill due to powder flow differences between API formulation
blends.

Figure 1. APIs with a broad range of solubility were
evaluated in order to connect drug properties to dissolution performance.

Results: API dissolution performance was
evaluated for three viscosity grades of METHOCEL DC2 (K100LV, K4M, K100M).
Figure 2 displays the results of tablet formulations containing METHOCEL K4M DC2;
percent API release at 2, 4 and 12 hours is plotted as a function of API
solubility. The amount of API released at a given time point is greater as API
solubility increases. The sensitivity to API solubility is most dramatic for
intermediate solubility, with very low or high solubility API reaching a
plateau where small changes in solubility to do not significantly impact
release.  

Figure 2. Percent API release as a function of API
solubility, demonstrating a similar correlation at 2, 4, and 12 h dissolution time
points.

The correlation of API solubility with drug release rate was
also evaluated using t₅₀ as a measure of release rate. This
different perspective on the same datasets provides new insight into dissolution
mechanisms of the tablet and the implications to formulation optimization.
Figure 3 displays t₅₀ values as a function of API solubility for
three viscosity grades of METHOCEL DC2. All three viscosity grades demonstrate similar
behavior; at low solubility there is a strong correlation between solubility and
t₅₀, but at higher solubility the observed t₅₀ value is
constant. This behavior can be explained considering the competing mechanisms that
occur during tablet dissolution. For poorly soluble APIs, the rate limiting
step is API exposure to the greater sink of dissolution media as the outermost
layer of swollen matrix erodes, followed by API dissolution into the media. When
API solubility is greater, the limiting factor becomes diffusion of dissolved API
through the swollen polymer layer and subsequent release into the greater sink
of dissolution media. While K100M results in greater t₅₀ values for
all APIs evaluated, followed by K4M and lastly K100LV, the differentiation
between grades was greatest for poorly soluble APIs. The difference in
performance indicates that for low solubility APIs, polymer viscosity is a
critical variable in formulation design.

Figure 3. Dissolution rate described by t₅₀
as a function of API solubility for three viscosity grades of METHOCEL DC2,
demonstrating the correlation to API solubility.

Conclusions: A key learning from this study is
that API release from matrix tablets prepared with the METHOCEL DC2 product
line is strongly impacted by API solubility and polymer viscosity. APIs of low
solubility are released through a dissolution mechanism limited by API
solubility and erosion of the outermost surface of the swollen polymer layer,
but at higher solubility the release is driven by diffusion of dissolved API
through the swollen polymer network. While higher viscosity polymers
demonstrated greater extended release, the impact of this effect is more
pronounced for lower solubility APIs and became negligible for higher
solubility APIs. These relationships provide formulation guidance on selecting the
appropriate viscosity grade of METHOCEL DC2 based upon API solubility.