(767f) Utilization of Quality By Design Principles to Define Formulation Best Practices for a Direct Compression Excipient

Utilization of
Quality by Design Principles to Define Formulation Best Practices for a Direct
Compression Excipient

Kathryn O. Hewlett (KOHewlett@Dow.com),
True L. Rogers (TLRogers@Dow.com), Karen
M. Balwinski (KMBalwinski@Dow.com), Jaime
L. Curtis-Fisk (JLCurtisFisk@Dow.com),
Robert L. Schmitt (SchmitRL@Dow.com),
Shrikant N. Khot (SNKhot@Dow.com)

Introduction:
Quality by Design (QbD) initiatives enable pharmaceutical manufacturers to proactively
design quality and performance into drug products, with the ultimate goal to
maximize safety and efficacy for the patient. Hydrophilic matrix tablets
represent one of the most prevalently utilized modified-release oral drug
delivery systems, which are relatively straightforward to develop and
cost-efficient to manufacture. Hydroxypropyl methylcellulose (HPMC) is a common
rate-modifying polymer incorporated into hydrophilic matrices.  The
water-soluble HPMC particles are uniformly distributed throughout the matrix
tablet. Upon contact with aqueous gastrointestinal media, the particles hydrate
and swell. The particles coalesce to form a swollen polymer network layer. The
release of active pharmaceutical ingredient (API) from the tablet is modulated
by both diffusion through the swollen network and erosion of the outermost
surface.

Matrix tablet performance can be
impacted by a number of variables, such as API physicochemical properties
(solubility, crystalline morphology), physicochemical properties of the
rate-modifying polymer (particle shape and size, viscosity grade), formulation
composition (filler, glidant, lubricant selection) and manufacturing
methodology (blending, direct compression vs. granulation, tableting
conditions). The Dow Chemical Company has recently begun commercial-scale
production of a new direct compression grade HPMC, METHOCEL™ DC2, to complement
the finer particle size, but less flowable controlled release grade, METHOCEL™
CR. We used QbD principles to characterize properties and performance of matrix
tablets containing METHOCEL™ DC2 in order to determine and balance optimal
performance regimes for tablet physical properties and modified-release (MR). The
results of these investigations will be presented along with formulation
guidances and best practices. Particular emphasis will be placed on filler
selection, HPMC molecular weight and morphology grade, and polymer
concentrations utilized to ensure robust MR performance.

Methods: Gliclazide is a poorly soluble sulfonylurea
used to treat non-insulin dependent diabetes mellitus and was used as
model API. HPMC concentrations of 10, 20, 30, 40, and 50% (w/w) were
investigated to cover the performance design space. The new K100LV, K4M, and
K100M DC2 grades of HPMC were utilized as rate-modifying polymers, and the corresponding
CR grades were used as comparative controls. Fillers investigated were Flow-Lac
lactose (Meggle), Avicel PH102 microcrystalline cellulose (FMC), Starch 1500
pregelatinized starch (Colorcon), DiTab dicalcium phosphate (Rhodia), and
Manogenn powdered mannitol (SPI Polyols). Tablets were produced via direct
compression on a pilot-scale Manesty Beta Press at 50-rpm turret speed. Tablet
physical properties, such as weight and tensile strength, were characterized
using a Sotax HT 100 - 500NV instrument. Modified-release performance was
characterized using the USP II paddle method in either a Varian VK 7010 
dissolution system equipped with a Varian Cary 50 UV visible diode array
spectrophotometer (Agilent Technologies, Santa Clara, CA USA) or a Distek 2100
single-bath dissolution system (North Brunswick, NJ USA) equipped with an
Agilent 8453 diode array spectrophotometer (Agilent). Each tablet tested for MR
performance was positioned in a hanging basket to minimize dissolution
measurement error.

Results: Figure 1 shows the modified release
performance of METHOCEL™ K100LV CR and DC2 as a function of time for
formulations with differing HPMC content. Burst release occurred at low HPMC
concentrations (10 and 20%) with both morphology grades. Increasing the level
of HPMC in the formulation resulted in a shift into a robust MR performance
regime. Above this robustness transition, modified release performance from both
CR and DC2 matrix tablets was consistent. Further increase of HPMC level
minimally impacted API release rate once the robust regime was reached, so
there is a diminishing impact with further increase in HPMC concentration once
inside the robust regime.

Figure 1. Release of gliclazide over time, as a
function of METHOCEL grade and formulation level.

Optical imaging reflected the trends observed from dissolution testing. Figure
2 shows images taken after 4 hours of swelling for tablets comprising 10% (a)
and 40% (b) METHOCEL™ K100LV CR. At lower HPMC concentration, the polymer
content was insufficient to achieve a continuous swollen network. As a result,
the swollen network was unable to maintain structural integrity, causing burst API
release as the tablet rapidly eroded. Higher HPMC concentration delivered a continuous
swollen network. Dark regions in the figure represent water and areas devoid of
swollen network, and the dry or partially hydrated matrix appears as grey or
white. The white line in approximately the center of each image represents the
location of the initial dry tablet surface. After 4 hours, the swollen network
of the 10% HPMC formulation was noncontiguous (Fig. 2a). A large region near
the top of the image was devoid of swollen network. The presence of voids in
the swollen network is consistent with the observed burst release at lower HPMC
concentrations. By contrast, the 40% formulation had a contiguous, swollen network
layer surrounding the tablet and delivered robust MR performance (Fig. 2b).

Figure 2. Optical images of (a) 10% and (b) 40% CR tablets
after 4 hours of swelling.

Tablet filler selection also impacts MR performance. Figure 3 shows MR profiles
of the gliclazide formulation containing 30% METHOCEL™ K4M DC2 with a range of
soluble and insoluble fillers. Depending upon filler solubility, the API release
rate can be increased or decreased. Once inside the robust regime, filler solubility
can be used to adjust MR performance to the desired target.

Figure 3.The
effect of filler solubility on gliclazide release rate. Tablets were formulated
with 30% METHOCEL DC2.

Conclusions: When working with matrix tablets,
many factors must be considered to obtain robust MR performance. This work
focused on examining the role of filler selection, the molecular weight and
morphology grade of HPMC, and polymer concentration necessary to ensure robust
MR performance. A new, direct-compression grade HPMC, METHOCEL™ DC2, was
compared to METHOCEL™ CR, and both morphology grades enabled robust MR
performance at comparable levels. As the HPMC concentration was increased, the
formulation transitioned into a robust regime of consistent MR performance.
Further increase in HPMC concentration had diminishing impact once inside the
robust MR regime. Filler solubility also impacted MR performance and could be
used to fine-tune the desired release rate. The systematic framework utilized
while conducting this study enabled us to define formulation guidances and best
practices for the new direct compression grade of HPMC. There is now a clear
understanding of the influences of HPMC grade, polymer level, and filler
selection on MR performance.