POLYMER CHEMISTRY’S INFLUENCE ON CR TABLETS MANUFACTURED VIA DIRECT COMPRESSION

Citation: Mahmoudi N, McIntyre K, Lee J, Bertrand Holly, Zhang Y, Onofre F, Faham A, “Polymer Chemistry’s Influence on Controlled-ReleaseTablets Manufactured Via Direct Compression”. ONdrugDelivery Magazine, Issue 109 (July 2020), pp 54–57

Nasrin Mahmoudi, Kevin McIntyre, Joseph Lee, Holly Bertrand, Yeli Zhang, Fernanda Onofre and Amina Faham investigate the effect of a simple direct compression method on controlled-release matrix tablet formulations.

It is common industry practice to produce hydrophilic matrix tablets using a wet or dry granulation process. Either method will help achieve the required powder flow properties for a successful compression and a robust formulation, but compared with those relatively complicated processes, simple direct compression manufacturing is preferred. In a controlled-release matrix tablet formulation, hydroxypropyl methylcellulose (hypromellose) and polyethylene oxide are often used as key polymer excipients to control drug release. The chemical, physical and mechanical properties of these polymers have significant influence on manufacturing processes and product attributes.

“The chemical, physical and mechanical properties of these polymers have significant influence on manufacturing processes and product attributes.”

In the case study that follows, we will examine discoveries made by the research team at DuPont Nutrition and Biosciences (DuPont) on the influence of polymer chemistry in matrix tablet performance manufactured through a simple direct compression method. A particle-engineered grade of DuPont’s proprietary form of hypromellose (METHOCEL™ K100M DC2) and a high-molecular-weight grade of its polyethylene oxide with inherently good flow properties (POLYOX™ WSR-301) were selected for the evaluation as rate-controlling polymers. Propranolol hydrochloride was used as a soluble model drug.

A Look at Composition

Matrix tablet formulations consisted of 20% w/w propranolol HCl as a model drug, 30% w/w hypromellose (METHOCEL™ Premium K100M DC2) or polyethylene oxide (POLYOX™ WSR-301) as a release-rate-controlling polymer, 40% w/w microcrystalline cellulose (Avicel® PH102) and 9% lactose monohydrate (Fast Flo®) as filler, 0.5% w/w colloidal silica (SiO2, Cab-O-Sil®) as anti-adherent and 0.5% w/w sodium stearyl fumarate (Alubra®) as lubricant.

Preparing the Powder Blend

The research team began by incorporating the ingredients into 1 kg batches. They preblended silicon dioxide with Avicel®, passing the subsequent mixture through a 20-mesh screen. The pre-blend silicon dioxide mixture, propranolol HCl and fillers were then passed through a conical mill (Quadro® Comil® Scalable Lab System) at 2,500 rpm for de-lumping and to ensure uniform distribution of the drug. The final mix was blended with the rate-controlling polymer and lubricant in a 4-qt V-blender (with no intensifier bar) at 25 rpm for 15 minutes.

Powder Blend Testing

Particle size distribution of the rate-controlling polymers – METHOCEL™ Premium K100M DC2 and POLYOX™ WSR-301 – were measured using a laser diffraction technique. The bulk and tapped densities of each blend were measured to obtain Carr’s Compressibility Index (Equation 1), an indication of the flowability of a powder in which lower values indicate better flow properties; and the Hausner ratio (Equation 2), a number correlated to the flowability of granular material where Vt is the tapped density of powder (g) and Vb is the bulk density (mL).

Time for Compression

Each blend was compressed into 400 mg tablets on a four-station Korsch rotary tablet press, using a 13/32 SRC tooling at a turret speed of 20 rpm. A compression profile was generated at five compression forces (4, 6, 8, 10 and 12 kN). The resulting matrix tablets were evaluated for physical properties, assay and content uniformity, hydration and gel properties, drug release and stability. Tablet properties, including weight and dimensions (n=5), were measured manually. Crushing strength was measured using a Dr Schleuniger 8M Pharmatron tablet hardness tester. Friability of tablets (n=16) was performed at 100 drops using a VanKel 45-2000 friability tester, according to USP. Tensile strength (TS) of tablets was calculated, and tablets with TS of 2 MPa were selected for further comparison studies.

The uniformity of each tablet was assessed by dissolving them one by one (n=10) into 100 g of methanol, followed by centrifugation and dilution of 2.5 g of supernatant with 50 g methanol. Drug concentration was measured by UV spectroscopy at 290 nm in a 1 cm cell with a methanol blank. Biorelevant dissolution testing was carried out using USP Apparatus 2 at 100 rpm with a buffer of 0.1N HCl for 90 minutes, followed by media replacement with 900 mL pH 6.8 phosphate buffer.

Hydration Properties and Gel Strength

The DuPont team measured polymeric hydration and gel strength from the prepared matrix tablets using a Stable Micro System TA-XT2 Plus texture analyser set to “compression test mode”. The instrument was equipped with a flat-end, cylindrical acrylic probe with a half-inch (1.27 cm) diameter to measure force while travelling downwards onto the hydrogel formed by polymer hydration. To prepare samples for texture analysis, placebo tablets of METHOCEL™ K100M DC2 and POLYOX™ WSR-301 were manufactured using a compaction simulator targeting a TS of 2 MPa. The active tablets with the same TS were also tested for gel strength. The tablet samples were hydrated in 0.1N HCl (2h) and transferred into deionised (DI) water (25 ml) followed by testing at one, three, five and 24 hours after DI water hydration. All samples were tested in triplicate at each time interval.

Results

Figure 1: Particle size distribution of METHOCEL™ Premium K100M DC2 and POLYOX™ WSR-301.

Figure 1 shows particle size distribution of the release-rate-controlling polymers, METHOCEL™ Premium K100M DC2 and POLYOX™ WSR-301. Densities and flow indices of both formulation blends are shown in Table 1. Clear differences in particle size distribution, densities and flow properties were found.

IDDescriptionBulk Density
g/cc
Tapped Density
g/cc
Carr’s
Compressibility
Index (%)
Hausner ratio
F1Propranolol/METHOCEL™ K100M DC20.440.5417.81.2
F2Propranolol/POLYOX™
WSR-301
0.460.507.31.1

Table 1: Formulation blends properties.

The METHOCEL™ powder with smaller mean particle size (85 μm) contributed to the higher density of the blend and the higher Carr index (18). As expected, the POLYOX™ with a larger mean particle size (177 μm) contributed to the lower Carr index (7.3), lower tapped density and improved flow properties of the POLYOX™ formulation blend.

Regardless of the differences in blend flow properties, both tablet formulations demonstrated low weight variation with an RSD of less than 0.5%, which indicates satisfactory flow properties of the blends.

Figure 2: Tabletability of the propranolol formulation.

Tabletability of the propranolol tablet formulations are shown in Figure 2. POLYOX™ tablet formulations demonstrated higher tablet hardness and tensile strength, which indicates higher compactability of the POLYOX™ polymer with no influence on performance demonstrated by comparable dissolution (Figure 3).

Figure 3: Comparative dissolution profiles of propranolol tablets.

Friability of both tablets was low, 0.1% (TS, 2.24 MPa) and 0.06% (TS, 2.63 MPa) for the METHOCEL™ and the POLYOX™ formulations, respectively.

“Both formulations demonstrated high tablet tensile strength, low tablet friability, good content uniformity and great blend flow properties.”

Uniformity of dosage-unit testing for the METHOCEL™ K100M DC2 matrix tablet samples displayed a mean weight of propranolol HCl of 80.8 ±1.5 mg/tablet (n=10) or 101.0 ±1.9% of the 80 mg label claim. The calculated USP acceptance value (AV) of 4.5 satisfied the USP requirement of less than or equal to the maximum allowed acceptance value (L1) of 15.0. For the POLYOX™ WSR-301 matrix tablets, the mean weight of propranolol HCl was 81.6 ±0.8 mg/tablet (n=10) or 102.0 ±1.1% of the 80 mg label claim. The calculated USP AV of 2.5 satisfied the USP requirement of less than or equal to the maximum allowed acceptance value (L1) of 15.0.

The extended drug-release profiles of both tablet formulations were shown to be robust, as shown in Figure 3. While the propranolol HCl release from POLYOX™-based tablets was slightly faster, the difference was not significant and both profiles were similar with an f2 similarity factor – a measure of the closeness between two dissolution profiles – greater than 71.

The stability study of both tablet formulations indicated no significant changes in drug release after storage for one month under conditions of accelerated stability. The comparative dissolution profiles of the tablets are shown in Figure 4.

Figure 4. Comparative dissolution profiles of propranolol tablets – stability evaluation.

Studying hydration showed that POLYOX™ hydrates faster and becomes softer than METHOCEL™ K100M DC2, an observation found in gel strength studies as well. As shown in Figure 5, less force is needed for the probe to travel into the POLYOX™ gel layer as compared with the METHOCEL™ gel layer surrounding the tablets.

Figure 5. Comparative gel strength of METHOCEL™ K100M DC2 tablets and POLYOX™ WSR-301 tablets.

Direct Compression Success

DuPont successfully employed METHOCEL™ K100M DC2 and POLYOX™ WSR-301 to manufacture matrix tablets using a simple direct compression method. The two robust matrix tablet formulations for propranolol HCl, a soluble model drug, were studied in parallel. Both formulations demonstrated high tablet tensile strength, low tablet friability, good content uniformity and great blend flow properties. The propranolol HCl release profiles from both matrix tablets were similar and remained stable after one month of storage under accelerated stability conditions. The investigation demonstrated that both polymers may be successfully used in matrix tablet manufacturing via a direct compression process, which is more cost-effective than dry or wet granulation methods. This has lasting implications for an industry in which simplicity can greatly increase the speed to market of potentially life-saving drugs.

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