Compaction Characterisation of Piroxicam Amorphous Solid Dispersions Formulations

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Amorphous solid dispersions (ASDs) have been widely used to improve the bioavailability of poorly water-soluble drugs [1]. They are comprised of high molar mass polymer carriers that stabilise the active pharmaceutical ingredients (APIs) in their amorphous state.

The ASD used in this study has 16% piroxicam (PRX) and 84% polyvinylpyrrolidone-acetate (PVPVA) carrier. The polymer concentration, in this case,is high and it can cause poor tabletability and fail the disintegration target for immediate release [2-3]. We have conveniently used Kollitab™ DC 87 L (KTab) as a combined filler, binder, disintegrant and lubricant. KTab is a coprocessed excipient based on 87% of lactose monohydrate, 9% of Kollidon® CL-F (KCL-F), 3% of Kollicoat® IR and 1% of sodium stearyl fumarate. This material provides improved flow, good compaction and enhanced disintegration time [4].

Here, we firstly study the impact of changing the PRX-PVPVA/KTab ratio on the formulation tabletability and compressibility.

This is followed by investigating the influence of the PRX-PVPVA/KTab ratio on three critical quality attributes (CQAs), tensile strength, disintegration time and friability at fixed compression settings.

Finally, this work shows the effects on disintegration time and tensile strength assigned to adding 10% of KCL-F in E50 PRX PVPVA/KTab formulation.

Experimental Design

The STYL’One Nano (MEDELPHARM, FR) instrumented tablet press was used to characterise the compaction properties of formulations containing 20% (E20), 50% (E50), and 80% (E80) of PRX-PVPVA extruded ASDs, the co processed diluent KTab and 0.5% magnesium stearate. The lubricant was added to guarantee that formulations with high amorphous dispersions content (E50-E80) would be sufficiently lubricated. The same procedure was used to evaluate a fourth formulation with 50% ASD and 10% KCL-F (Table 1). The experiment set up and tablet compression were controlled by the Alix software (MEDELPHARM, FR).

The formulation powders were compacted using Euro D flat round tooling (ø =11.28 mm). First, the punch tare procedure and tooling deformation calibration were performed. Then, the filling height was adjusted to obtain the targeted tablet weight (300 mg). A V-shaped profile was used to provide compaction pressures around 40, 80, 120, 160, 200, 240 and 280 MPa.

Tensile strength (MPa) and solid fraction (%) were measured to assess tabletability and compressibility profiles. Friability (n=10) and disintegration time (n=6) were measured using standard methods.

Results

Tabletability profile

Figure 1 shows the tabletability profiles (tensile strength vs compression pressure) of E20, E50 and E80 formulations. In general, the tensile strength increases with the compression pressure. An increase in tensile strength is also observed as the amount of PRX-PVPVA ASD decreases at each pressure; E20 > E50 > E80. Compression settings within 160-280MPa produced E80 tablets with tensile strength around 1.0-1.5MPa, whereas E20 yielded tablet strength ranging between 2.0 and 3.25MPa. E20 produces higher tensile strength due to the higher percentage of KTab in the formulation. As expected, the lactose particles in KTab fragment and form bonds under pressure, producing strong compacts [4].

The tabletability profile can be a useful tool for formulators to select the compression pressures required to produce tablets that will withstand handling and transportation. A tensile strength of 2.0MPa, in most cases, would produce robust tablets. In this study, formulations E20 and E50 should be processed at 160 and 200MPa, respectively, whereas E80 would not reach more than 1.5MPa even at 280MPa. Although a higher compression pressure results in higher tensile strength, operating above 250MPa increases the risk of punch wear and tear and possibly induce tablet lamination due to over-compression.

Adding excipients that could deform at relatively low pressures or exhibit adhesive properties could also improve tabletability and help to achieve the target tensile strength of 2MPa. The KCL-F was selected because of its capacity to provide strength to tablets and to quickly expand upon contact with water. This experiment evaluates the extent to which KCL-F could improve the tablets tensile strength and disintegration time.

For that, a fourth formulation was manufactured and tested in parallel to the binary formulations (E20-E80). The formulation proposed has equal ratio of PRX-PVPVA/KTab to manufacture tablets with the desired dose (20mg PRX in 125mg PRX-PVPVA ASD) whilst achieving a reasonably small tablet size (250-300mg).

Figure 2 shows the tabletability profile of formulations with 50% PRX-PVPVA/KTab. The formulation E50+10KCL has 10% KCL-F. The tabletability profile shows that the addition of KCL-F promoted a significant gain in tensile strength when compared to the formulation with the same amount of PRXPVPVA (E50).

The compaction mechanism and fine grade (45.7μm) explain the KCL-F binding properties; it plastically deforms under pressure. Its particle size (45.7μm) range is much smaller than PRX-PVPVA (200μm) and KTab (160μm) allowing the disintegrant particles to fill void spaces between ASDsdiluent particles. The KCL-F particles distributed through the powder bed dominate the compaction response increasing the bonding capacity [5]. This is an effective strategy to increase tensile strength.

Compressibility profile

Figure 3 depicts solid fraction as a function of compression pressure (compressibility profile).

An increase in compression pressure causes a non-linear increase in the solid fraction of the three formulations tested.

For example, compression pressures between 40MPa and 160MPa result in a 15% gain in solid fraction, while increasing pressure from 160MPa to 280MPa produces a 5% rise in the solid fraction. After 200MPa, the solid fraction values plateau out.

The compressibility profiles of E50 and E50+10KCL-F indicate a significant gain in solid fraction between 40 to 160MPa (Figure 4).

After reaching 85% solid fraction at 160MPa, a subsequent increase in compression pressure yields only a 5% gain in the solid fraction. The profile similarity demonstrated that the PRX-PVPV/KTab ratio and the addition of KCL-F hardly affected the formulation’s compressibility.

PRX-PVPVA ASDs tablet performance

The four formulations were compressed at a pressure equivalent to 200MPa, aiming to produce 300mg tablets. Tensile strength, friability and disintegration time were measured to assess formulation performance (Table 2). The results confirmed that a smaller PRX-PVPVA/KTab ratio improves tablet tensile strength. In addition, the disintegration time decreased from 22 to 4 minutes with the increase of KTab percentage because its primary component is lactose (87%), a water-soluble diluent.

The addition of 10% disintegrant in the E50 formulation resulted in a shorter disintegration time (14 to 11 minutes). The disintegrant absorption and swelling properties compensate for the delay in water intake caused by the PRXPVPVA polymer network gelation.

The friability test assessed the ability of tablets to resist handling and transportation. Interestingly, formulations E20 and E80 passed friability criteria (<1%), while the formulation with equal ratio PRX-PVPVA/KTab failed the test (1.13%). Adding 10% disintegrant to a 50% ASD formulation substantially minimised friability to 0.32%.

See the full brochure Piroxicam Amorphous Solid Dispersions here:

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Source: MEDELPHARM brochure Piroxicam Amorphous Solid Dispersions

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