Twenty grams in two weeks: Material sparing tablet development of direct compression formulations for immediate release applications

Abstract

Material-sparing tablet development (MSTD) describes an approach to tablet formulation development that uses the active pharmaceutical ingredient’s (API) material properties to guide formulation design. The work presented here expands on this methodology and demonstrates its application for any API. Four APIs were randomly selected from the Boehringer Ingelheim opnMe platform to demonstrate the universal applicability of the MSTD regardless of the API properties. Small batches of each API (<20 g of API) were used to mimic early-phase development. Each API was analyzed for particle morphology, flowability, density, and compression behavior. Formulations were then designed to complement these API properties using standard tableting excipients. The powder blends were tested for flowability (≤ 12 mm Flodex) and tensile strength (> 2 MPa) to ensure manufacturability. Tablet disintegration (< 15 min) and friability (NMT 0.8 % loss) were tested to verify tablets met current federal performance standards. Stability testing was done to determine excipient compatibility and overall drug product stability (NMT 0.3 % API loss). This work demonstrated that for a wide variety of different APIs, formulations could be designed and tested for critical manufacturing attributes, and possible failure points could be determined using less than 20 g of API in less than 14 days.

Introduction

Tablets are the most popular method of drug delivery due to their high patient compliance, high production capacity, and comparatively lower manufacturing cost [[1], [2], [3]]. Direct compression (DC) is the preferred method of making tablets as it is the simplest and most economical method. In direct compression, the API and powder excipients (i.e., fillers, disintegrants, lubricants, and glidants) are blended and then fed into a tablet press where pressure is exerted on the powder to form a cohesive compact (tablet). Industrial-scale tablet presses can produce tablets at a rate of up to 450 tablets per second [4], so DC powder blends used to make tablets must be able to consistently feed, compress, and eject at rates that do not hinder production. Any issues with the flowability of the powder blend will result in inconsistent tablet size and compression pressure, which will impact patient dosing and tablet performance [5]. The powder blends must also form cohesive tablets at rates and pressures feasible for industrial tableting equipment [6]. Finally, the tablets made from the powder blend must meet industry standards for hardness, disintegration, and stability [7,8].

Due to the rigorous criteria a DC formulation must meet to be viable for industrial-scale manufacturing, pre-clinical formulation development is often conducted on large-scale tableting equipment to ensure the scalability and industrial viability of the final formulation. Unfortunately, this approach, coupled with the common trial-and-error methods of formulation development, requires kilograms of API and months to years of development work [9,10]. This large investment of resources at such an early phase in drug development is especially problematic given that 90 % of APIs that enter phase I clinical trials will fail to make it to the market [11]. To address this issue, a quality-by-design approach known as material-sparing tablet development (MSTD) has been used to improve the efficiency of formulation development, reduce costs, and shorten the timeline of getting medications to patients [[12], [13], [14]]. In addition to reducing the material and time cost of developing DC formulations, one of the most significant advantages of MSTD is the rapid development and production of tablets for use in pre-clinical and early-phase clinical trials. The Korsch XP-1 automated lab-scale tablet press used to measure DC formulation performance in this work can also produce phase I clinical trial-size quantities of tablets at a rate of 60–3600 tablets per hour, and it can operate with as little as 10 g of powder blend. The flexibility to formulate and produce tablets quickly using less material will enable faster progression to animal studies and clinical trials for safety and toxicity evaluation.

The work described herein applies and expands on the MSTD approach to demonstrate that regardless of the physical-chemical properties of the API, a DC formulation can be developed, or critical failure attributes can be identified using less than 20 g of API in less than two weeks. The key to MSTD is to understand and utilize the material properties of the API and excipients to develop formulations that complement the API, reducing the amount of time and API required. Using small-scale test methods and formulating based on material properties, the limited API is used more efficiently while still assessing the quality of the powder blends and tablets and evaluating manufacturing feasibility. The strategic use of small tablet sizes and reducing the sample size further conserves API and enhances the efficiency of the evaluation process. This work improved MSTD by adding formulation stability testing with only a moderate increase in timeline and API usage. Chemical instability due to reactions between the API and excipients (or contaminants in excipients) have been reported to cause API degradation [15]. In traditional long-term stability testing, tablets would be sealed in containers for months to years at elevated humidity and temperatures then checked periodically to assess the degradation kinetics and product stability [16]. The addition of expedited stability testing to MSTD was done to identify excipient incompatibilities earlier on in the formulation development process. While long-term stability testing would still need to be done on the final drug product, expedited stability testing would identify incompatibilities earlier in the development timeline thus saving time and resources should reformulation be needed.

The nominated formulations exhibited good flowability, chemical stability, and homogeneity and they yielded mechanically robust tablets that effectively delivered API. Setting thresholds for powder blend and tablet performance criteria allowed for rapid screening and elimination of unfeasible formulations, which ultimately shortened the timeline for formulation development and reduced the amount of API required. This work was meant to mimic the pre-clinical stage of formulation development and thus assumes that solubility analysis and optimization would have already been completed before beginning formulation development. The APIs used in this study had solubility on the order of μg/mL, which likely contributed to their abandonment during development (Fig. S1 and Table S1). Therefore, this study primarily focused on the mechanical properties of the formulations and how they can be optimized for DC or identify reasons why certain APIs may not be suitable candidates for DC.

Materials: BI 638683 (BI-1), BI 639667 (BI-2), BI 666877 (BI-3), and BI 729802 (BI-4) were donated by Boehringer Ingelheim and used as received. The molecular structures of the APIs are shown in Fig. 1. APIs were randomly chosen from Boehringer Ingelheim OpnMe platform with no prior knowledge of their physical-chemical properties. It was assumed that random selection of APIs would generate a diverse portfolio of APIs to highlight the versatility of the MSTD approach. Fastflo® 316 (LAC) (Kerry Inc.), Avicel® PH-102 (MCC) (Dupont), Emcompress Anhydrous® (DICAL) (JRS Pharma), and Explotab® (SSG) (JRS Pharma) were donated and used as received. Magnesium stearate (MS) (LFA) was purchased and used as received. The average particle size (D50) of LAC, MCC, and DICAL as reported by the manufacturer is 129 μm, 80–140 μm, and 145 μm respectively.

HPLC-grade acetonitrile and methanol were obtained from Oakwood Chemical Co. (Estill, SC, USA). Deionized water (18.2 MΩ·cm) was generated using a purification system from Total Water Treatment Systems Inc. (Madison, WI, USA) and used for the preparation of HPLC mobile phases and dissolution media. Sodium dodecyl sulfate (SDS) was purchased from Fisher Scientific and used as received.

Intrinsic powder flowability tester (Flodex, Hansen) was used to analyze the flowability of pure API for formulation development, and the powder blends for manufacturability. In industrial formulation development, it is not necessary to quantify the flowability of pure API powders. A qualitative assessment of powder flowability is sufficient to guide formulation development. However, for the sake of this study and highlighting the variation of flowability between different APIs, intrinsic flowability was used to quantify the API flowability. If formulation development had been done without quantifying flowability, the API usage would have been <5 g per API.
To quantify intrinsic flowability, 20 g of pure API powder was sieved with a # 20 sieve (850 μm pore size) and loaded via funnel into the Flodex apparatus. The Flodex value was reported as the smallest orifice the powder would freely flow through 3 consecutive times. The lower the Flodex value the better the intrinsic flowability of the powder. The same procedure was used for blend analysis, except only 10 g of each blend, minus magnesium stearate, was used for testing to prevent lubricant overmixing. Avicel PH-102 is a common tableting excipient and has been reported as the standard for flowability that is industrially viable [17] and therefore was used to set the threshold for successful flowability. Therefore, powders with flowability comparable to or lower than Avicel PH-102 were classified as having successful flowability.

Samples were prepared in a level 1000 clean room to minimize contamination. 1–3 mg of API was dispersed onto carbon tape and compressed air was used to remove excess powder in the hood. Samples were sputter coated with 10 nm of gold/palladium and imaged on a scanning electron microscope (FEI Teneo, Thermo-Fisher). Images for each API were taken at different magnifications due to the diversity in particle sizes. ImageJ software was used to measure discrete particles for length and width and particle lengths were then plotted to determine the particle size distribution of the pure APIs. Particle morphologies were classified using the Handbook of Mineralogy published by the Mineralogical Society of America [18].
The true densities of the pure APIs were measured using a 10 cm3 insert on a helium pycnometer (AccuPyc II 1345, Micromeretics). Sample mass was between 1 and 6 g for all APIs tested due to the difference in bulk density. The test was set for ten purges and ten test cycles, but run precision was used to stop the experiment when the variation between five consecutive measurements was below 0.05 %. The average of all five cycles is the true density used to for Heckel analysis. Pressure and equilibration rates were 19.5 psig and 0.005 psig/min, respectively.

Heckel plots were generated for pure APIs using the method outlined by Patel et al. to prevent negative porosity calculations during Heckel analysis [19]. The mass of API needed to reach a volume of 0.104 cm3 was calculated using Eq. (1).

The tablet press was lubricated using a solution of 1 % magnesium stearate in acetone to apply a thin layer of lubricant to the tooling surface. After the acetone evaporated, the API was manually loaded into the tablet press (XP-1, Korsch) equipped with 6 mm flat circle tooling (Natoli Tooling). Tablets were compressed at a rate of ten tablets per minute (corresponding to 2–5 ms dwell time). Displacement and force readouts for the upper and lower tooling during the entire compression and decompression cycle were recorded and used to calculate the in-die tablet density at varying compression pressures [20]. The in-die density of the tablet was divided by the theoretical 100 % compaction density (true density) measured via helium pycnometer to obtain the relative density (D) (Eq. (2)). By plotting ln (1/(1-D)) as a function of compression pressure (P), a Heckel plot is obtained and the relationship between compression and material response can be elucidated using the Heckel equation (Eq. (3)). In the Heckel equation: D is the relative density, P is the compression pressure corresponding to D, k is the reciprocal of the material’s yield pressure, and A is the in-die bulk density at no pressure. The yield pressure of the compression and decompression curve correspond to “in-die” plastic yield pressure and “in-die” elastic yield pressure, respectively, and are used to determine the predominate compression behavior for a given material. In this study linear regression of the Heckel plots were initially analyzed between the 20–80 MPa region of the compression and decompression phases to calculate the slope of the line. However, the analysis regions were adjusted on each plot until a linear fit of ≥0.98 was achieved. The inverse of the slope was calculated and used to determine compression behavior of each API for use in formulation design.

Using an API loading of 10 %, 10 g batches of each formulation were made (Table 3). All excipients except magnesium stearate were mixed in a Turbula (T2F, WAB) mixer for 5 min at 120 rpm and then sieved with # 20 and a #40 or #60 sieve (850, 425, 250 μm pore size respectively). Three grams of the powder blend were aliquoted for making tablets, and the remainder was used to test flowability. Before tableting, magnesium stearate was added to the powder aliquot and mixed in the Turbula mixer for an additional minute.

To evaluate the API’s impact on flowability, placebo versions of the formulations were made and tested via flodex. The amounts of LAC, MCC, and DICAL in the formulation were increased accordingly to maintain the ratios of the respective fillers and increase the powder volume.
100 mg of powder blend was weighed and manually loaded into the die. Tablets were made from 50 MPa to at least 500 MPa of compression pressure for all formulations. For tensile strength analysis, the dimensions of each tablet were measured using digital calipers (547-500S, Mitutoyo) after ejection. Tablets were then tested for diametrical breaking force (TBH 125, Erweka). Eq. (4) was used to calculate the tensile strength of tablets: where F is the diametrical breaking force, D is the diameter of the tablet, and t is the thickness of the tablet. The results were plotted as a function of compression pressure. Only one tablet per compression pressure was tested for tensile strength to conserve powder.

Tablets made at varying compression pressures were dusted and then weighed. Three tablets per formulation per compression pressure were analyzed instead of the traditional ten tablets to keep with the material sparing nature of the work. In compliance with United States Pharmacopeia (USP) <1216>, tablets were loaded into a friabulator (45–2100, Vankel) and rotated for 4 min at 25 rpm. Tablets were dedusted and weighed again, and the percentage mass loss was calculated.

In keeping with the material sparing nature of the work, if tablets passed friability, the same tablets were used for disintegration testing according to USP standard <701> for uncoated tablets. Immersion fluid was reverse osmosis water at 37 °C and pH 6.5–7. Basket oscillations were 30 strokes per minute with a standard six-tube sample basket (PTZ-S, Pharmatest). The timer started when the bottom of the basket touched the water and stopped when all pieces of the tablet had passed through the wire mesh. Three tablets per formulation were tested.
HPLC standard calibration curves were made for each API (Agilent 1100), and all curves had ≥0.999 linearity. Each API required different HPLC conditions (Table S2–4). Tablets were randomly selected for content uniformity analysis. The average and standard deviation for each formulation were calculated from the quantification of API in 5 individual tablets instead of 10 to conserve material. Tablets were weighed and then placed in a 100 mL volumetric flask before disintegrating using either 90:10 acetonitrile-water or 90:10 methanol-water. Samples were sonicated for 15 min and filtered with a 0.2 μm PTFE syringe filter before HPLC analysis. API concentration was calculated using the standard curve. An acceptance criterion of no more than 15 passes the USP <905> standard for acceptable consistency in dosage form. Since acceptance criteria (AV) (Eq. (4)) is calculated using both the average API loading (x̄) and the relative standard deviation (SD), it evaluates both the amount of API added to the formulation and the tendency for a blend to segregate. M is the reference value for target API dosing. If 98.5 % ≤ x̄ ≤101.5 %, then M= x̄. If x̄ >101.5 % then M = 101.5 %. If, as was the case in this study, x̄ <98.5 %, then M = 98.5 %.

A modified protocol of the accelerated stability assessment program (ASAP) [21,22] was used to screen the short-term stability of the formulations. Increasing the temperature and humidity increases the degradation rate of the API and can be used to highlight API stability issues and exaggerate incompatibilities between the API and excipients. The full ASAP procedure is intended to model and predict the long-term shelf stability of final products (three-year stability). A reduced timeline and number of testing conditions were used in this study since the intended use of these formulations (pre-clinical and early-phase clinical trials) would require stability for only a few months, not years. If the formulations show promising results in early clinical trials, a more thorough ASAP study will be done on the nominated formulations.

Tablet samples were placed inside water vapor permeable vials then placed in humidity chambers with different saturated salt solutions to achieve specified temperature and humidity conditions (20 °C/65 % RH, 20 °C/43 % RH, and 70 °C/75 % RH). These conditions are a subset of the temperature and humidity conditions used in the published ASAP method [21,22] to reduce the number of samples needed for testing. These conditions are intentionally harsh to stress the drug product and expose potential excipient incompatibilities or API sensitivity to heat and humidity. A diagram of the humidity chamber setup can be found in Fig. S2. After five days, samples were analyzed via HPLC using the same sample preparation method outlined in content uniformity testing. Percent degradation was calculated via Eq. (6) to normalize for API content and HPLC variation. Degradant peak areas were reported as a percentage of the main band API peak area. Degradant peaks greater than 0.3 % of the area of the API peak had sufficient degradation to signal an excipient incompatibility or API instability [21].

The dissolution study was performed using a 1 % (w/v) solution of SDS in water as the dissolution medium, due to the limited solubility of the API in 0.1 N HCl (Fig. S1). Although the dissolution medium is not biologically relevant, the test was conducted to support the disintegration results and demonstrate that the tablet breaks apart and releases the API. The dissolution testing was conducted in 900 mL of media at 37 °C ± 0.5 °C using a paddle apparatus (USP Type II) at a rotation speed of 100 rpm. The test was conducted on tablets produced at compression pressures that demonstrated adequate friability and disintegration time. In alignment with the material-sparing approach, a single tablet was tested per formulation per compression pressure. Samples were withdrawn at 0, 10, 30, 45, and 60 min, filtered through a 0.2 μm PTFE syringe filter, and analyzed via HPLC. API concentrations were determined using a standard calibration curve.

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