Optimization of a Twin screw melt granulation process for fixed dose combination immediate release Tablets: Differential amorphization of one drug and crystalline continuance in the other

Interest in Twin Screw Melt Granulation (TSMG) processes is rapidly increasing, along with the search for suitable excipients. This study aims to optimize the TSMG process for immediate-release tablets containing two different drugs. The hypothesis is that one poorly water-soluble drug requires amorphous conversion for improved dissolution, while the other water-soluble drug, with a higher melting point (T_m), remains more stable in its crystalline form. Ibuprofen (IBU) and Acetaminophen (APAP) were chosen as the model drug combination to test this hypothesis. Various diluents, binders, and disintegrating agents were assessed for their impact on processability, crystallinity, disintegration, and dissolution during development. The temperatures used during processing were below the T_m of all components, except for IBU. Melted IBU acted as a granulating aid in addition to the binders in the formulation, facilitating granule formation. Physicochemical analyses by Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) confirmed the complete conversion of IBU into an amorphous state and the preserved crystalline nature of APAP. Saturation solubility studies showed an improvement in IBU’s solubility by ∼ 32-fold in 0.1 N HCl. Poor tablet disintegration performance led to the addition of disintegrating agents, where osmotic agents (sorbitol and NaCl) were found to significantly enhance disintegration compared to super disintegrants. The optimized formulation showed an enhanced IBU release (∼20 %) compared to the physical mixture (∼12.5) in 0.1 N HCl dissolution studies.

Introduction

In recent years, the pharmaceutical industry has shown a growing interest in adopting continuous manufacturing processes for the design, optimization, and production of pharmaceutical products. Continuous manufacturing technologies involve the integration of sequential manufacturing steps into a unified system, allowing the entire process to occur in a streamlined process in a single location without delays (Maniruzzaman and Nokhodchi, 2017). In comparison to traditional batch processing, continuous manufacturing stands out as a more adaptable method, facilitating superior production scalability. This adoption of continuous processing is typically motivated by the need for fast and cost-effective high-volume production. Beyond large-scale production, continuous manufacturing technology can reduce development costs for new medications and enhance the ability to produce smaller batch volumes of targeted therapies tailored to smaller patient populations (Domokos et al., 2021, Nambiar et al., 2022). Despite the array of technologies available for continuous manufacturing, recent years have witnessed a substantial shift within the pharmaceutical sector towards incorporating Hot Melt Extrusion (HME) as an essential component of continuous manufacturing processes. This transition is driven by the potential benefits it possesses, such as improved product quality, enhanced process efficiency, and increased flexibility in drug formulation and production (Gallas et al., 2023). This process involves the controlled heating of materials like drugs, polymers, etc. above their Tm or glass transition temperature (Tg), and extruding them typically in a molten, semi-solid state. HME can be used to create a variety of products and processes (eg: wet granulation) with slightly modifying the equipment (Patil et al., 2024).

HME technology can also be employed for a granulation method such as Twin Screw Wet Granulation, Twin Screw Dry Granulation, and Twin Screw Melt Granulation (TSMG), which outperforms traditional wet and dry granulation techniques (Dhaval et al., 2022, Rao et al., 2021). TSMG efficiently disperses thermal and shear energy throughout the system, resulting in the formation of uniform granules. This process is particularly beneficial for achieving an even distribution of low-quantity materials throughout the system (Steffens and Wagner, 2019). Furthermore, TSMG provides greater flexibility in terms of selecting residence time, temperature, and screw speeds, which aids in preventing thermal degradation of formulation components (Forster et al., 2021). The high flexibility in choosing screw configuration allows for adjustments in distributive and dispersive mixing levels, as well as control over the degree of agglomeration, particle growth, and homogenization (Steffens and Wagner, 2019).

In the TSMG process, various excipients like diluents, binders, and disintegrating agents (for immediate-release formulations) can be used as intragranular materials. Usually, the temperatures in TSMG are maintained above the glass transition temperature of the binder, which aids in the granulation. Therefore, the concentration of the binder and its glass transition temperature relative to the Tm of API are critical attributes in choosing the binder. Sometimes, temperatures above the Tm of API may be used, if the amorphous nature of API is desired in the end product (Batra et al., 2021). The physical and chemical stability of the API, among other things, determines whether to convert the API into amorphous or retain the crystalline nature in the formulation, during the manufacturing process. Sometimes, the molten API can act as a binder or as a co-binder during the melt granulation. The granules generated by TSMG have reduced porosity, as the molten binder and/or API fills the internal space of the granules, aided by the continuous pressure applied within the extruder (Steffens and Wagner, 2021). Hence, it is crucial to include an intragranular disintegrant during the TSMG process, and if necessary, the disintegrant may also be added extra granularly (Perissutti et al., 2003, Walker et al., 2007).

The primary objective of this study was to establish a continuous manufacturing process utilizing TSMG to produce immediate-release fixed-dose combination tablets. Wherein, it is hypothesized that one of the drugs requires amorphous conversion to enhance its solubility and dissolution properties, while the other drug exhibits high solubility in its natural crystalline form. However, converting the latter drug into an amorphous state could compromise its stability. Additionally, the drug that needs amorphization should have a melting temperature lower than the drug that stays undisturbed in its crystalline state. Therefore, we have chosen Ibuprofen (IBU) and Acetaminophen (APAP), a widely marketed fixed-dose combination, as model drugs.

The study investigates the impact of various factors, including the concentrations of excipients such as diluents, binders, and disintegrants. Additionally, various process parameters like screw configuration, screw speed, and barrel temperature are examined to assess their influence on the characteristics of the final product. Emphasis is placed on understanding the factors affecting the crystallinity of IBU and APAP, disintegration, and dissolution of the compressed tablets.

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Materials

APAP was procured from Mallinckrodt pharmaceutical company and Ibuprofen was supplied by BASF. Most of the excipients and polymers used in the project (Ludipress®, Ludiflash®, Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® VA 64, Kollidon® 25, Kollidon®30, and Kollicoat® IR) were gifted by BASF Pharma. NEOSORB® (Sorbitol) gifted by Roquette, sodium chloride procured from Fisher Scientific, and all other organic solvents used of analytical grade procured from Fisher Scientific.

Siva Ram Munnangi, Nagarjuna Narala, Preethi Lakkala, Sateesh Kumar Vemula, Sagar Narala, Lindsay Johnson, Krizia Karry, Michael Repka, Optimization of a Twin screw melt granulation process for fixed dose combination immediate release Tablets: Differential amorphization of one drug and crystalline continuance in the other, International Journal of Pharmaceutics, 2024, 124717, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124717.

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