Evaluation of the Potential of Novel Co-Processed Excipients to Enable Direct Compression and Modified Release of Ibuprofen
Abstract
Background/Objectives: Improving the production rates of modern tablet presses places ever greater demands on the performance of excipients. Although co-processing has emerged as a promising solution, there is still a lack of directly compressible excipients for modified-release formulations. The aim of the present study was to address this issue by investigating the potential of novel co-processed excipients for the manufacture of modified-release tablets containing ibuprofen.
Methods: The excipients were prepared by melt granulation of lactose monohydrate with glyceryl palmitostearate as a binder. The influence of glyceryl palmitostearate particle size, ibuprofen content, compression pressure, and compression speed on the compaction behavior of the tablet blends was analyzed.
Results: Novel co-processed excipients ensured good flowability and acceptable mechanical properties of the tablets containing up to 70% ibuprofen. Furthermore, lipid-based co-processed excipients proved to be very promising for directly compressible formulations with high-dose, highly adhesive active pharmaceutical ingredients such as ibuprofen, as they do not require additional lubricants. The influence of compression speed on the tensile strength of the tablets prepared was not pronounced, indicating the robustness of these directly compressible excipients. The investigated lipid-based excipients enabled a prolonged release of ibuprofen over 10 h.
Conclusions: The novel lipid-based co-processed excipients have shown great potential for directly compressible formulations with modified release of high-dose, challenging active pharmaceutical ingredients.
Introduction
Although tablets can be prepared by various methods, they are most commonly prepared by compression of powder particles or granules [1]. Compression of the mixture of the active pharmaceutical ingredient (API) and excipients usually requires granulation prior to compression into tablets due to poor flowability and/or compression properties. The use of directly compressible diluents can in some cases help to overcome the problems associated with the poor flow/compaction properties of the API and enable the use of direct compression as the simplest, most time, energy, and cost-efficient method of tablet manufacturing. For this reason, great efforts have been made to improve the functionality of commonly used excipients, such as lactose, by modifying the particle size, morphology, crystallinity, porosity, and surface area through the application of various processing techniques [2]. However, the requirements for good flowability and good compression behavior often pose conflicting demands on particle engineering. Therefore, it can be a great challenge to modify a single excipient to achieve improved flowability and good compaction properties while maintaining high dilution capacity, all of which are required for direct compression.
The increasing demand for high-performance excipients is being further driven by innovations and improvements in tablet presses. Modern tableting machines can produce hundreds of thousands of tablets per hour up to more than one million tablets per hour [3,4,5]. It has been reported that various tableting issues, such as die wall and punch-sticking, tablet defects (e.g., capping and lamination), and weight variations, are becoming more prominent in high-speed production [6,7,8]. With the rapid improvement in production rates of modern tableting machines, the requirements for directly compressible formulations are constantly increasing. Furthermore, compression per se is a continuous process. The development of equipment that enables the accompanying unit operations in direct compression (e.g., weighing and mixing) to be carried out continuously, as opposed to traditional batch processing, and the introduction of process analytical technology (PAT) as a tool for process control and monitoring, have brought direct compression even more to the fore as the method of choice in tablet production. However, this places even higher demands on the performance of directly compressible excipients, especially for formulations with APIs characterized by poor flow and/or compression properties [9]. The development of co-processed excipients has arisen as a promising solution to these growing challenges. The International Pharmaceutical Excipients Council defines a co-processed excipient as a combination of two or more excipients designed to physically alter their properties in a way that cannot be achieved by simple physical mixing, and without significant chemical alteration [10]. An appropriate processing technique is applied to achieve a purely physical interaction between excipients, leading to improved functionality and synergy between them [11]. Conventional methods such as spray drying and wet granulation are still most commonly used for co-processing [2,11,12]. However, a few recent studies have shown the great potential of melt granulation as a more environmentally friendly method for the production of high-performance, multifunctional co-processed excipients [13,14,15,16].
Since the introduction of co-processing in the late 1980s, various co-processed excipients have been developed for direct compression of immediate-release tablets, many of which are intended for orally disintegrating tablets [17,18]. Many of these excipients are lactose-based [2,19]. Interestingly, there is only one commercially available co-processed excipient that is designed for direct compression of modified-release formulations, namely, lactose co-processed with hypromellose [20,21]. There are few reports in the scientific literature on the development of directly compressible, co-processed excipients for modified-release formulations, and these generally involve complex and/or energy-intensive preparation methods [22,23]. For example, Patel and coworkers prepared the co-processed excipient consisting of glyceryl monostearate, dicalcium phosphate dihydrate, and polyvinylpyrrolidone K30 by wet granulation [22]. Serrano-Mora et al. developed a co-processed excipient for controlled-release formulations by preparing solid lipid nanoparticles of Compritol® 888 ATO and adsorbing them onto a directly compressible dicalcium phosphate dihydrate [23].
Despite the tremendous efforts that have been directed towards the development of directly compressible excipients in recent decades, formulations with a high API content represent a major challenge. Highly dosed APIs greatly affect the overall processability of the tableting mixture, making wet granulation often the only choice [24,25]. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that is widely used in solid oral dosage forms. It is administered in relatively high single therapeutic doses, ranging from 200 to 800 mg [26]. Its poor flowability, poor compression properties, and a strong tendency to stick to punch surfaces during tablet compression are well-known and widely described in the literature. These properties in combination with the high ibuprofen content in the tableting mixture make the tableting of ibuprofen formulations quite challenging and in most cases lead to a granulation step prior to tableting [27,28,29,30].
Given these challenging properties, ibuprofen was selected in this study as a model API for direct compression with novel co-processed excipients containing lactose monohydrate and Precirol® ATO5 (glyceryl palmitostearate). In our previous studies, lipid-based co-processed excipients have shown great potential for direct compression, not only in terms of their good flowability and compactability but also their antiadhesive and lubricating properties [15,16]. In addition, lipid excipients are known as matrix-forming agents in modified-release tablets [31,32]. However, to our knowledge, lipid excipients have not yet been used to prepare co-processed lactose-based excipients for modified-release formulations. This article is a revised and expanded version of a paper entitled ‘From co-processing by melt granulation towards direct compression of high ibuprofen loaded formulations’, which was presented at the 14th CESPT, Ohrid, North Macedonia, 28–30 September 2023. Namely, the present study builds on the results of the conference paper on the influence of formulation and compression-related parameters on the compaction behavior of novel co-processed excipients [33]. This research was continued and the potential of co-processed excipients for use in formulations with prolonged release was evaluated. Therefore, the aim of the present study was to evaluate the suitability of novel co-processed excipients obtained by in situ fluidized bed melt granulation for the production of modified-release tablets with challenging, high-dose API by direct compression. More specifically, the goal of this study was to investigate the influence of initial particle size of Precirol® ATO5, ibuprofen content, compression pressure, and compression speed on the compaction behavior of ibuprofen tablet blends as well as ibuprofen dissolution from directly compressed tablets.
Download the full article as PDF here Evaluation of the Potential of Novel Co-Processed Excipients to Enable Direct Compression and Modified Release of Ibuprofen
or read it here
Materials
Co-processed excipients were prepared by using glyceryl palmitostearate (Precirol® ATO 5 , Gattefossé S.A.S, Saint-Priest Cedex, France) as a meltable binder and lactose monohydrate (Carlo Erba Reagents, Milan, Italy) as a filler. Ibuprofen (Fagron, Rotterdam, The Netherlands) was selected as the model drug. Sodium Hydroxide (Fisher Scientific, Loughborough, UK), potassium phosphate monobasic (Sigma-Aldrich Chemie GmbH, Steinheim, Germany), and hydrochloric acid (Avantor Performance Materials Poland S.A., Gliwice, Poland) were used for dissolution media preparation.
Following excipients are mentioned in the study besides other: Compritol® 888 ATO, polyvinylpyrrolidone K30
Aleksić, I.; Glišić, T.; Ćirin-Varađan, S.; Djuris, M.; Djuris, J.; Parojčić, J. Evaluation of the Potential of Novel Co-Processed Excipients to Enable Direct Compression and Modified Release of Ibuprofen. Pharmaceutics 2024, 16, 1473. https://doi.org/10.3390/pharmaceutics16111473
Read also our introduction article on Binders here:
