Flow Behavior of Co-Processed Excipients Using Lactose and Microcrystalline Cellulose as Bulk Fillers

Abstract

Powder flow is a constant concern in the production of solid dosage forms. Its concise and reliable determination and improvement are challenges for the pharmaceutical industry. Lactose (Lac) and microcrystalline cellulose (MCC) are both widely used pharmaceutical fillers either alone or mixed. In this study, flow determination was performed through methods described on the European Pharmacopoeia. The results obtained showed poor flow and cohesive behavior for Lac and MCC powders and their mixtures (co-processed excipients). The 50% Lac_MCC mixture, with colloidal silicon dioxide (CSD) as the glidant in different proportions, showed relevant improvements in flow. In addition, the effective angle of wall friction (φx), the effective angle of internal friction (φe), arching, and ratholing were also determined, demonstrating the flow behavior in the discharge equipment. Outlet diameters that prevent blockages or insufficient powder flow were also determined. With this study, it was concluded that it was possible to prepare a co-processed excipient with optimal flow behavior composed of Lac_MCC and CSD as a glidant.

Introduction

For many diseases, solid oral dosage forms (SODFs) are the best option for their treatment due to their features, such as dosage accuracy, compliance, stability, and price, among others [1]. Their formulation and manufacture, involving active pharmaceutical ingredients (APIs) and excipients, to produce a medicine with quality, safety, and efficacy, pose many challenges, both in the choice and characterization of raw materials, as well as in certain critical manufacturing steps. Many of these challenges, such as formulation development, good flow, correct particle aggregation, and desired disaggregation of granules and tablets, can be solved by using the right excipients [2,3]. But what is the right excipient? The right excipient is one with the appropriate physicochemical and mechanical characteristics to create SODFs with suitable structural and functional characteristics that facilitate dissolution and permeation (improving bioavailability). An excipient can be a colorant, diluent, binder and adhesive, lubricant, glidant, and disintegrant [4,5,6,7,8].

As a rule, all excipients should be inert, but some have a recognized action or effect in certain circumstances that is undesirable [9]. Since most of them are present in greater amounts than the API, and therefore influence its release, their choice must be judicious in terms of their physicochemical properties and rheology (flow). The aim of this selective choice is to ensure a good manufacturing process, adequate API release and stability, and patient compliance, as well as other aspects that guarantee quality, safety, and efficacy during use or storage [3,4]. In addition to these pharmaceutical factors, this choice also depends on cost, accessibility and purpose, regulatory approval, and suppliers.

Excipients are generally classified according to their functions. One of the categorizations involves delineating these primary substances into those that affect compressibility (such as diluents, lubricants, glidants, binders, anti-adherents) and those that impact biopharmaceutical, chemical, and physical stability (such as disintegrants, flavorings, sweeteners, colorants) [10]. They also can be classified into modified, co-processed, and novel excipients [11]. In addition, the terms “multifunctional excipients” and “high-functionality excipients” are also often referenced in the literature [12]. Besides these classifications these raw materials are also classified into four categories, as described below [6]: (a) Single chemical entity, that corresponds to excipients with a single excipient [6]; (b) Physical mixture of excipients corresponding to the mixture of two or more excipients without any considerable alteration, i.e., each one remains physically different and separate at a particulate level [13]; (c) New chemical entities or novel excipients, corresponding to a new excipient used for the first time or via a novel mode of administration [14]; (d) Co-processed excipients, that correspond to two or more known excipients which, through co-processing methods (granulation, spray drying, melt extrusion, and milling), undergo modifications to their physical properties without altering their stability or chemical composition; this procedure was initially created to improve the flow, compressibility, and disintegration of solid formulations [15].

Formulations containing one or more of these excipients intended to produce SODFs can have inappropriate pharmacotechnical properties, such as poor flow. When this happens, the processing of these dosage forms is compromised, affecting the content uniformity, the granulation and tableting performance, as well as the hardness, friability, API release of the tablets and granules, and the mass of capsules and tablets [16]. This parameter depends on the particle’s characteristics, such as size, surface texture, shape and density, interactions with each other, and interactions with surfaces of the equipment, such as the design of the hopper, the angle of the wall, and the diameter of the orifice. In addition, environmental conditions such as relative moisture and temperature as well as other factors such as static electricity and the force of gravity can also influence flowability [17,18,19].

This is a mandatory property because it conditions the processing of SODFs, that should be evaluated and improved if necessary. Among the various techniques employed to enhance flow characteristics, the incorporation of glidants is frequently regarded as a primary option. Colloidal silicon dioxide (CSD), magnesium stearate (MgSt), and talc are the most used glidants [20]. The concentrations of these adjuvants in the mixtures are minimal (0.1–0.5% for CSD, 0.25–5% stearate, and 1–10% for talc), and their distribution must be uniform to produce the best lubricating effect [21,22,23,24]. The action of glidants to produce their effects can be expressed by different mechanisms: reduction in cohesion forces (van der Waals attractions) between particles, reduction in surface roughness by filling in the irregularities and depressions on the surface of the particles, reduction in void spaces between them, and consequently, reduction in interparticle friction coefficient [20,25,26,27]. Of the products cited above, CSD has good glidant characteristics due to its amorphous nature, the small size of its particles, and the sphericity of the same [20,21,28].

Their nano scale (approx. 10–40 nm) [29,30], which can have a negative effect due to particle aggregation, is extremely relevant to their action as lubricants. For values less than 10 nm, glidants reduce contact force because they fail to separate particles through their spacer action, thus having the opposite effect [31]. During the mixing process, these aggregates break down and their particles disperse, adhering to the surfaces of the filler (diluent) or API particles, which are typically micron-sized. With specific surface area values (BET, m2 g−1) ranging from 90 to 330 and a tamped density of approximately 50 to 280 g cm−1 (Evonik), these glidants have excellent characteristics for improving the flow of powders and powder mixtures. Its action, based on the mechanisms already described, results from a separation of the surface of the filler (diluent) particles by the creation of glidant points (roughness, asperities) through van der Waals forces, with a concomitant reduction in the cohesive/adhesive forces between the filler particles [32,33]. However, an optimal amount of glidant depends on the mixing conditions and the morphology of the powders [34]. In more recent developments, nanomaterials (NMs) have emerged as significant components within glidants across numerous industrial domains, including pharmaceuticals and cosmetics, among others [25,35]. The European Commission described NMs as natural, incidental, or manufactured material containing free particles, in aggregate or agglomerate form, of which at least 50% of the particles, in numerical size distribution, have one or more external dimensions between 1 and 100 nm [36].

Among the various methods to assess the flow characteristics of the bulk powders, powder mixtures, mixtures with glidants, and granulates without or with glidants prior to their processing are those described in the Ph Eur. The most frequently used are the repose angle, compressibility index (CI) and Hausner ratio (HR), flow through orifice, and shear cell [18,37,38,39,40].

Conventional methods produce results influenced by several factors that can lead to values that are not representative of the parameter under analysis. For example, the angle of repose is a quick and easy method that does not represent an intrinsic property of the powder. It is based on determining the angle formed in relation to the horizontal base by a cone-like pile of powder, created when it passes through a funnel-like container [41]. The formation of this cone depends on particle segregation, consolidation, powder aeration, and gravitational force. Therefore, the values determined depend on the bulk powder density, the friction and cohesive forces between particles, and the friction forces between particles and funnel walls, as well as the cohesive strength of the powder itself. When the angle is greater than 40°, the powder flow is classified as poor (cohesive powder) [42,43]. Regarding the aerated and tapped densities of the powders that allow the calculation of the CI and HR, their values can vary greatly due to the number of voids existing between their constituent particles and the non-uniformity of the taps. The parameters are related to the consolidation state of the material with and without tapping. Aerated density results from dividing the mass by the volume it occupies without tapping, while the tapped density results from dividing the mass by the volume it occupies after tapping [42,44]. Both CI and HR allow an understanding of powder flow behavior in terms of its cohesiveness, that is, in terms of particle–particle friction that occurs in a moving powder mass and not in a static condition. These parameters depend on several factors, such as apparent densities of the powder, variation in powder volume due to gravity under tapping, and lack of control of external stress during tapping [42,45]. The HR, which is derived from the ratio of tapped density to aerated density, serves as a valuable metric for comprehending particle friction by quantifying the resistance that the particles exert on their movement. HR values above 1.46 mean that the powder has a very poor flow, and below 1.25, that it has a fair flow [42,46]. CI, like the previous one, demonstrates the resistance that the powder particles, due to their interactions, imposes on the flow. It is an indirect determination of the flow and compressibility resulting from the reduction in the powder volume obtained by the difference between the aerated and tapped densities. CI values below 20% correspond to fair powder flowability [45].

Of the various methods mentioned, the measurement using a shear cell tester produces the most reliable results, with an accurate and precise assessment of powder flow. This method is based in the determination of the flow index (ffc) that relates the unconfined yield strength (σc) with the major principal consolidation stress (σ1). Its numerical values allow for determining the powder flow based on a scale of 0 to >10 [18]. Unconfined yield strength (σc) or compressive strength represents the stress that promotes failure, named “incipient flow”, of the consolidated bulk solid. When this occurs, the consolidated bulk solid begins to flow. The flow function (FF), which is solely determined by cohesion and pre-consolidation stresses [47,48], devoid of any friction coefficients, is derived from the σc versus σ1 curves, utilizing the MohrCoulomb approach. For a storage duration (t) of 0, this is referred to as the instantaneous flow function (IFF), while for a storage duration (t) exceeding 0, it is termed the time flow function (TFF) [17,21,22,49,50,51]. Through the shear cell method, it is also possible to determine other parameters that help in flow characterization such as the effective angle of internal friction (φe), effective angle of wall friction (φx), critical arching and critical ratholing, HR, and CI. Within these parameters, φe and φx allow for predicting the slopes of the equipment wall surfaces and the outlet dimensions [52,53] for an efficient flow. The discharge process is more influenced by external stress (σ0), which depends on the powder density and the outlet diameter, than by σ1. For Jenike, formation of the arch only occurs when ffc is less than 1.3 (very cohesive powder) [19,54]. Thus, the larger the σ1, the larger σc will be, and, therefore, the greater the probability that σc will exceed σ0. When this occurs, there is a greater ease of obstruction in the powder flow under the influence of two contradicting factors (σ0 and σc) [18,55]. σ1 versus σ0 represents the factor flow and σ0 the stress “at the abutment of the dome” according to Jenike [56,57].

Since powder flow is a real problem in processing and production of SODFs, improving this parameter brings benefits to the pharmaceutical industry in terms of product quality and production costs. Therefore, the aim of this work was to prepare and evaluate the flow behavior of a mixture of two excipients both with poor flow, lactose (Lac) and microcrystalline cellulose (MCC), in different proportions, to verify whether there was a synergistic effect on the improvement of the flow. Lac and MCC are both widely used pharmaceutical fillers, with their effectiveness determined by their specific formulation and properties due to their distinct flow behaviors and compressibility characteristics. Lac exhibits brittleness, whereas MCC functions as a plastic deformer with superior compressibility, and their interplay or specific grades can notably influence flow characteristics [58,59]. In a second phase and due to the obtained results, the addition of colloidal silicon dioxide (CSD) as a glidant in different ratios was studied to improve the flow behavior of the mixture, Lac_MCC (50:50%, w/w).

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Materials

Lactose (batch: 217155-P-1) and microcrystalline cellulose (batch: 181117-P-2) were purchased from Acofarma, Barcelona, Spain. Colloidal silicon dioxide (CSD), Aerosil R972 Pharma) (batch: 1032083012) was a gift from Evonik, Essen, Germany.

Salústio, P.J.; Cingel, D.; Nunes, T.; Catita, J.; Sousa e Silva, J.P.; Costa, P.J. Flow Behavior of Co-Processed Excipients Using Lactose and Microcrystalline Cellulose as Bulk Fillers. Powders 2026, 5, 4. https://doi.org/10.3390/powders5010004

Read also our introduction article on Microcrystalline Cellulose here: