Fluid bed granulation – Process optimization

Introduction

Fluidized bed granulation (FBG) is a well-established industrial process for a variety of value-added granular products and product intermediates. In pharmaceutical manufacturing, FBG is used to achieve granular intermediates for oral solid dosage forms, primarily tablets. Uniform size distribution and bulk density are often critical material attributes of the intermediate granules, the former being a proxy for compositional homogeneity, and the latter for consistent tableting. While fluid bed granulation is a highly capable process, it can be more expensive compared to other technologies, and requires effective balance of control variables. Hence, it is often used for more challenging formulations where other processes lack sufficient capability. The focus of the current work is on the control of granule size and shape distributions in the context of a challenging pharmaceutical formulation; where the objective of having a narrow size distribution correlates with compositional uniformity, and the control of shape distributions affects packing and densification in tableting.

Micronization is an important technology in the pharmaceutical industry, where the diameter of powder particles is reduced to the micrometer as well as nanometer scale in some cases, to enhance the dissolution rate of Active Pharmaceutical Ingredients (APIs), subsequently improving their bioavailability [[1], [2], [3]]. Granulation, a process of agglomerating particles by creating bonds between them, is employed to produce granules with defined characteristics or to enhance powder functionality [4]. Fluidized bed granulation is a form of wet granulation, which utilizes a liquid to bind particles, forming discrete granules that are dried within the process and then discharged for use in downstream processing. Usually, the liquid is an aqueous solution of a binder polymer. Wet granulation is especially applicable to formulations that are poorly suited for a dry-mixing and direct-compression pathway. These formulations include cases where it is advantageous to have micronized powders (e.g., D90 < ∼50 μm), especially with extremes in API content: either very low (e.g., less than around ∼5 % of the total mass) or very high (i.e., more than ∼40 % of the total mass) API content in a mixture. For low-dose formulations, achieving content uniformity is critical, as the small amount of API must be evenly distributed throughout the mixture. High-dose formulations often present challenges related to flow properties and bulk density, which wet granulation can help optimize.

Ideally, the FBG process introduces the binder as an atomized spray coming into contact with the fluidized powder. Optimizing the fluidized spray zone in an FBG system is crucial for producing granules with consistent quality and desired attributes, making it an integral part of the granulation process in pharmaceutical manufacturing and other industries. The effectiveness of the spray zone directly influences the characteristics of the formed granules, including size, shape, and uniformity. However, stable fluidization of finely micronized powder has challenges. Geldart’s type “C” powders are characterized as being cohesive and difficult to fluidize with gas flows [5,6]. As a result, the initial stages of fine-powder granulation can be especially challenging in a fluidized bed. Having a distribution of particle sizes can help stabilize fluidization; but finer powder is vulnerable to elutriation away from the spray zone [7].

Granulation is most effective in the spray zone, yet the finer powder is typically swept away from the spray zone by the fluidization air flow, which introduces a fundamental contradiction and highlights the importance of flow fields in the production of uniform granules. Classically, this problem statement has been managed industrially through iterative optimization of inlet airflow and binder spray rates to empirically control elutriation, however this approach is inefficient and experimentally burdensome.

The manipulation of powder surface chemistry, whether through upstream processes like milling or in a pre-mixing step, plays a pivotal role in shaping the properties and performance of granules in pharmaceutical formulations. In this context, the introduction of a pre-granulation step, which involves pharmaceutical formulations containing powders (excipient and active) and binder solutions, emerges as a means of influencing the granule structure and its ensuing property-performance profile [8]. Of particular significance in this study is the exploration of pre-wetting, a process in which a powder pre-blend (e.g., pharmaceutical excipient(s) and API) is “primed” with a relatively small amount of moisture prior to fluidization and granulation with a spray-binder [9]. The effect of pre-wetting the pre-blend is especially relevant to microcrystalline cellulose (MCC) excipients that are highly absorbent [10]. For example, the penetration time of a viscous binder solution in a static bed having a blend of MCC and micronized acetaminophen (μ-APAP) was shown to be significantly accelerated by pre-wetting the powder [11].

The inclusion of powder pre-wetting in the overall FBG process is of interest with formulations having micronized drug substances. Pre-wetting the powder mix establishes a “pre-granulated” state having cohesive interaction between drug and excipient particles, making a micronized drug less susceptible to elutriation during the transfer and early stages of the fluid bed granulation process. Pre-wetting provides a means toward more robust and stable processing and manufacturing of high value-added products such as pharmaceuticals.

In this paper, we consider flow paths of particles in a toroidal fluidized bed granulator: the Xelum R&D Fluidized Bed Granulation System (Hüttlin GmbH, Syntegon Company, Schopfheim, Germany) having sensors and adjustable parameters for monitoring and controlling the granulation process. One of the key parameters used to evaluate the quality of granules produced by FBG is the particle size distribution (PSD). The PSD can be described using various metrics, one of which is the geometric standard deviation (σg), a dimensionless parameter that provides a measure of the spread of the PSD and is commonly used to evaluate the degree of uniformity of the granules. In this study we consider that the breadth of the resulting granule size distributions correlates with flow path residence times; more narrow size distributions were obtained by minimizing the mass fraction weighted residence time in the elutriation-blowback loop. The analysis of in-line pressure drop data was used to infer the balance of residence times in the fluidization (i.e., binder spray) and elutriation loops. Strategies for achieving narrow granule size distributions include dynamic control of blowback pressures during the granulation process and pre-wetting the mixture in advance of fluidization.