Investigation of the Electrokinetic Potential of Granules and Optimization of the Pelletization Method Using the Quality by Design Approach

Abstract

The preparation of pellets using a high-shear granulator in a rapid single-step is considered a good economic alternative to the extrusion spheronization process. As process parameters and material attributes greatly affect pellet qualities, successful process optimization plays a vital role in producing pellet dosage forms with the required critical quality attributes. This study was aimed at the development and optimization of the pelletization technique with the Pro-CepT granulator. According to the quality by design (QbD) and screening design results, chopper speed, the volume of the granulating liquid, binder amount, and impeller speed were selected as the highest risk variables for a two-level full factorial design and central composite design, which were applied to the formula of microcrystalline cellulose, mannitol, and with a binding aqueous polyvinylpyrrolidone solution. The design space was estimated based on physical response results, including the total yield of the required size, hardness, and aspect ratio. The optimized point was tested with two different types of active ingredients. Amlodipine and hydrochlorothiazide were selected as model drugs and were loaded into an optimized formulation. The kinetics of the release of the active agent was examined and found that the results show a correlation with the electrokinetic potential because amlodipine besylate can be adsorbed on the surface of the MCC, while hydrochlorothiazide less so; therefore, in this case, the release of the active agent increases. The research results revealed no significant differences between plain and model drug pellets, except for hydrochlorothiazide yield percent, in addition to acceptable content uniformity and dissolution enhancement.

Introduction

Pellets can be defined as free-flowing, spherical, or semi-spherical particles with a controllable narrow size distribution of an average size of 0.5 mm to 2 mm, intended generally for oral administration. They have advantageous characteristics over single delivery systems, which include free-flowing spherical particles with a smooth texture, optimum drug content, and different drug control-release profiles, in addition to mixing incompatible active pharmaceutical ingredients in the same dosage form. They also improve drug absorption from the GIT and bioavailability with low drug toxicity and low dose-dumping irritation [1,2,3]. Although extrusion spheronization is the most applicable pelletization technique, especially for high drug loading capacity, it is a time-consuming multistep process that requires a high level of control of all process variables during mixing, granulation, extrusion, and spheronization, while the formation of spherical particles by adding a moisturizing liquid to the powder ingredient before or during agitation with a high-shear granulator (direct pelletization) in a single step means less time, cost, and binder liquid consumption with uniform distribution [1,2,3].

The impeller speed is the most important factor that influences the wet granulation technique [4]. It has an effect on the different physical properties of the resulting granules. Many authors reported that increasing impeller speed at a low range value led to a decrease in porosity, size, and friability; moreover, it increased strength and roundness [2]. On the other hand, at a high range value, it produced high-density rigid granules with less roundness and particle size due to the excessive breaking of the granules [2,5,6,7]. In addition, it had an effect on the stability and coating potential of some drugs due to a proportional relationship with process temperature, hardness, and surface free energy [8,9,10]. However, the effect of the impeller was related to the physical properties of the material used, especially binder viscosity because impeller speed affected the distribution of the binder [11], while some authors found that a highly viscous binder produced a small granule size with low porosity and dissolution due to the formation of bridges and kinetic energy between the particles [12]. Others found that granule size increased with a highly viscous binder, leading to reduced consolidation and deformation [6]. On the other hand, it was established that increasing the binder amount resulted in enhancements in granule growth, size, hardness, and flow properties [2] but neither the binder flow rate nor the method of binder addition had an effect on size [5] or granule strength [13]. In contrast, other authors mentioned the different effects of binder flow rate on the size of granules (positive quadratic effect, negative effect) [7,14]. Although the use of a lower impeller speed without a chopper resulted in a large granular size [2], the chopper speed has a significant effect on median particle sizes at high impeller speeds, and it was found that the appropriate selection of a combination of impeller speed and chopper speed contributes to the control of granular size [8,15]. Moreover, using a chopper enhances homogeneity, reduces the size of granules, and subsequently produces a narrow particle distribution [2,11,13] but it has no effect on hardness [10], porosity [13], and process temperatures [8,10].
Even though the water amount had the most significant effect on median diameter (D50), liquid pore saturation, and size, it did not affect the density of granules. Also, using a high water quantity with high impeller speed and long process time produced granules with a narrow size distribution and a large size [16].

The application of quality by design (QbD) to identify and adjust the relationship between critical process parameters (CPPs), critical material attributes (CMAs), and critical quality attributes (CQAs) is considered an essential tool to determine high-risk factors in the process using risk assessment methods such as the Ishikawa diagram. This identifies all sources of risk by determining the cause and effect (qualitative method) and failure mode and effect analysis (FMEA), which estimate the risk value using a combination of severity, probability, and detection (quantitative method) [17,18]. Then, using factorial design to optimize the process, is considered a very important tool to obtain a lot of information about the main factors and their interactions; this has significantly minimized the number of experiments, cost, and time required for the production of a pharmaceutical dosage form with acceptable characteristics—besides the precise determination of design space—which joins all the process parameters and material attribute ranges that ensure obtaining of predetermined critical quality attributes [19,20].

The success of the direct pelletization process can be achieved by combining the QbD approach and design of experiment (DoE) for the precise harmonized selection and control of the process variables that influence the characteristics of the pellets produced with the Pro-CepT granulator, as reported in a few papers [9,10,15].
This study aimed to estimate the effect of direct pelletization process variables on pellet quality and to determine and optimize the design space for low-load drug pellets by using a Pro-CepT granulator. Another aim was to investigate the dissolution and electrokinetic potential of the pellets at the optimized point, as well as their correlations. In our studies, two different types of active ingredients were chosen, one anionic and one cationic, in order to study the behavior, dissolution, and zeta potential of active ingredients with different properties.

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2. Materials and Methods

2.1. Chemicals

In this experimental research, amlodipine besylate and hydrochlorothiazide (Sigma-Aldrich (St.louis, MO, USA)) were chosen as model drugs. Microcrystalline cellulose (MCC, Vivapur 102) was purchased from JRS Pharma (Patterson, NY, USA), while mannitol (Mannitum) and polyvinyl pyrrolidone were supplied by Hungaropharma Zrt. (Budapest, Hungary). Distilled water was used as the granulating binder.

2.2. Risk Assessment

QTPPs, CQAs, CMAs, and CPPs were determined based on the previous literature background and preformulation studies, and, then, the risk assessment study was applied using two different methods. The first one was the Ishikawa diagram, which showed all the potential factors that may affect product quality, while the risk estimation matrix (REM) and Pareto chart were made by LeanQbD software (QbD Works LLC, Fremont, CA, USA/Version 1.3.6., 2014) that were used to determine the most important parameters to be considered during the experimental design.

2.3. Preparation of Blank Pellets

The pellets were prepared by direct pelletization methods. A total of 60 g of microcrystalline cellulose (MCC), 40 g of mannitol, and different amounts of polyvinylpyrrolidone (PVP) according to DoE were homogenized in a Turbula mixer (Willy A. Bachofen Maschienenfabrik, Basel, Switzerland) for 5 min. The mixture was wetted and kneaded in a Pro-CepT granulator (ProCept NV, ZelZate, Belgium) with water used as a granulation solution. The resulting pellets were dried in an air-ventilated oven (Memmert GmbH+Co. KG, Büchenbach, Germany) at 40 °C for 2 h. According to the DoE results, the design space was determined and optimized using three different parameters within the target values. The optimized formulation was loaded with two APIs (amlodipine besylate and hydrochlorothiazide).

Mahmoud, A.A.K.; Hassan, A.A.A.; Dobó, D.G.; Ludasi, K.; Janovák, L.; Regdon, G., Jr.; Csóka, I.; Kristó, K. Investigation of the Electrokinetic Potential of Granules and Optimization of the Pelletization Method Using the Quality by Design Approach. Pharmaceutics 2024, 16, 848. https://doi.org/10.3390/pharmaceutics16070848

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