The Development and Characterization of Layered Pellets Containing a Combination of Amorphized Amlodipine Besylate and Hydrochlorothiazide Using a High-Shear Granulator

Abstract

Background/Objective: The high-shear granulator is considered an effective piece of equipment for layering pelletization because it enhances drug amorphization and improves drug dissolution. This study aimed to apply a high-shear granulator to prepare layered pellets containing a combination of hydrochlorothiazide and amlodipine besylate with improved physicochemical properties.

Methods: Different molar ratios (2:1, 1:1, and 1:2) of the hydrochlorothiazide and amlodipine besylate mixture were deposited on the surface of the inert spheres of the microcrystalline cellulose (MCC) core by the mechanical effect of the high impeller speed. The resulting layered pellets were characterized using X-ray powder diffractometry (XRPD) and differential scanning calorimetry (DSC) to estimate the degree of the drug amorphization, and consequently a dissolution test was performed to determine the degree of the enhancement of the percentage of release. Additionally, micro-computed tomography (micro-CT) and a texture analyzer were used to determine the morphological characteristics and hardness of the resulting pellets, and then a stability study was performed.

Results: On the basis of the micro-CT images, the MCC core was successfully loaded with a uniform layer of the drug combination at the pellet surface, which exhibited higher diameters than pure cellets. Furthermore, the drug combination in layered pellets was partially amorphized with a lower crystallinity percentage, a lower intensity, a broadening of the hydrochlorothiazide melting peak, and a higher cumulative release of both drugs with good stability, except pellets with a molar ratio of 1:2 that were recrystallized with a higher crystallinity percentage of 79.9%.

Conclusions: Modifying the physical form and dissolution behavior of the hydrochlorothiazide and amlodipine besylate combination was achieved by single-step layering pelletization.

Introduction

One of the most commonly used methods for improving the dissolution of poorly water-soluble drugs is the conversion of the crystalline form to an amorphous form carried out via a thermodynamic transformation by a melting-based or solvent-based method [1]. These methods have numerous drawbacks, including their high energy consumption, the large amount of polymer needed, the hygroscopicity of the polymer, lower stability, the risk of toxicity and drug degradation related to the residual solvent (solvent-based method), and the high temperature (melt-based process) [2,3]. On the other hand, applying layering pelletization has a beneficial effect on the drug distribution and consistent dose administration [4]. In this technique, drugs in the form of a solution or suspension or powder are loaded onto inert pellet cores, such as microcrystalline cellulose, tartaric acid, sucrose, and isomalt [5,6], that act as carriers, and it contributes to the masking of unpleasant tastes and improving the dissolution rate of drugs [7].

Among these pellet cores, microcrystalline cellulose is widely used in layering pelletization, as it has an ideal roundness with a smooth surface, lower friability, and higher mechanical resistance than sugar cores [8,9]. The layering pelletization of liquid drug requires the optimization of different parameters, such as the application rate, atomization type, and drying process, in addition to the type and concentration of the binder that can adversely affect the surface of the pellet, while the layering of the drug powder is associated with shorter process times and less process parameters due to the fact that it does not require a liquid binder, making it a good choice for moisture-sensitive drugs [9,10,11].

Additionally, applying mechanical force in the layering pelletization process using a fluidized bed or high-shear granulator in a single step is considered a highly stabilized and economically alternative technique without the utilization of solvents or heat [1,2,12]. Although this process can be performed through a single step and can change the physical properties of drugs (amorphization of crystalline drugs), it faces a huge risk with regard to recrystallization and the failure of the production of a single phase due to the excessive mechanical force and heat created within the granulator. This can be minimized by the appropriate selection of the process temperature [2] and the preparation of the co-amorphous form using a stabilizer of a low-molecular-weight co-former or another drug(s) with a high drug binding affinity that reduces molecular mobility by forming a constant chemical bond such as, a hydrogen bond, ionic bond, and π-π bond, in addition to using a stabilizer with a high Tg (glass transition temperature). This ensures an increase in the Tg of the co-amorphous material, producing more than the Tg of the required drug, and decreases the recrystallization probability [13,14,15].

Kondo et al. prepared amorphous indomethacin and loaded it on the surface of microcrystalline cellulose spheres using a high-shear granulator. Despite the higher solubility and dissolution rate of the resulting pellets, they had low stability, and this was overcome by adding L-arginine, which formed a co-amorphous system with indomethacin with enhanced dissolution and better stability than the crystalline drug form and the pellets containing the amorphous indomethacin alone [1,2]. Furthermore, drug–drug amorphization has many beneficial effects in the manufacture of different drug combinations, with improved solubility, harmonized synergetic pharmacological effects, fewer side effects, and therapeutic doses required, as long as it matches the ratio of the formulated drugs [16,17,18].

Amlodipine besylate is an antihypertensive agent that acts as a calcium channel blocker. It has a weak basic structure and a crystalline physical form with a melting point of 200 °C and a pKa of 9.1, which is classified in the biopharmaceutical classification system as BCS I [19], and it amorphizes when it is prepared as a solid dispersion with polyvinylpyrrolidone K30 at a weight ratio of 5:95, which improves its physical stability [20]. Furthermore, the co-amorphous system of amlodipine besylate with candesartan in the molar ratio 1:1 demonstrates better dissolution behavior than crystalline drugs, in addition to having better stability in the formulation that contained polyvinylpyrrolidone [21]. On the other hand, hydrochlorothiazide is an antihypertensive agent that acts as a diuretic thiazide and has been classified as BCS IV, which has poor solubility and permeability in addition to a crystalline structure with a melting point of 270 °C and a pKa of 9.09 [22,23]. Many researchers have mentioned improving solubility by using a solid dispersion with cyclodextrin [24], a water-soluble co-former (arginine) [25], a drug co-former like telmisartan [26] or atenolol [27], and simvastatin [28].

The combination of amlodipine besylate and hydrochlorothiazide is frequently used as a treatment for hypertension because it has a greater therapeutic effect in lowering blood pressure than single drugs in addition to minimizing metabolic side effects of hydrochlorothiazide, improving the blood’s level of low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Moreover, the application of a high-shear granulator in the co-amorphization of the drug combination is considered a good technique that produces pellet dosage forms with improved physiochemical properties and therapeutic outcomes [29]. Many researchers have focused on preparing amorphous powders using traditional amorphization techniques, which require an additional manufacturing process to obtain the final dosage form. However, the conversion of the drug alone and with a co-former to an amorphous form by layering pelletization has been mentioned in only two studies [2,30]. The combined amorphization and layered pelletization process of drug combinations using a high-shear granulator has not been investigated and is presented for the first time in this study.

This study focused on the formulation of a multiparticle system loaded with an amlodipine besylate and hydrochlorothiazide combination using a novel approach of solvent-free direct pelletization in a high-shear granulator.

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Chemicals

In this experimental investigation, microcrystalline cellulose spheres with a mean diameter of 1000 μm (Pharmatrans Sanaq AG, Basel, Switzerland) were used as carriers of the drug mixture (cellet), while talc (Molar chemicals Kft, Budapest, Hungary) acted as a glidant. Hydrochlorothiazide and amlodipine besylate were purchased from Sigma-Aldrich (St. Louis, MO, USA). Potassium bromide (J&K Scientific Limited, Beijing, China) was applied in pellet characterization by Fourier transform infrared spectroscopy (FTIR), and the hydrochloric acid solution (0.1 N) was used as the dissolution medium for the resulting pellets.

Mahmoud, A.A.K.; Ludasi, K.; Dobó, D.G.; Sebők, D.; Kukovecz, Á.; Hornok, V.; Sajdik, K.; Szabó, T.; Sovány, T.; Regdon, G., Jr.; et al. The Development and Characterization of Layered Pellets Containing a Combination of Amorphized Amlodipine Besylate and Hydrochlorothiazide Using a High-Shear, Granulator. Pharmaceuticals 2025, 18, 1496. https://doi.org/10.3390/ph18101496

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