Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control

Introduction

The drug dissolution of solid formulations depends on the solubility and dissolution rate of the drug substances and—in case of release—a number of parameters additionally influence the release kinetics: for example, drug substance interaction with formulation components (excipients), compression force and hardness in case of tablets and kind of binder in granulates, pellets and generally in polymer coatings. The knowledge of the dissolution rate and the release kinetics is essential and indispensable for optimum pharmacotherapy. Dissolution of solid substances runs approximately with first order kinetics due to diffusion processes. Certain drug formulations show zero order release with equal amounts released in equal time intervals. The superposition of several processes, for example, wetting of the solid drug dosage form, dissolution of the solid drug substance, diffusion of the drug molecules out of the dosage form, swelling of the dosage form in case of matrix formulations and swelling and water uptake of insoluble films leads to kinetic processes not meeting unambiguous zero or first order or square or cubic root equations. The release data are linearized by several models to evaluate the best approach. The coefficient of determination CoD of the linearized curve gives hints to the best adaptation and to the probability of the dominating process [1,2,3,4,5,6].

The model-independent parameters difference factor f1 and similarity factor f2 are used for release profile comparison; f1 describing the relative error between two release profiles calculated from the cumulatively released amounts at a certain time T for a test and a reference formulation or in general between two formulations—for example in the drug’s development. f2 is based on the sum of deviation squares of the released drug amounts of two release profiles [4,5,7,8,9].

Increasing attention is given to drug-loaded pellets and their release control by slowly swelling matrix systems or a final functional coating. The release of drug substances from matrix pellets prepared by extrusion/spheronization and finally coated with different amounts and types of insoluble ethylcellulose has been investigated [10,11,12]. Other authors report on the influence of the filler type on the drug release [13], the effect of the pH value of the release fluid [4], the storage conditions of drug and methylcellulose matrix pellets [14], the amount of enteric polymer coating [15] and the salt concentration of the release fluid [16]. The influence of talc and hydrogenated castor oil on the dissolution behaviour of metformin-loaded matrix pellets with an acrylic-based sustained release coating [17], the sustained release of Lisinopril from mucoadhesive matrix pellets [18] and the sustained-release of sinomenine hydrochloride from pellets manufactured by a novel whirlwind fluidized bed process have all been investigated [19].

Drug-layered inert pellets coated with polymer (heterogeneous pellets) were investigated in a similar way regarding the influence of the release kinetics by different modifications of the ethylcellulose coating [20], by ethylcellulose mixed with different amounts of polyvinylpyrrolidone (PVP) as pore former for controlled drug release [21], by alternating layers of ethylcellulose and polyvinylacetate [22], by various ethylcellulose coating levels and final curing [23] and by ethyl cellulose coating of acetaminophen-layered sugar pellets [24]. With a polyacrylate coating, the drug release from layered pellets was found to be retarded [7,25]. Variation of polymer type and layer thickness permits the control of the release rate in a wide range [8].

In our own earlier investigations heterogeneous pellets were manufactured by fluidized bed technology with a Wurster inlet. Inert microcrystalline cellulose pellets were coated with excipients and the easily water-soluble model drug sodium benzoate [26,27,28]. These sodium benzoate pellets (SB pellets) exhibited a narrow particle size distribution, high sphericity and homogeneous layers and gave very quick sodium benzoate release. For retarded release, the SB pellets were coated in a second step with different amounts of ethylcellulose, once more by fluidized bed technology with a Wurster inlet [29]. The release rate diminished with increasing layer thickness, as expected. Furthermore, the fluidized bed processes were controlled by in-line particle size measurement with the spatial filter velocimetry SFV probe [27,28] for process control regarding particle size, particle size distribution and ethylcellulose layer thickness.

The aim of the present project was the manufacturing of heterogeneous pellets in the fluidized bed with a Wurster inlet, the control of the process by in-line particle size and coating layer thickness measurements, the investigation of the kinetics of sodium benzoate release considering different kinetic models, the interpretation of the partial processes involved in the release, the correlation of the release rate with the polymer layer thickness and the detection of the coating process endpoint for the improvement of the pellet product quality regarding controlled drug release.

For drug pellet manufacturing, a similar experimental approach as the one in [26,27,28] was chosen. Relatively small initial inert pellets (Cellets®175, median 170 µm), referring to a large specific surface area, were coated with a solution of sodium benzoate and a low amount of the water soluble PVP as a binder to improve the mechanical stability of the layer. In a second step (see [29]), the SB pellets were coated with different amounts of insoluble but slowly swelling polyacrylate for retarded release. The risk of undesirable agglomeration of those small pellets during sodium benzoate and polymer coating was practically eliminated by adjusting the process parameters and adding talcum to the coating fluid as an antistick agent. The SFV probe was installed for in-line particle size measurement and detection of agglomerates.

The drug release was investigated and discussed applying zero order, first order, square root and cubic root equation kinetic models. Finally, the most probable release kinetics model was identified by the calculation of curve parameters—area under the curve (AUC), dissolution efficiency (DE) and mean dissolution time (MDT)—and by comparison of the CoD of the different kinetic models. The difference of the release profiles and the similarity of different polyacrylate layered pellet lots were calculated by the difference factor f1 and similarity factor f2. The linearization approach of the dissolution profiles is suitable for first order kinetics; for other release profiles a nonlinear approach can describe the dissolution curves more accurately and with a smaller standard deviation of the fitting parameter than the linearization-based calculation method [30].

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Materials

Pellets of microcrystalline cellulose (Cellets^®175, particle size range 150–200 µm, median 170 µm, IPC, Dresden, Germany), sodium benzoate (Applichem, Darmstadt, Germany, solubility 57 g in 100 g water at room temperature), PVP (Kollidon^®25, Carl Roth, Karlsruhe, Germany), talcum (Talkum Pharma, C. H. Erbslöh, Krefeld, Germany), magnesium stearate (VEG Pharma, Rome, Italy) and polyacrylate dispersion (Eudragit^®NE 30D, Evonik Industries, Darmstadt, Germany, containing ethylacrylate- methylmethacrylate copolymer 30% w/w) were used. All substances conform to European Pharmacopoeia (Ph.Eur.) quality.

Langner, M.; Priese, F.; Wolf, B. Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control. Pharmaceutics 2024, 16, 1307. https://doi.org/10.3390/pharmaceutics16101307

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