Study and Characterization of Polyvinyl Alcohol-Based Formulations for 3D Printlets Obtained via Fused Deposition Modeling

Three-dimensional (3D) printing has emerged as a new promising technique for the production of personalized dosage forms and medical devices. Polyvinyl alcohol is prominently used as a source material to produce 3D-printed medicines via fused deposition modeling (FDM)—a technology that combines hot melt extrusion and 3D printing. A preliminary screening of three grades of PVA indicated that partially hydrolyzed PVA with a molecular weight (MW) of 31,000–50,000 and plasticized with sorbitol was most suitable for 3D printing. Paracetamol was used as a model drug. The materials and the produced filaments were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The complex viscosity (η*) of the polymer melts was determined as a function of the angular frequency (ω) at the printing temperature to assess their printability. Three-dimensional printlets with a 40% infill exhibited an immediate release of the API, while tablets with a higher infill were prone to a prolonged release regardless of the filament drug loading. A factorial design was used to give more insight into the influence of the drug-loading of the filaments and the tablet infill as independent variables on the production of 3D printlets. The Pareto chart confirmed that the infill had a statistically significant effect on the dissolution rate after 45 min, which was chosen as the response variable.

1. Introduction

Three-dimensional (3D) printing has emerged as a new promising technique for the production of personalized dosage forms and medical devices. It has many advantages over conventional pharmaceutical technologies, including personalized dosing for specific groups of patients, combining multiple drugs with varying concentrations in individual “polypills”, and customization of the drug release. The small size and the ability of 3D printers to connect with a healthcare database allow for the production of small batches or even individual medicines for every patient at the point of care (hospital or community pharmacy) [1,2,3]. As 3D printing creates objects with versatile and complex geometries, it allows for the production of implants [4], patient-specific medical devices [5,6], and unconventional tablet shapes [7,8]. The principal mechanisms of 3D printing are a powder bed, photopolymerization, selective laser sintering, and extrusion-based methods, the latter being semi-solid extrusion and fused deposition modeling (FDM) [1,3,9]. The release kinetics of FDM 3D-printed dosage forms is widely reported to depend on the properties of the used polymer, the geometry of the printed object, and its infill percentage. The drug loading of the polymer matrix could have an impact on the drug release [2,10,11].

Concerning FDM for pharmaceutical applications, the incorporation of the active pharmaceutical ingredient into the filament is crucial. The two principal methods reported in the literature are soaking a commercial filament in a solution of the active pharmaceutical ingredient (API) [12] and hot melt extrusion (HME) [5,7,8,13,14]. The drug loading achieved by soaking is low, and thus, it is suitable for low-dose preparations. In addition, the substance should be soluble and the filament insoluble in the particular solvent [12]. Hot melt extrusion allows for the inclusion of a higher percentage of active ingredient(s) [13] and has the advantage of increasing the solubility and bioavailability of poorly water-soluble drugs [1].

Different thermoplastic pharma-grade polymers, such as polyvinyl alcohol [14], hypromellose [15], hydroxypropyl cellulose [15], ethyl cellulose [15,16], and methacrylic acid copolymers [13,17] have been screened for the production of FDM filaments. Partially hydrolyzed polyvinyl alcohol (PVA) was chosen for this study. It is a hydrophilic, non-toxic, semi-crystalline water-soluble polymer that enhances bioavailability by forming solid amorphous dispersions [18,19], which makes it suitable for the production of solid oral dosage forms. It is also a source material for commercial filaments [7,12]. However, it is seldom used in HME because of its high processing temperature and the narrow interval between its glass transition (Tg) and degradation temperature (Tdeg). There have been successful attempts to extrude partially hydrolyzed grades by adding hydrophilic plasticizers containing hydroxyl groups, such as glycerin [20] and sorbitol [19], which form hydrogen bonds with the PVA molecule and lower its Tg. Such experiments have also been conducted focusing on the production of strands for FDM 3D printing for pharmaceutical applications [14,21,22,23,24].

The design of experiments (DoE) and quality by design (QbD) principles have recently been implemented in studies involving FDM 3D printing [11,14,22,25,26,27,28]. QbD uses both science and quality risk management in order to obtain thorough knowledge about the products, processes, and process control [29]. Some researchers have applied DoE to filament extrusion, analyzing the effect of the process parameters on filament quality [26]. Others have concentrated entirely on the filament formulation, applying a mixture design to evaluate the combined effect of different excipients on the drug release of the 3D-printed tablets [27]. However, more experimental designs gravitate towards the printing parameters [14,22,28] or a combination of the printing parameters and filament formulation [11,25]. The defined response variables usually involve drug release and occasionally solvent extraction [11], tablet mass, and manufacturing time [28]. The interpretation of the results has generally included ANOVA and response surface methodology (RSM) [14,25,27,28]. Although the Pareto chart is a widely used statistical tool that evaluates the effect of the input variables on the defined responses [30,31], it has only been reported once in relation to the 3D printing of medicines [25].

The aim of the present study was to evaluate the influence of two input variables (the drug loading of extrudates and the infill percentage of tablets) on the dissolution rate of 3D printlets using statistical approaches. Three grades of partially hydrolyzed PVA were tested as potential excipients for FDM pharmaceutical dosage forms. To the authors’ best knowledge, this is the first systematic screening of the suitability of different grades of PVA for the production of filaments for 3D printing for pharmaceutical applications.

2.1. Materials

Three grades of polyvinyl alcohol with varying molecular weight (MW) were used in this study. “PVA 1”, with a MW of 13,000–23,000 and 87–89% degree of hydrolysis, and “PVA 2” with a MW of 31,000–50,000 and 87–89% degree of hydrolysis, were purchased from Acros Organics (Geel, Belgium). “PVA 3”, with a MW of 70,000 and 87–89% degree of hydrolysis, was acquired from Valerus (Sofia, Bulgaria). Polyethylene glycol 6000 “PEG” (Clariant Produkte, Wiesbaden, Germany) and sorbitol “Sorb” (DHW, Dessau-Roßlau, Germany) were used as plasticizers. Magnesium stearate, “MgST”, was purchased from Union Derivan (Barcelona, Spain). Paracetamol (Hebei Jiheng Pharmaceutical Co., LTD, Hengshui, Hebei, China) was used as a model drug. Commercial PVA filament was purchased from Shenzhen Lankeda Technology Co., Ltd. (Shenzhen, China).

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Ilieva, S.; Georgieva, D.; Petkova, V.; Dimitrov, M. Study and Characterization of Polyvinyl Alcohol-Based Formulations for 3D Printlets Obtained via Fused Deposition Modeling. Pharmaceutics 2023, 15, 1867. https://doi.org/10.3390/pharmaceutics15071867

Study and Characterization of Polyvinyl Alcohol-Based Formulations for 3D Printlets Obtained via Fused Deposition Modeling

1. Introduction

2.1. Materials

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