Development of vacuum compression molded tablets with rapid drug release and a comparison of dissolution profiles between molded and FDM 3D-printed tablets

Abstract

In recent years, there has been much interest in the development of personalized and on-demand tablets by FDM 3D-printing of melt-extruded filaments. Alternatively, the filaments can also be converted into molded tablets. However, drug release rates from tablets produced by both methods are very slow and not amenable to immediate-release drug products. We previously reported a novel approach called acid-base supersolubilization (ABS), whereby dissolution rates of poorly water-soluble basic drugs from FDM 3D-printed tablets could be greatly increased by interaction with added weak acids. Here, we investigated whether such acid-base interaction applying the ABS principle could similarly increase drug dissolution rates from molded tablets. Haloperidol, a basic drug with low and pH-dependent solubility, was used as the model drug, and molded tablets were prepared by the vacuum compression molding (VCM), where filaments containing 1:1 and 1:2 M ratios of haloperidol and malic acid along with Kollidon VA64 were prepared at 15 % w/w drug loading. Broken filaments were compressed into VCM tablets under a vacuum at high temperatures. The tablets thus produced gave very high pH-independent dissolution rates, with > 90 % haloperidol dissolving in 60 min. Dissolution rates were similar from both molded and FDM 3D-printed tablets, and thus, the two methods can be used interchangeably depending on the drug development needs.

Introduction

Preparation of tablets by applying molding technologies like injection molding (IM), vacuum compression molding (VCM), etc., and three-dimensional (FDM 3D) printing using fused deposition modeling have certain similarities and differences. All IM, VCM, and FDM 3D printing produce hard compacts and involve hot melt extrusion (HME). The primary difference between the two molding techniques is that IM generally involves injecting molten mass produced by hot-melt extrusion (HME) into particularly shaped molds or cavities by a technique called calendaring such that solid nonporous compact is produced upon cooling (Vynckier et al. 2015), while in VCM, the extrudates are filled into cavities and subjected to elevated temperature and pressure such that nonporous and hard compacts are formed (Shadambikar et al., 2020, Dhumal et al., 2024). Unlike molding, in the FDM 3D printing process, drug-loaded filaments produced by HME are printed layer by layer into hard compacts using commercially available 3D printers, where, based on the infill density, the porosity of the 3D printing tablet varies, higher for lower infill density and minimal for 100 % infill density (Trenfield et al., 2018).

One major disadvantage of hard compacts obtained by one of these methods is that they usually lead to tablets with slow and incomplete drug release, while rapid drug release is often desired after oral administration of solid dosage forms (Ebrahimi et al., 2023, Selen et al., 2014). In one study, Shadambikar et al. (2020) reported that the drug release from VCM tablets in simulated gastric fluid ranged from 0 to 20 % w/w after 6 h of dissolution testing. Indeed, most of the studies with molded drug products reported in the literature have been focused on the development of slow and controlled-release oral dosage forms (Keszei et al., 2006, Quinten et al., 2009a, Quinten et al., 2009b, Quinten et al., 2011, Psimadas et al., 2012) or the development of slow-release implants (König et al., 1997, Rothen-Weinhold et al., 1999, Chiu Li et al., 2002, Eder et al., 2017, Koutsamanis et al., 2019, Koutsamanis et al., 2020). Similarly, Cailleaux et al. (2021) observed that most of the FDM 3D-printed products are also slow-release; out of 56 products reported in the literature at that time, 43 had sustained or delayed release, 4 were developed for both immediate and sustained release, and 9 were immediate release. Although the dissolution rates from the FDM 3D-printed tablets could be increased by introducing pores and channels or lowering infill densities within tablets, the dissolution rates still remain relatively slow (Serajuddin. 2023).

The slow and incomplete drug release observed from FDM 3D-printed and molded tablets is due to the compact and non-disintegrating nature of tablets and the type of polymers and formulations used (Serajuddin. 2023). In recent years, our laboratory has conducted extensive studies to increase the dissolution rates of drugs from FDM 3D-printed tablets (Solanki et al., 2018, Wei et al., 2020, Patel and Serajuddin, 2021, Patel and Serajuddin, 2022 & Patel and Serajuddin, 2023, Serajuddin, 2023). The primary objective of the present investigation was to determine whether the technology we developed to increase dissolution rates of FDM 3D-printed tablets may also be applied to increase drug release rates from molded tablets using Kollidon VA64 (K64) as a polymer carrier.

One of the strategies that we applied to enhance drug release from FDM 3D-printed tablets (Patel and Serajuddin, 2021, Patel and Serajuddin, 2022 & Patel and Serajuddin, 2023, Serajuddin, 2023) involved the interaction of poorly water-soluble basic drugs with weak acids that would not form salts with the basic drug but would greatly increase its solubility (Parikh et al., 2016, Shah and Serajuddin, 2015, Shah and Serajuddin, 2014, Singh et al., 2013). In one example, Singh et al. (2013) increased the solubility of haloperidol, a basic drug with pH-dependent solubility, from its intrinsic solubility of ∼ 1 µg/mL (Avdeef et al., 2016) to > 1 g per gram of water by interaction with weak acids like malic, tartaric, and citric acids. Because of such an extremely high increase in solubility by the acid-base interaction in aqueous media, the authors called the technique acid-base supersolubilization (ABS). Amorphous solids were formed upon drying of such concentrated solutions or when the free base and the acids were heated together in a melt extruder or otherwise (Parikh and Serajuddin, 2018); the amorphous materials were physically stable and did not lead to the crystallization of drugs even at high humidity. It should be mentioned here that the ABS principle is not the same as adjusting the microenvironmental pH of solutions or amorphous solids (Shah and Serajuddin, 2014); it requires high amounts of acids to achieve high drug solubility. Singh et al. (2013) observed that the haloperidol to weak organic acid molar ratio must be at least 1:2 to achieve a high solubility of > 300 mg per gram of solution.

By using the ABS principle to increase drug solubility and convert both drug and acid into an amorphous state, Patel and Serajuddin (2021) developed rapidly dissolving FDM 3D-printed tablets containing mixtures of haloperidol and glutaric acid or haloperidol and malic acid with the polymer Kollidon VA64 (K64), where over 80 % drug release in < 30 min at pH 2.0 and 6.8 from printed tablets with 100 % infill density was observed. Such formulations had the added advantage that the melt extrusion temperature of filaments and the printing temperature of tablets could be reduced from ∼ 150 °C and ∼ 210 °C, respectively, in the absence of added acid to ∼ 115 °C and ∼ 120 °C, respectively, in the presence of glutaric acid and ∼ 125 °C and ∼ 100 °C, in the presence of malic acid, thus greatly reducing processing temperatures.

In the present investigation, formulations of Kollidon VA64-haloperidol-malic acid and Kollidon VA64-haloperidol-glutaric acid systems that were previously developed for rapid release from FDM 3D–printed tablets were VCM-processed into molded tablets. Dissolution rates of haloperidol from the VCM tablets thus produced were then studied at pH 2.0 and 6.8 to determine whether increased dissolution rates could also be obtained from molded tablets and how they would compare with those of 3D-printed tablets. Although many different methods are available for molding polymers and pharmaceutical dosage forms (Zema et al., 2012, Fu et al., 2020), we have applied the relatively new method of VCM (Shadambikar et al. 2020) where filaments of different formulations were first prepared by hot-melt extrusion (HME), the filaments were then broken or milled into powders, and, finally, they were molded into tablets under vacuum and at elevated temperatures by applying heat and pressure. Thus, the VCM method has certain similarities with the FDM 3D-printed tablets, where the filaments are melted and printed into tablets at elevated temperatures. Therefore, a direct comparison between VCM and FDM 3D printing could be meaningful. If the performance of the two methods is similar, VCM could replace FDM 3D printing or could serve as a pre-evaluation tool for the development of FDM 3D-printed tablets.

Materials

Haloperidol (Halo) in its free base form (molecular weight: 375.9 g/mol; pK_a: 8.0; melting point: 151.5 °C), glutaric acid (GA, molecular weight: 132.1 g/mol; melting point: 95–98 °C), and malic acid (MA, molecular weight: 134.1 g/mol; melting point: 130 °C) were purchased from VWR (TCI America, Portland, OR, USA). Polyvinylpyrrolidone-vinyl acetate copolymer marketed under the name Kollidon® VA64 (K64) was received from BASF (Tarrytown, NY, USA) as a gift.

Nirali G. Patel, Hari P. Kandagatla, Daniel Treffer, Abu T.M. Serajuddin, Development of vacuum compression molded tablets with rapid drug release and a comparison of dissolution profiles between molded and FDM 3D-printed tablets,
International Journal of Pharmaceutics, 2025, 125511, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125511.