Hydrophilic and Amphiphilic Macromolecules as Modulators of the Physical Stability and Bioavailability of Piribedil: A Study on Binary Mixtures and Micellar Systems

Abstract

This study presents an innovative approach that utilizes polymers with different topologies and properties as potential matrices for the poorly water-soluble active pharmaceutical ingredient piribedil (PBD). We investigated amorphous solid dispersions (ASDs) as well as micellar systems composed of PBD and (i) the commercial amphiphilic copolymer Soluplus, (ii) self-synthesized hydrophilic linear PVP (linPVP), and (iii) self-synthesized hydrophilic star-shaped PVP (starPVP). Differential scanning calorimetry, X-ray diffraction, Fourier-transform infrared, and broadband dielectric spectroscopy were applied to gain comprehensive insights into the thermal and structural properties, intermolecular interactions, global molecular dynamics, and recrystallization of the API from the amorphous PBD–polymer ASDs. The primary objective was to evaluate the impact of the type and topology of macromolecules, as well as the composition of binary formulations, on the physical stability of PBD in the amorphous form, phase transition temperatures, the API’s recrystallization rate, and ultimately, the release of drug in the prepared ASDs and micelles. Most importantly, our research led to the discovery of new polymorphic form (II) of PBD that has not been previously described in the scientific literature. We also revealed that ASDs containing hydrophilic PVP polymers exhibit the best performance in stabilizing the amorphous form of the API, with the starPVP systems showing the highest stabilization effect. In contrast, for micellar systems, Soluplus turned out to be the most suitable candidate in terms of forming the self-assembles of the lowest size distribution among all systems. The long-term stability of the amorphous drug in PBD–Soluplus micelles was higher compared to PBD–starPVP ASD. Moreover, an improvement in the bioavailability of the API contained in all tested formulations (binary and micellar systems) was observed, with PBD–starPVP micelles exhibiting the most desirable drug release profile within the polymer matrix, as well as the highest concentration of released drug. The obtained data highlight the crucial role of the type and topology/architecture of the polymer in the design of novel pharmaceutical formulations.

Introduction

The pharmaceutical industry is considered to be one of the fastest-growing sectors of the economy. However, despite this, it still struggles with a significant challenge─the poor water solubility (and consequently low bioavailability) of many active substances (APIs)/drugs available on the market, which results in their unsatisfactory therapeutic effect. (1−4) Moreover, patients have often to take higher doses of pharmaceuticals, leading to undesirable side effects. (5)

One way to overcome these problems and improve the bioavailability of APIs is amorphization, i.e., the transformation of the initial crystalline substances into amorphous ones. The resulting material is characterized by a lack of long-range order compared to the crystalline form, which leads to improved solubility and bioavailability of APIs. (6,7) However, amorphous substances are thermodynamically unstable, possess a high Gibbs free energy, and, as a result, show a high tendency to recrystallization, i.e., return to their energetically favorable crystalline form during storage or use of the products. (7,8) To stabilize these systems, various excipients, EXCs (both low- and high-molecular-weight compounds) are widely applied. Among them, polymers are gaining popularity as innovative pharmaceutical additives.

It should be emphasized that polymers are considered as one of the most effective EXCs for stabilizing the labile amorphous form of APIs, due to numerous favorable properties. (9−12) The key benefits of using them in pharmaceutical formulations include: (i) a high glass transition temperature (Tg), which significantly increases Tg of the entire drug-polymer system, (13) (ii) reduction of the molecular mobility of the drug, (14,15) (iii) an increase in the activation energy of API nucleation; (16,17) (iv) the ability to synthesize “tailor-made” macromolecules adapted to specific types of drugs through various controlled polymerization methods, i.e., polymers with targeted molecular weights (Mw) and low dispersity (Đ); (18) (v) the possibility of modifying polymer chain ends to build subsequent polymer blocks and produce (co)polymers, thereby fine-tuning macromolecular properties to suit specific applications.

(19) Given these unique features, polymers can significantly influence the dissolution, distribution, and transport of drugs within the human body. However, it is crucial to ensure that the polymer matrix is carefully selected for the specific API, the expected/desired properties, and also the used drug delivery system (DDS).

Among advanced DDSs, micellar systems and amorphous binary mixtures (BMs), also known as amorphous solid dispersions (ASDs), stand out as promising approaches for targeted therapy and controlled release. (20) However, as mentioned earlier, for these new formulations to work effectively, the polymer matrix must be carefully selected for the specific DDS. (21) Micellar DDSs primarily utilize amphiphilic polymers, which contain both hydrophilic and hydrophobic segments. Such a structure enables them to self-assemble in aqueous environments, forming micelles with cores capable of solubilizing hydrophobic APIs. (22) These systems offer several advantages, such as enhanced drug stability, controlled release, and the ability to modify the micelle surface for tissue specificity. As a result, they are widely applied in formulations of APIs with low water solubility and targeted DDSs, including cancer therapies and vaccines. (23,24) On the other hand, in amorphous BMs/ASDs, mostly hydrophilic polymers, due to their strong affinity to water, are primarily used to enhance the drug bioavailability by improving wettability, solubility, and dissolution rate.

These systems may reduce or completely damp the crystalline order and stabilize disordered APIs, preventing their recrystallization and maintaining higher concentrations in solution. (12,25) Among the well-known amphiphilic polymers, a copolymer Soluplus, deserves attention. There are increasingly frequent reports indicating its significant ability to enhance the solubility of hydrophobic APIs. (26−28) Consequently, it has been proposed as a carrier for oral drug administration, (29,30) ocular, (31,32) and topical applications, (33,34) as well as intravenous injections in cancer treatment. (27,35) Due to amphiphilic properties, it can self-assemble into micelles with a hydrophilic outer shell and a hydrophobic core that entraps the hydrophobic drug, thereby facilitating its dissolution. (22) Applying Soluplus in micellar DDSs with chosen APIs has been reported in several papers. (36−38) There are also works that describe the impact of this polymer on the physical stability of amorphous APIs prepared by various methods, (39,40) and even the liquid crystalline order of some pharmaceuticals, e.g., itraconazole. (41) In turn, among hydrophilic macromolecules, one can mention polyvinylpyrrolidone (PVP), which is frequently used in various pharmaceutical formulations due to several exceptional properties (high Tg, excellent water solubility, biocompatibility, nontoxicity, chemical stability, good adhesion, and emulsifying properties). (42,43) It acts as an effective stabilizer for many amorphous APIs by reducing their molecular mobility through e.g., enhanced intermolecular interactions. (43,44) Importantly, both approaches─micellar formulations and amorphous BMs, with the appropriate selection of polymer carriers─form the foundation of modern, advanced therapeutic systems, which not only enhance treatment efficacy but also minimize side effects, opening new possibilities in the design of effective medications.

It is important to highlight that, despite ongoing investigations into new polymeric-based pharmaceutical formulations, scientists still predominantly focus on applying various polymer matrices without delving into more complex aspects, such as polymer topology (linear and branched). However, it is well-known that macromolecules with the same chemical composition but differing in architecture/structure can exhibit distinct properties (e.g., various phase transition temperatures, hydrodynamic radius, degree of crystallinity, solubility, or number of functional groups at the chain ends). (45−48) This suggests that such polymers might also cause varied effects on the bioavailability of active substances in drug-polymer formulations. Recognizing this overlooked scientific area, our research group has undertaken detailed research into the impact of macromolecular topology on the physicochemical and pharmacokinetic parameters of poorly bioavailable APIs. Preliminary studies on metronidazole-PVP systems demonstrated that the polymer topology influences drug-polymer interactions and miscibility (the branched polymer was miscible with the active substance in a wider range of concentrations compared to the linear macromolecules). (49) Additionally, we revealed that the dispersity of the polymer is crucial for stabilizing amorphous forms of APIs. (49−52) For instance, investigations on ASDs of the rapidly crystallizing drug─naproxen─and PVPs of varying topologies showed that macromolecules with tightly controlled parameters (targeted Mw, and low Đ) effectively suppress the recrystallization of API from the amorphous form. In contrast, a commercially available PVP with high Đ (containing both high- and low-molecular-weight fractions) was the weakest inhibitor of the recrystallization process. (52) Moreover, research on ASDs based on the extremely poorly water-soluble drug itraconazole demonstrated a significant improvement in API solubility (up to 20-fold) when dispersed in a star-shaped polymer matrix compared to a linear one. (51) This clearly indicates that strict control over macromolecular parameters (such as Mw, Đ) and architecture is crucial for designing advanced API-polymer formulations.

Inspired by previous intriguing results and aiming to further explore this fascinating scientific area, we developed new ASDs and micellar DDSs based on piribedil (PBD) – a poorly water-soluble and rapidly recrystallizing drug – and polymers with various architectures. As matrices, a commercially available amphiphilic graft copolymer known as Soluplus, composed of three distinct polymer blocks (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol, PCL–PVAc–PEG), as well as innovative, self-synthesized PVP matrices with linear (linPVP) and three-arm star-shaped (starPVP) topologies, were selected. Applying PBD and the polymers described above, we created amorphous BMs and micellar systems in various API to EXC weight ratios, which were subsequently investigated using various experimental techniques. It should be clearly emphasized that just in this paper, using macromolecules of very similar molecular weight and different composition and topology, we have touched on all key aspects related to (i) the character of the polymer matrix (amphiphilic vs. hydrophilic), (ii) macromolecular topology (linear vs. branched), and (iii) the type of DDS (micelles vs. binary mixtures) to precisely determine which factors are important for improving the physical stability of API, drug release and consequently the bioavailability of the examined API. By closely following the results presented in this work, important conclusions can be drawn regarding the deliberate design of new drug-polymer pharmaceutical systems.

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Materials

1-vinyl-2-pyrrolidone (VP, > 99%, Sigma-Aldrich) was passed through an alumina column before use to remove the inhibitor. 2,2′-Azobis(2-methylpropionitrile) solution (AIBN, 0.2 M in toluene, Sigma-Aldrich), cyanomethyl methyl(4-pyridyl) carbamodithioate (CTA1, 98%, Sigma-Aldrich), 1,3,5-tris(bromomethyl)benzene (97%, Sigma-Aldrich), sodium diethyldithiocarbamate trihydrate (Sigma-Aldrich), diethyl ether (pure for analysis, Chempur), methanol (99.85%, PureLand), dichloromethane (DCM, 99%, Honeywell), chloroform-d (99.8% D, contains 0.03% v/v TMS, Sigma-Aldrich), Soluplus (Mw∼118 000 g/mol, Đ = 2.05, BASF), crystalline PBD (IUPAC name 2-[4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl]pyrimidine, 98%, Angene) were used as received. Acetonitrile for HPLC, ammonium acetate, sodium chloride, and anhydrous sodium dihydrogen phosphate were purchased from Th. Geyer Ingredients GmbH & Co. KG (Höxter-Stahle, Germany). Sodium hydroxide was purchased from VWR Chemicals (Leuven, Belgium). 3F Powder was obtained from the biorelevant.com LTD (London, United Kingdom). Pronoran (Les Laboratoires Servier, France) was purchased from the local pharmacy. Ultrapure water was self-produced from Hydrolab Ultra UV (Hydrolab Sp z o.o., Straszyn, Poland).

Luiza Orszulak, Aldona Minecka, Roksana Bernat, Taoufik Lamrani, Karolina Jurkiewicz, Barbara Hachuła, Magdalena Tarnacka, Monika Geppert-Rybczyńska, Maciej Zubko, Marcela Staniszewska, Michał Smoleński, Justyna Dobosz, Grzegorz Garbacz, Kamil Kamiński, and Ewa Kamińska, Hydrophilic and Amphiphilic Macromolecules as Modulators of the Physical Stability and Bioavailability of Piribedil: A Study on Binary Mixtures and Micellar Systems, Molecular Pharmaceutics Article ASAP, DOI: 10.1021/acs.molpharmaceut.5c00276