Role of Phospholipids on Drug Dissolution in Polymer Solid Dispersions Prepared by Hot-Melt Extrusion

Abstract

The development of solid dispersions (SDs) has gained increased attention in recent decades, leading to successful delivery systems for various marketed products. In general, combinations of polymers and lipids in SD formulations have shown promising results in reducing the disadvantages associated with the isolated use of hydrophilic excipients such as copovidone (COP) and Soluplus (SLP). This study investigated the influence of the phospholipid (soy phosphatidylcholine, PPC, 15 and 30%, w/w) on the dissolution performance of drug-polymer SDs prepared by hot melt extrusion. A low-solubility model drug (ritonavir, RTV) was selected for the study. A complete drug amorphization was observed for all extrudates despite the PPC presence. However, PPC improved the process yield without requiring a plasticizer. Morphology and particle size analyses revealed the effects of PPC addition in the aqueous dispersions prepared from SDs, denoting a higher polymer–lipid interaction in COP dispersions and the formation of micrometric structures in both COP and SLP dispersions. COP-based SDs produced almost instantaneous increases in RTV dissolution of up to 7-fold, while SLP-based SDs achieved progressive increases over 5-fold. Importantly, PPC incorporation in COP-based SDs did not have an apparent effect on RTV dissolution but significantly improved drug dissolution from the SLP-based SDs. In summary, the role of the lipid mainly depends on the drug-polymer interactions and lipid concentration. Adding phospholipids enables the thermal process without needing other adjuvants.

Introduction

Poorly water-soluble drugs are one of the most significant hurdles in the development of pharmaceutical formulations due to their low oral absorption and bioavailability. Pharmaceutical industries and the scientific community have been keen on exploring technological strategies to develop formulations with enhanced dissolution rates and absorption, thereby improving their therapeutic effectiveness. (1)

In this scenario, solid dispersions (SDs) have gained attention in the past decades, leading to promising delivery systems for various marketed products. (1−3) This approach can improve biopharmaceutical properties through particle size reduction, drug dispersion at the molecular level, and increased wettability. These mechanisms promote the drug’s supersaturation state in biological fluids, thus accounting for a higher passive absorption by intestinal cells. (3,4)

The physicochemical properties of excipients used in the SD formulations and their specific intermolecular interactions are essential in achieving and maintaining supersaturation states in a wide range of pH. (5,6) In particular, combinations of polymers and lipids have shown promising results in reducing the disadvantages of the isolated application of hydrophilic excipients, ensuring optimal stability and performance. (7,8) Nevertheless, the enhancement of dissolution rates depends on the nature of the lipid-polymer interaction, which may be influenced by the combination of materials. (8)

Further to the effects of excipient association, the technique used in SD preparation can affect the properties of the final drug product. Various studies have demonstrated extensive differences in dissolution rates of physical mixtures and hot melt extrudates in aqueous medium. (6,8−11) Hot melt extrusion (HME) is a solvent-free process highly efficient in obtaining amorphous SDs due to its capacity to yield molecular-level mixtures. (10,12,13) Despite the limited number of studies on lipid-polymer SDs using HME, the results are encouraging, with high dissolution rates, (14) indicating that this approach requires more investigation.

In this study, six SDs based on mixtures of copolymers Soluplus and Plasdone S-630 (copovidone) in association with Lipoid S100 (amphiphilic lipid soybean phosphatidylcholine) were processed by HME. The effect of each polymer–lipid combination on the physicochemical properties of the powder was evaluated, including particle size distribution and morphology analysis. Additionally, the impact on the dissolution rates of model drug ritonavir (RTV), chosen for its physicochemical characteristics as a poorly water-soluble drug belonging to the biopharmaceutical classification system class II, (15) was also investigated. Excipients were selected based on compatibility with RTV (16−18)

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Materials and Methods

RTV (lot 04135, 97.6%) was kindly donated by Cristália Produtos Qumicos e Farmacêuticos Ltd. (Itapira, Brazil). Copovidone (COP, Plasdone S-630, average molecular weight of 47 kDa) was donated by Ashland Inc. (São Paulo, Brazil). Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (SLP, Soluplus, average molecular weight of 118 kDa) was from BASF (Ludwigshafen, Germany). Purified soybean phosphatidylcholine (PPC, Lipoid S100, lot 579001160709) was from Lipoid GmbH (Ludwigshafen, Germany). Polyethylene glycol 400 (PEG) was obtained from Labsynth do Brasil (Diadema, Brazil). Colloidal silicon dioxide (CSD, Aerosil 200) was acquired from Sigma-Aldrich (São Paulo, Brazil). The solvents and other chemicals were analytical or HPLC grade.

Danilo Monteiro de Carvalho, Ana Carolina Mendes Lourenço, Guilherme Gomes Moreira, Fritz Eduardo Kasbaum, Ana Luiza Lima, Marcilio Cunha-Filho, Stephânia Fleury Taveira, and Ricardo Neves Marreto, Role of Phospholipids on Drug Dissolution in Polymer Solid Dispersions Prepared by Hot-Melt Extrusion, ACS Omega Article ASAP, DOI: 10.1021/acsomega.5c0186

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