Comparative Evaluation of Kollidon®VA64, SoluPlus®, and Aquasolve™ Hpmcas H-L Polymers: Impacts on Oral Spray Dried Powders

Summary

Ritonavir (RTV) is an anti-HIV protease inhibitor and antiretroviral medication to treat HIV /AIDS and especially COVID-19 infection. But it has low aqueous solubility which limits its oral bioavailability. Over the last decade, spray drying has become one of the most widely accepted solubility enhancement strategies in the pharmaceutical industry and academia. The spray drying process is a low-cost, solventbased, scalable, continuous, and consistent technique to prepare an amorphous solid dispersion (ASD) of a hydrophobic drug in a single step. Even though the spray drying process has many advantages, it is a complicated system regarding process and formulation parameters. The formulation parameters such as the composition of feed (drug, polymeric carrier, and solvent) greatly impact the physicochemical properties of the spray-dried amorphous powder. Polymer selection is very crucial to developing a physiochemically stable and highly soluble ASD. However, there is a notable lack of comprehensive studies focusing on the impact of polymer type on spray dried powders. So, the objectives of this study were to perform a comparative evaluation of the impacts of Kollidon®VA64, SoluPlus®, and AquaSolve™ HPMCAS H-L polymers on spray-dried dispersion powders (SDP) of ritonavir. Powder characterization, DSC analysis, stability, solubility, and dissolution studies were performed. Short-term chemical stability studies supported that the RTV-ASD powders were stable for three months. The solubility of the coarse RTV crystalline powder was significantly increased through the ASD powders with various polymers, compared to the physical mixtures. Dissolution studies showed that the rank order was SoluPlus®>Kollidon®VA64>AquaSolve™ HPMCAS H-L SDPs for both inlet temperatures.

Introduction

The spray drying method has attracted high attention in pharmaceutical drug development to overcome the solubility and dissolution challenges of oral dosage forms with low aqueous soluble drugs. Almost 40% of the top 200 oral-marketed drug products in the USA have low solubility. Moreover, 90% of new chemicals and 75% of compounds in the development pipeline of the pharmaceutical industry have low aqueous solubility (Arif Muhammed, Mohammed,
Visht, & Omar Yassen, 2024; Siriwannakij, Heimbach, & Serajuddin, 2021). Amorphous solid dispersions (ASD) are solid dispersions in which the active ingredient is dispersed within an excipient matrix in a substantially amorphous form. The amorphous structure of the drug is essential for increasing its solubility and dissolution, because no energy is required to break the drug’s crystal lattice. Spray drying is one method to prepare an ASD and is based on the transformation of a drug-carrier combination in a fluid state (e.g. solution, suspension, or emulsion) into dried powders, by atomizing the drug-carrier in heated air (Corrigan, 1985). Spray drying has advantages due to being energy intensive, continuous ,and commercially scalable drying process in single operation with no handling (Bhujbal et al., 2021; Mujumdar, 2006; Ogawa et al., 2018; Singh & Van den Mooter, 2016). In addition to solubility and dissolution
enhancement, it provides uniform and controllable particle size. Spray drying is employed for more than half of all commercially available amorphous solid dispersion products (Jermain, Brough, & Williams III, 2018; Pandi, Bulusu, Kommineni, Khan, & Singh, 2020). Even though spray drying has advantages, the role of formulation and process parameters on the quality and reproducibility of the drug product is incompletely understood. Process parameters include inlet temperature, drying gas properties, spray gas flow, feed rate, and airflow rate. Additionally, formulation
parameters include the composition of the feed such as solvent type, solid content, carrier type ,and ratio.

For example, the composition of the feed affects the surface tension and viscosity (Paudel, Worku, Meeus, Guns, & Van den Mooter, 2013). Polymer type and ratio are especially important due to an active substance is expected to have higher solubility in the polymeric carrier through the possibility of stronger favorable intermolecular interactions (Paudel, Van Humbeeck, & Van den Mooter, 2010). Even though the selection of the polymeric carrier is crucial to
potentially developing a physicochemically stable and highly soluble formulation of a poorly soluble drug, there is a notable lack of comprehensive studies focusing on the impact of the polymer type on spraydried powders.

In this study, the aim was to bridge this gap by investigating the impacts of polymers on the physicochemical properties, stability, solubility, and dissolution profiles of spray-dried powders (SDP). Ritonavir (RTV) was selected as a model drug, as it is an orally active anti-HIV protease inhibitor and antiretroviral medication to treat HIV/AIDS and especially COVID-19 infection. It is a poorly soluble drug, with its low solubility limiting oral absorption and oral bioavailability. To overcome this problem, the preparation of spray-dried powders of RTV was considered. Previously, with a focus on the systematic approach of polymer selection for ASD formulation via film casting, Kollidon®VA64, SoluPlus® and AquaSolve™ HPMCAS H-L combination (1:1 w/w) were selected as appropriate polymers for the spray dryer process of RTV (Oktay & Polli, 2024). Therefore, these polymers were used as carriers in spray-dried powders here, and the comparative evaluation of these polymers was performed in this study. SoluPlus® is an amphiphilic polymer due to possessing hydrophilic and lipophilic groups, and it can function as a solubility enhancer via the formation of colloidal micelles in solution (Alshahrani et al., 2015). SoluPlus® is a graft copolymer of polyvinyl caprolactam-polyvinyl acetate (lipophilic) and polyethylene glycol 6000 (hydrophilic) (Linn et al., 2012). Moreover, SoluPlus® has low hygroscopicity which aids the stability of ASDs. Kollidon®VA64 is also a copolymer composed of a chain structure of two monomers, namely N-vinylpyrrolidone and vinyl acetate (Bühler, 2008). Hypromellose acetate succinate (HPMCAS) is a cellulosic polymer, and grades of HPMCAS differ in chemical substitution of acetyl and succinoyl functional groups (Honick et al., 2019). HPMCAS has a high glass transition temperature which can prevent recrystallization and increase the stability by delayed kinetics of spraydried powders (Al-Obaidi & Buckton, 2009). Here, the impacts of these polymers on the SDP particle size, powder densities, flowabilities, moisture content %, yield %, drug content %, stability, RTV solubility, and RTV dissolution profiles from spray-dried powders were evaluated.

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Materials

Ritonavir (ChemShuttle; Blue Current Inc.; Hayward, California), polyvinylpyrrolidone-vinyl acetate (Kollidon®VA64)(BASF SE; Ludwigshafen Germany), Polyvinyl caprolactam-polyvinyl acetate + polyethylene glycol graft copolymer (SoluPlus®) (BASF SE; Ludwigshafen Germany), 1:1 ratio (w/w) combination of hypromellose acetate succinate (AquaSolve™ HPMCAS) H and L grades (Ashland Inc; Covington, KY) were used to prepare the spray dried powders. Solvents were in analytical grade and obtained from Fischer Scientific (Fischer Scientific; Hampton, NH) and Sigma Aldrich (Sigma-Aldrich; St. Louis, MO).

FABAD J. Pharm. Sci., 50, 2, 355-370, 2025, Comparative Evaluation of Kollidon®VA64, SoluPlus®, and Aquasolve™ Hpmcas H-L Polymers: Impacts on Oral Spray Dried Powders, Ayse Nur OKTAY, James E. POLLI, Doi: 10.55262/fabadeczacilik.1662288, RESEARCH ARTICLE, Received: 20.03.2025, Revised: 24.05.2025, Accepted: 3.07.2025