Combined pre-formulation approach for the selection of naproxen-polymer-solvent candidates for the preparation of amorphous solid dispersion

This poster has been presented at the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology which took place in Prague, Czech Republic.

Combined pre-formulation approach for the selection of naproxen-polymer-solvent candidates for the preparation of amorphous solid dispersion

Introduction

Naproxen is generally classified as a Biopharmaceutics Classification System (BCS) Class II compound,
characterized by low aqueous solubility in low pH media and high permeability.
To enhance the oral bioavailability of such poorly soluble drugs, amorphous solid dispersions (ASDs)
have been widely used, where the active substance is molecularly dispersed within a polymeric matrix.
One of the key manufacturing techniques for production of ASDs usually involve a drug–polymer–
solvent system, the selection of which must satisfy specific physicochemical and process-related
criteria to ensure efficient manufacturing, safety, stability, and performance of the resulting dosage form.
The aim of this study was to narrow down the list of possible drug–polymer–solvent systems for the
formulation of naproxen ASDs, using a specific workflow (Fig.1).

Materials

Naproxen (Biosynth, Slovakia)
PVP K25 (Povidone)
Kollidon VA 64 (copovidone)
Soluplus (BASF SE, Germany)
Eudragit E PO (poly (butyl methacrylateco-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate 1:2:1; Evonik AG, Germany)
Apinovex LV (polyacrylic acid; Lubrizol Advanced Materials, Inc., USA)
PVAl SRP 80, 4-88, and 3-82 (polyvinyl alcohol; Merck AG, Germany)
Acetonitrile, chloroform, THF, ethyl acetate and xylene were of Pharmacopeia grade and used as received

Methods

Screening based on solubility parameters (SP): solvent screening for naproxen and the selected polymers was conducted using the Hansen Solubility Parameters in Practice (HSPiP) software [1], which applies the solubility parameter (SP) approach to assess the likelihood of drug–solvent, polymer–solvent, and drug polymer compatibility. Yamamoto–Molecular Breaking (Y-MB) and the Hoftyzer– Van Krevelen (H–VK) methods were used for this purpose. The solubility distance (Ra) was calculated from the dispersion (δD), polarity (δP), and hydrogen bonding (δH) parameters of the drug or polymer (1) and solvent (2) [1]:
Ra2 = 4(δD1 − δD2)² + (δP1 − δP2)² + (δH1 − δH2)²
Smaller Ra values indicate a higher likelihood of dissolution; solvents with Ra ≤ 5 (VK) were selected for further assessment.
Solubility tests: were performed for naproxen in the selected solvents, using a shake-flask method. Alongside, a parallel experimental visual assessments of the solubility of the polymers in the same solvents, as well as in water at gastric related media (0.1 N HCl) [2] were performed.
Precipitation test: was performed in 0.1 N HCl [2] solution with pre-dissolved polymer (60, 40, and 20 wt. %). Specified amount of naproxen solution in acetonitrile (20 mg/mL), to achieve the proportion of 500 mg of naproxen per 1 L of dissolution medium (0.5 mg/mL), was added. UV absorption was determined directly within 10 mm pathlength quartz cuvettes (at room temperature) with UV-1900i spectrophotometer (Shimadzu, Japan). Spectra were recorded at 5-minute intervals over a 2-hour period (n = 3).

Fig. 1. Workflow for solvent and polymer selection for naproxen formulation development

Table 1. Ranking of solvents by ICH, boiling point, HSP values, and saturated solubility

Table 2. Solubility parameters for Soluplus

Results

Solvents for naproxen with Ra ≤ 5 (VK) were obtained and ranked according to ICH class, boiling point; naproxen solubility in these solvents was evaluated and compared with solubility parameters obtained with HSPiP software (Table 1).
Based on the Ra values, THF, chloroform, ethyl acetate, and xylene were identified as the most suitable organic solvent candidates for naproxen (Table 1).
According to the ICH classification, ethyl acetate is the least toxic among these solvents, whereas chloroform and THF exhibit the lowest boiling points. Experimental saturated solubility testing confirmed that THF provides the highest solubility for naproxen, dissolving up to 376.5 mg/mL, while xylene showed the poorest solubility, with a maximum of 3.9 mg/mL (Table 1).
The SP-based approach for polymer-drug-solvent screening has limitations, as it does not fully account for specific molecular interactions, including hydrogen bonding, therefore theoretical predictions often deviate from experimental solubility outcomes. Regarding polymers, the SP of individual structural subunits were used to estimate suitable solvents, however, the approach does not account for the relative contributions of each subunit, as well as their proportions and spatial distribution in the polymer chain, which explains the deviation of theoretical solubility predictions from experimentally observed results.
Visual solubility assessment showed that all investigated polymers were soluble in water at gastric pH (0.1 N HCl) [2]. Used PVA grades at a concentration of 50 mg/mL were insoluble in all tested organic solvents, whereas Soluplus and Kollidon VA 64 were soluble in all solvents except xylene at the same concentration, while PVP K25 exhibited solubility only in chloroform. (Table 2)
To identify polymers that enhance drug solubility and reduce precipitation un under gastric conditions, precipitation tests were carried out for naproxen with polymers PVP K25, Kollidon VA 64, Eudragit E PO, Apinovex LV, and PVAls (SRP; 4-88; 3-82) at a 60 % polymer load (considering naproxen-polymer solid dispersion) and Soluplus at 60 and 20 % polymer load. The best precipitation inhibition results were obtained with Soluplus. Soluplus at 20% load outperformed other tested polymers at 60% load (Fig. 2). Among other polymers at 60% load, PVAl polymers showed only modest precipitation inhibition, while PVP K25, Kollidon VA 64, Apinovex LV, and Eudragit E PO unexpectedly accelerated naproxen’s precipitation.

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Source: Gurkina K, Horváth ZM, Kačanovs R, Mohylyuk V. Combined pre-formulation approach for the selection of naproxen-polymer-solvent candidates for the preparation of amorphous solid dispersion. 15th PBP; Prague, Czech Republic, 2026.03.23-26; DOI: 10.13140/RG.2.2.24155.94240.
Leading Research Group

Materials: Nanoproxen, Kollidion VA 64 (BASF) , Soluplus (BASF), Eudragit E PO (Evonik), Apinovex (Lubrizol), PVAl SRP 80, 4-88, and 3-82 (polyvinyl alcohol; Merck AG, Germany)