The Effect of the Particle Size Reduction on the Biorelevant Solubility and Dissolution of Poorly Soluble Drugs with Different Acid-Base Character

Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution.

In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements.

Introduction

In recent years, the number of molecules belonging to BCS class II (low solubility, high permeability) and class IV (low solubility, low permeability) increased significantly, therefore improving the solubility of poorly soluble drugs became one of the most important challenges of the pharmaceutical industry [1,2]. Nowadays, several different solubility-enhancing techniques are available. There are methods based on physical changes such as particle size reduction, change of crystallinity (polymorphous or amorphous) or solid dispersion formation. Both physical and also chemical methods such as pH modification, complex or salt formation, or mixed methods such as supercritical fluid preparation or use of different solubilizing agents are known [3,4].

Particle-size reduction is one of the most commonly used processes in the formulation development. Due to the size reduction, the surface area of the particles increases, allowing a greater interaction with the solvent and improving the dissolution. There are two major types of size reduction based on the dimension of the size of the particle: micronization (particles between 1–1000 µm) and nanonization (particles in the submicron range, <1 µm) [5]. Micronization is a widely used method to enhance the bioavailability of an API. It is usually performed by milling (jet/ball milling) or high-pressure homogenization. Equilibrium solubility is not affected by micronization, but the dissolution rate will improve [3,6]. In contrast, nanonization can affect both the solubility and the dissolution rate, because under the critical 1µm size limit, the equilibrium solubility of a compound is not independent from the surface area anymore [7]. This can explain, why not only the velocity of the dissolution, but also the concentration of the saturated solution increases [8]. There are two major types of methods to approach nano-sized particles: top-down and bottom-up techniques. Top-down techniques such as milling or homogenization are producing very small particles, but they require stabilizers (most commonly polymers), and the heat forming during the process can cause damage in the substance. Precipitation or sol-gel formation belongs to the bottom-up techniques. These methods are mostly cost efficient and they result in smaller particle size with a narrow size distribution. However, the substance should be soluble at least in one solvent, and the product can contain solvent residues [5,8,9,10].

Knowing the accurate solubility of a drug in the early stages of development is essential for a successful product. There are many factors that can influence this parameter, including but not limited to: pH and degree of ionization, solubilizing agents, temperature, particle size and crystalline structure [11,12,13]. To obtain such solubility data, which is important in terms of bioavailability, buffers with a pH that is relevant in the gastrointestinal tract should be applied. Usually, pH = 1.2–1.6 buffers are used to simulate the gastric media, pH = 6.5 buffers are commonly used to imitate the fasted-state intestinal pH conditions, while pH = 5.0 buffers help to mimic fed-state intestinal conditions [14,15]. However, the adjusted pH alone does not describe the actual situation in the gastrointestinal tract, therefore using biorelevant media (BRM) can provide a more precise outcome. These media were invented to model additional important properties of the gastrointestinal fluids, including solubilization by bile salts and lecithin. These agents can solubilize the molecules resulting in a higher solubility [15,16]. The equilibrium solubility of a compound can be measured by several different techniques, however the “gold standard” is still the saturation shake-flask method (SSF) [17]. After reaching the equilibrium, where the solid and the solvent phases are in balance, the concentration of the saturated solution provides the equilibrium solubility, but the remaining solid phase also should be analyzed to reveal the possible polymorph or salt transformations [18,19].

In our previous work, we determined the biorelevant solubility of four drugs representing different acid-base characters and studied the effect of pH, solubilizing agents and the food effect for the compounds, rivaroxaban, furosemide, papaverine and niflumic acid. In that study, the solubility was measured by the SSF method, but the solid phase was not analyzed [20].

In this work, we provide a more comprehensive investigation of factors, which can influence not only the solubility but the dissolution in BRM. The first goal of this study was to prepare size-reduced samples with a simple and commonly used technique, dry milling. Furthermore, the aim of this work was to investigate the effect of the particle size and the effect of the different characteristics of the excipients on solubility and dissolution. In addition, the solid particles were analyzed from the preparation until the end of the solubility measurements using different analytical methods. Finally, the relation between the solubility results and the molecular characteristic of the polymer excipients was confirmed.

The model compounds are furosemide (BCS IV) as an acid, papaverine hydrochloride (BCS II) as a salt of a base and niflumic acid (BCS II) as an ampholyte [20]. From the commercially available substances (named here as original or starting materials) micro- and nanonized forms were prepared. In the preparation of nano-sized products, polymer excipients were used to prevent the aggregation of the particles. The solubility of all samples was measured in a phosphate buffer with pH = 6.5 (FaSSIF blank) and an acetate buffer with pH = 5.0 (FeSSIF blank) and in the biorelevant dissolution media (FaSSIF and FeSSIF full) (biorelevant).

In the case of the original substances and the micronized forms, all the solubility and dissolution measurements were performed with the pure substance and in the presence of the excipients used for nanonization, therefore the possible effect of these excipients was also studied. The solid-state analysis at the end of the solubility measurements was performed with powder X-Ray Diffraction (PXRD). After the solubility measurements, the particle size of the solid phase from the sample was measured with a laser diffraction particle size analyzer (Mastersizer^TM).

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Materials

Niflumic acid (NIF) was purchased from Sigma-Aldrich Co. Llc. (St. Louis, MO, USA), papaverine hydrochloride (PAP) from Molar Chemicals Ltd. (Halásztelek, Hungary), and furosemide (FUR) from TCI Europe N.V. (Haven, Belgium). From the commercially available substances micro- and nano-sized products were prepared by milling (Retsch Ball Mill (Retsch Hungary, Budapest, Hungary), 400 rpm, 2 h) at the University of Szeged. The milling time and rpm were identical for micronization and nanonization, but for nano-sized products the polymer excipients were added in 1 to 1 mass ratio. Two different polymers were used: polyvinyl alcohol (PVA) and polyvinylpyrrolidone-25 (PVPK-25) purchased from Sigma-Aldrich Co. Llc. (St. Louis, MO, USA). The distilled water of Ph. Eur. grade was used. All other reagents (sodium chloride, sodium hydroxide pellets, acetic acid, sodium dihydrogen phosphate) were of analytical grade. SIF powder was purchased from Biorelevant (London, UK).

Csicsák, D.; Szolláth, R.; Kádár, S.; Ambrus, R.; Bartos, C.; Balogh, E.; Antal, I.; Köteles, I.; Tőzsér, P.; Bárdos, V.; Horváth, P.; Borbás, E.; Takács-Novák, K.; Sinkó, B.; Völgyi, G. The Effect of the Particle Size Reduction on the Biorelevant Solubility and Dissolution of Poorly Soluble Drugs with Different Acid-Base Character. Pharmaceutics 2023, 15, 278. https://doi.org/10.3390/pharmaceutics15010278