How Do Cryo-Milling and Lyophilization Affect the Properties of Solid Dispersions with Etodolac?

Abstract

Background: Solid dispersions (SDs) of etodolac (ETD), a poorly water-soluble drug model, were developed to enhance its solubility and dissolution rate by employing various preparation methods and hydrophilic or amphiphilic polymers.

Methods: Polyvinylpyrrolidone-poly(vinyl acetate) copolymers (PVP/VA), hydroxypropyl methylcellulose (HPMC) and poloxamer were used as carriers, while cryo-milling and lyophilization were utilized as routine methods to SDs preparation. Obtained SDs were characterized by drug content, solubility, dissolution rate and moisture content. The physical structure of SDs was estimated via scanning electron microscopy (SEM), whereas differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were employed to assess the potential drug-carrier interactions.

Results: SD formulations demonstrated enhanced solubility of ETD in aqueous media, including water and buffers (pH 5.5 and 7.4). DSC analysis confirmed that PVP/VA and poloxamer ensured better ETD dissolution and protection against recrystallization. Furthermore, FTIR indicated the formation of hydrogen bonds between ETD and polymer, particularly in lyophilized dispersions.

Conclusions: The optimized SD formulation for ETD contained PVP/VA and/or poloxamer as carriers and was obtained via lyophilization. This SD formulation exhibited the most favorable properties, enhanced the solubility and dissolution of ETD in aqueous media and effectively reduced its crystallinity.

Introduction

Poor water solubility is one of the main reasons for inadequate drug bioavailability and unsuccessful formulation development steps. To improve solubility, different strategies are employed and various techniques are studied, such as micronization, salt formation, complexation, use of surfactants and solubilizers [1,2,3]. Solid dispersions (SDs) constitute one of the approaches to enhance drug solubility, especially promising for drugs belonging to a Biopharmaceutics Classification System (BCS) class II, characterized by low solubility and high permeability [4,5,6,7]. SDs are described as a mixture of at least two components, a hydrophobic drug and a hydrophilic matrix. They can lead to particle size reduction, increased wettability and porosity, reduced agglomeration and drug amorphization (Figure 1) [8,9,10].

Etodolac (ETD) is chemically described as 1,8-diethyl-l,3,4,9-tetrahydropyrano-[3,4-b] indole-1-acetic acid and represents the selective COX-II (cyclooxygenase) inhibitor non-steroidal anti-inflammatory drug (NSAID) [11,12].

It has analgesic, anti-inflammatory and antipyretic activity and can be used to treat acute pain, rheumatoid arthritis and osteoarthritis. Due to its low solubility (0.016 mg/mL) [12] and some drawbacks of conventional oral therapy (gastrointestinal disturbances, frequent dosing), the alternative ways to drug administration—buccal, topical and nasal route—are reviewed. Some studies present utilization of ETD in topical dosage form, e.g., liposomes, solid lipid nanoparticles, nanostructured lipid carriers, cubosomes, ethosomes, nanosuspensions, nanoemulsions, film-forming spray and gels. Madhavi et al. [13] found that liposome and ethosome gels containing ETD exhibited better pharmacokinetic and pharmacodynamic profiles (prolonged half-life, increased mean residence time in the body and greater reduction in edema in a rat model) compared to conventional industrial gel. Increased ETD skin permeability was also achieved by Patel et al. [14], who incorporated the drug into a gel based on solid lipid nanoparticles. Other researchers who combined topical preparations (creams, gels) with innovative drug carriers (nanoemulsions, nanosuspensions, nanostructured lipid carriers, cubosomes) also demonstrated that these systems are promising formulation strategies for ETD and then highlighted the need to continue the exploration of new, advanced carriers for ETD [15,16,17,18,19,20,21,22,23].

The carriers used in SDs present crystalline form (e.g., urea, sugars), representing the first generation of SDs, or in amorphous state (e.g., PVP, HPMC), representing the second generation of SDs. SDs containing other excipients, such as an additional polymer or surfactant, are known as the third generation of SDs [1,24,25,26]. Many methods are available for SDs preparation, including solvent evaporation, spray drying, hot-melt extrusion (HME), ball milling (grinding), lyophilization (freeze-drying) and electrospinning. Among the commonly used technologies, spray-drying and HME are considered as standard methods for SDs preparation. Spray-drying provides good molecular dispersion but possesses the risk of exposure to organic solvents, while HME requires high processing temperatures, which can lead to decomposition of excipients and API [27,28,29,30]. Given these challenges and exploring alternative solutions, other preparation techniques such as cryo-milling and lyophilization seem to be attracting approaches. In our study, we chose these two methods to prepare optimized SDs. Cry-omilling, a modified form of conventional ball milling (at room temperature condition), is a solvent-free, low-temperature and simple method to obtain SDs. This method has been widely employed in pharmaceutical research to enhance drug solubility [31,32,33,34]. In comparison to ball milling, during cryo-milling, the ingredients are frozen using liquid nitrogen to minimize the risk of thermal degradation of the drug and other components [32].

During milling, drug amorphization probably occurs as a result of milling-induced disorders, generated by major mechanical perturbations (reduction in particle size, polymorphic transformations, partial or complete amorphization) [32,35,36].

Lyophilization is a process in which water and organic solvent at the first stage is frozen, then removed from the sample by sublimation process [37,38]. An important merit of lyophilization is that drugs are not exposed to high temperatures. In this method, poor water-soluble drugs are preferred because they weakly bond to solvents and are more easily transformed in to dried form. In the literature, shorter dissolution times for lyophilized products have been reported compared to solid forms obtained by other methods (e.g., solvent evaporation) [8,39,40,41,42].

The prepared SDs can be examined using different analytical and instrumental methods. Commonly studied parameters of SDs are solubility, dissolution rate, physical state of drug (amorphous or crystalline) and morphology. The list of methods for SDs characterization is presented in Table 1. In our study, one method from each type was chosen to assess the properties of designed SDs.

Table 1. Methods for SDs characterization [1,26,43].

In this work, PVP/VA, HPMC and poloxamer were selected as ETD polymer carriers, based on previous studies [44]. PVP/VA (copovidone), known by its trade name as Kollidon VA64, is a copolymer containing six parts of vinylpyrrolidone and four parts of vinylacetate. It is characterized as an amorphous polymer that is soluble in hydrophilic solvents, commonly used as a binder and film-forming agent. In contrast to PVP (polyvinylpyrrolidone), PVP/VA is less hygroscopic, exhibits a glass transition temperature of approximately 100 °C and degrades at high temperature (above 230 °C) [7,45]. Hydroxypropyl methylcellulose (HPMC) is one of the most widely used cellulose ethers in solid dispersions and other pharmaceutical formulations. It is characterized as a non-ionic, water-soluble and non-pH-responsive compound. HPMC as a non-toxic, biocompatible and biodegradable ingredient is mainly used as dispersing and viscosity-modifying agent [46,47]. Even though this polymer lacks very strong hydrogen bond donor and acceptor groups, HPMC is used in many marketed drugs with SDs (tablet or capsule dosage form) [48,49,50]. In the structure of HPMC, both the hydrophilic (hydroxy) and lipophilic (ether) groups are identified, so it proves high drug–polymer miscibility and/or solubility [7,48,51].

In this work, the possibility of using SDs as an approach to improve the solubility of a poorly water-soluble drug model was evaluated. Etodolac (ETD) belongs to a Biopharmaceutics Classification System Class II and is characterized by low aqueous solubility. Polymers with varying physicochemical properties, including poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA), hydroxypropyl methylcellulose (HPMC) and poloxamer were tested as carriers. The choice of amorphous carriers—HPMC and PVP/VA—was based on the results from previous studies [31]. Cryo-milling and lyophilization were utilized as methods to obtain SDs formulations. SDs were characterized by drug content, solubility, dissolution rate, morphology, interactions and physical state of ETD. This study aims to assess the effects of the preparation methods of SDs—cryo-milling and lyophilization—on improving ETD solubility. This thesis is a continuation of prior work [44], which focused on SDs with ETD obtained by ball milling process.

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Materials

Etodolac (ETD) was obtained from Xi’an Health Biochemical Technology Co. (Xi’an, China). Kollidon VA 64 (polyvinylpyrrolidone-poly(vinyl acetale) copolymers, PVP/VA) was supplied from BASF (Burgbernheim, Germany), Pharmacoat 606 (hydroxypropyl methylcellulose, HPMC) from Shin-EtsuChemical Co. (Niigata, Japan) and poloxamer 407 (poly(ethyleneglycol)-block-poly(propyleneglycol)-block-poly(ethyleneglycol)from Sigma Aldrich (Steinheim, Germany). Potassium dihydrogen phosphate and sodium acetate were provided by Chempur (Piekary Sląskie, Poland), ethanol 96% and acetic acid from POCH (Gliwice, Poland) and acetonitrile from J.T. Baker (Deventer, Holland). Water for HPLC analysis was obtained by a Milli-Q Reagent Water System (Millipore, Billerica, MA, USA).

Czajkowska-Kośnik, A.; Wach, R.A.; Wolska, E.; Winnicka, K. How Do Cryo-Milling and Lyophilization Affect the Properties of Solid Dispersions with Etodolac? Pharmaceutics 2025, 17, 1379. https://doi.org/10.3390/pharmaceutics17111379