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Article

Aqueous Solution Spray Drying Preparations of Binary Amorphous Solid Dispersions

by
Wenling Zheng
1,2,
Junni Ke
2,
Kaerdun Liu
3,
Rongrong Xue
2,* and
Fenghua Chen
2,*
1
School of Chemical Engineering, Fuzhou University, Fuzhou 350116, China
2
School of Resources and Chemical Engineering, Sanming University, Sanming 365004, China
3
Innovation Development Division, China Resources Double-Crane Pharmaceutical Co., Ltd., Beijing 100102, China
*
Authors to whom correspondence should be addressed.
Crystals 2025, 15(4), 323; https://doi.org/10.3390/cryst15040323
Submission received: 7 February 2025 / Revised: 21 March 2025 / Accepted: 26 March 2025 / Published: 28 March 2025
(This article belongs to the Section Crystal Engineering)
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Versions Notes

Abstract

:
Spray drying of poorly water-soluble drugs in organic solvents is a mature process in the preparation of drugs amorphous solids dispersions (ASDs). The use of organic solvents is under increasing environmental protection and safety pressure and restricts the application of advanced polymers as proteins which are usually insoluble and unstable in organic solvents. Aqueous solution spray drying technology is a candidate method for preparing ASDs without the use of organic solvents. Increasing temperature and adding volatile additives can improve the solubility of poorly water-soluble drugs in water without introducing additional components and energy needed. In this work, ammonia assisted aqueous solution spray drying method was successfully used to prepare various ASDs of indomethacin (25%) with synthetic polymers as polyvinylpyrrolidone and proteins as β-lactoglobulin, lactalbumin hydrolysate, bovine serum albumin, with high yields, special micro golfs morphology, precise compositions and longtime stabilities, compared to high-temperature aqueous solution spray drying method. ASDs with lactalbumin hydrolysate and bovine serum albumin show better dissolution profiles than other ASDs. Aqueous solution spray drying is easily extended to prepare the ASDs of sulfamerazine and celecoxib, providing a possibility to avoid the use of organic solvents in advanced ASDs preparations via spray drying.

1. Introduction

Amorphous solid dispersions (ASDs) technology is popularly used to improve the solubility and bioavailability of poorly water-soluble drugs [1,2,3,4]. ASDs technology can improve the storage stability of the high-energy amorphous phase of active pharmaceutical ingredients (APIs), regulate the APIs release time, and make the APIs maintain a high concentration compared to their intrinsic solubility, which is beneficial for the application of the BCS class II drugs. Spray drying of aqueous solutions or aqueous dispersions is a mature technology. Spray drying can produce a powdered product with defined structural and dispersion characteristics, avoiding the residual solvent. However, in the field of ASDs, spray drying of drug and polymer organic solution, instead of an aqueous solution, is a well-established manufacturing technique to formulate ASDs [5,6,7]. Organic solvents are used in the spray-drying process to increase the solubility of poorly water-soluble drugs [8,9] because low-concentration solutions are not suitable for spray-drying. However, the wide application of organic solvents in spray drying makes this method face increasing environmental protection and safety (flammability, residual) pressure [10,11].
The use of organic solvents also restricts the development of advanced polymer carriers of ASDs. Proteins are a class of advanced potential carriers and have caught attention in the ASDs area for improving the oral bioavailability of poorly soluble drugs [12,13,14]. The reported protein carriers are usually extracted from foods such as milk and soybean, which is highly safe and exhibits excellent biocompatibility in oral. Proteins are potential stabilizing excipients for ASDs systems. The disadvantages of proteins as carriers include the possibility of protein denaturation and spoilage during the ASDs preparation process and storage, limited categories for various drugs, and high cost. Compared to traditional synthetic polymer carriers, proteins are usually not soluble in organic solvents. Mixtures of organic solvents and water are used to ensure the simultaneous dissolution of drug and protein. However, proteins face the risk of denaturation in organic solvents even if the ratio in the mixed solvents of organic solvents is not high, which is not safe for oral. The poor solubility and stability of proteins in organic solvents limit their application in the preparation of ASDs by spray drying.
The aqueous solution spray drying method is a candidate method for preparing the ASDs of poorly water-soluble drugs, which can avoid the use of organic solvents but can use proteins as carriers. The key problem in developing the aqueous solution spray drying method is to improve the aqueous solubility of poorly water-soluble drugs. Aqueous solution spray drying has been used for preparing the ASDs of slightly soluble theophylline [15] in our laboratory. It is still a challenge to develop a universal process for preparing the ASDs of poorly water-soluble drugs by aqueous solution spray drying. Increasing temperature and adding volatile additives are used here to increase the aqueous solubility of poorly water-soluble drugs without additional components introduced to the final products and additional theoretical energy needed, which are suitable for industry production. The acid-base properties are widespread in APIs and crucial for their pharmacological effects [16]. The solubility of drugs can be significantly enhanced by adjusting the pH conditions [17,18]. The ingredients, which are safe and removable during the spray drying process, are good choices for aqueous solution spray drying technique, such as alkaline ammonia [19,20], acidic CO2 [21,22], acetic acid [23], and ammonium carbonate [24,25].
Indomethacin (IND, Figure 1a inset) is a classical BCS II drug [26,27] selected as a model here, which has been extensively studied as a model in the field of ASDs [28,29,30]. In recent years, spray drying has been widely used in the preparation of various IND solid dispersions, especially ASDs (Table 1) [31,32,33,34,35,36,37,38,39,40], most of which use organic solvents. Some attempts have been made to prepare the ASDs by aqueous suspension spray drying to avoid the use of organic solvents [33,37,40]. For example, nano-dry-melting, which is a two-step method combining wet ball milling and aqueous suspension spray drying, provides an alternative option for ASDs manufacturing [33]. Proteins [31,34] have been used as carriers in ASDs of IND, for which organic solvents were used.
In this work, one-step ammonia-assisted aqueous solution spray drying was successfully used to prepare various ASDs of IND (25%) with synthetic polymers as polyvinylpyrrolidone (PVP), and proteins as β-lactoglobulin (BLG), lactalbumin hydrolysate (LAC), bovine serum albumin (BSA). Raman and IR spectra confirmed that these ASDs are mainly composed of neutral IND molecules. These ASDs show high yields, special micro golf morphology, precise compositions, longtime stabilities, and good dissolution profiles. ASDs with proteins, especially LAC and BSA, have better dissolution profiles than ASDs with PVP. Aqueous solution spray drying methods make it easy to prepare the ASDs of other poorly water-soluble drugs such as sulfamerazine (SMR) and celecoxib (CEL). Aqueous solution spray drying methods are green, robust, and feasible, which is of significance for the industrial production of ASDs of poorly water-soluble drugs.

2. Materials and Methods

2.1. Materials

Indomethacin (IND, C19H16ClNO4, 99%), sulfamerazine (SMR, C11H12N4O2S, 99%), celecoxib (CEL, C17H14F3N3O2S, 99%), polyvinylpyrrolidone K30 (PVP K30), β-lactoglobulin (BLG, 95%), lactalbumin hydrolysate (LAC), bovine serum albumin (BSA, 96%), whey protein, and corn protein were bought from Aladdin. Soy protein isolate was bought from Macklin. Ammonia water (25–28%, AR) was bought from Xilong Scientific. All the reagents are used without any treatments.

2.2. Methods

Calibration Curves. IND calibration curves with absorbance (Shimadzu UV-2550, Shimadzu, Japan) at 320 nm were established by using IND 50 vol% ethanol solutions, 10 vol% ethanol solutions or 1000 times diluted ammonia aqueous solutions in the concentration range of 0–100 μg·mL⁻1 with intervals of 10 μg·mL−1 (Figure S1). 50 μg·mL⁻1 IND 10 vol% ethanol solution was prepared by dissolving 5 mg of raw IND in 10 mL of ethanol and making up to volume with water in 100 mL volumetric flask, and the solution can maintain stable only for few hours. The calibration curves were linearly fitted based on the Beer-Lambert law. CEL calibration curves with absorbance at 251 nm and SMR calibration curves with absorbance at 270 nm were established by using 50 vol% ethanol solutions in the same way.
IND Solubilities. 20 mg of raw IND was added into 20 mL of water or PVP aqueous solution. The dispersions were incubated at 26, 60, and 90 °C overnight in an oven and boiled at 100 °C for 10 min on a hot stage. The beakers were sealed with aluminum foil to prevent water evaporation and light. The experimental evaporation rate of water is 2.5 ± 0.7% at 90 °C overnight and 5.4 ± 0.4% at 100 °C for 10 min, measured by a macroscopic thermogravimetric method. The supernatant was filtered with a PES membrane (0.22 μm), and 2 mL of the filtrate was collected and diluted with 2 mL of ethanol to prevent crystallization and operated in a sealed tube to prevent the evaporation of ethanol. The obtained solutions were measured by UV-vis absorption spectroscopy, and the IND solubilities were calculated by the IND calibration curves in 50 vol% ethanol. For 0.1% ammonia solution (1 mL of commercial ammonia water diluted in 1 L with deionized water), the amount of IND increased to 10 mg·mL−1. For 1% ammonia solution, the amount of IND increased to 30 mg·mL−1, and only the solubility at 26 °C was measured, and the solubility was calculated with the IND calibration curve in 1000 times diluted ammonia aqueous solutions. All the solubility tests were conducted in parallel four times. The concertation of 0.1% ammonia solution is determined as 0.024 ± 0.001% measured by titrating with 0.10 mM H2SO4 solution and methyl orange as an indicator. The 0.1% ammonia solution can maintain 87% ammonia after being kept at 100 °C for 10 min under open conditions. The IND solutions stability has been studied here. The IND aqueous solution is stable at room temperature. The concertation of IND aqueous solution can maintain 97.0% after 1 h of storage. The concertation of IND in 0.1% ammonia solution can maintain 95.1% after 1 h of storage.
Clarity Test of Protein Aqueous Dispersions. Dispersions of three concentrations (0.01, 0.1, and 1 mg·mL−1) of six proteins (BLG, LAC, BSA, whey protein, soy protein isolate, and corn protein) were prepared separately and observed whether the proteins could completely dissolve, thereby obtaining an estimate of their solubility.
High Temperature Aqueous Solution Spray Drying. For IND, 0.5 g of raw IND and 1.5 g of PVP were dissolved in 5 L of boiling deionized water. Spray drying (Shanghai Pilotech YC-015, inlet temperature 180 °C, outlet temperature ~110 °C, feed rate 10 mL·min−1, atomization air pressure 24 kg·cm−2, drying air flow rate 30 m3·h−1) was carried out after the drug and polymer are completely dissolved, confirmed that there is no Tyndall phenomenon irradiated with a laser pointer. The solution used for spray drying was kept in a slightly boiling state to prevent the precipitation of the drug. The reference amorphous IND was the quenching product of IND melt from 180 °C to room temperature [41,42]. For CEL, 0.5 g of raw CEL and 4.5 g of PVP were dissolved in 5 L of boiling deionized water and then spray-dried as above.
Ammonia Solution Spray Drying. 1 g of raw IND and 3 g of PVP were dissolved in 1 L of 0.1% ammonia water (1 mL of ammonia water dissolved in 1 L of water) at room temperature and then spray-dried using the experimental parameters mentioned above. For the other polymers, 1 g of raw IND and 3 g of LAC, BLG, or BSA were dissolved in 1 L of 0.1% ammonia water at room temperature and then spray-dried. For SMR, 1 g of raw SMR and 3 g of PVP, LAC, BLG, or BSA were dissolved in 1 L of 0.1% ammonia water at room temperature and then spray-dried. The concertation of SMR in 0.1% ammonia solution can maintain 96.4% after 1 h of storage.
Characterization. IND samples were characterized conventionally by powder X-ray diffraction (PXRD, Philips X′Pert Pro, PANalytical, Netherlands, Cu Kα, 40 kV, 30 mA, 5–30°, 4°·min−1), Fourier transform infrared spectrometer (IR, Shimadzu IRAffinity-1S, Shimadzu, Japan, 400–4000 cm−1, 2 cm−1), confocal Raman spectroscopy (Thermo Fisher Scientific, USA, DXR3xi, 532 nm, 5–40 mW, 0.002–0.02 s, 1000 scanning times, 50–3500 cm−1, 50 × objective lens), and scanning electron microscope (SEM, Thermo Fisher Scientific Apreo 2C, Hillsboro, OR, USA, 5 kV).
Drug Loadings Determination. 10 mg of ASDs was dissolved in 50 vol% ethanol solution and adjusted to 100 mL. Then, the solution was measured by UV-vis spectroscopy and the drug loading was calculated with the calibration curves in 50 vol% ethanol. Each sample was measured in parallel three times.
Dissolution Profiles. ASDs of IND containing 20 mg drug were added into 200 mL deionized water or pH 1.2 HCl aqueous solution and then kept at 37 °C in a water bath. The supernatant was filtered (0.22 μm PES membrane) and collected at a certain time (1, 2, 4, 8, 24, 48, 72, 96 h), and the IND concentrations were calculated by the calibration curve in 10 vol% ethanol. The experimental conditions for ASDs of CEL were the same as those of IND ASDs, SMR ASDs containing 200 mg drug were used and the experiment conditions are basically the same as IND ASDs except 2 mL of the filtrate were collected and diluted with 2 mL of ethanol to prevent crystallization. The dissolution profiles of each sample were measured in parallel three times.

3. Results

3.1. Aqueous Solution Spray Drying of IND

3.1.1. IND Solubility

IND (Figure 1a) is an acidic molecule with a carboxylic COOH group [43]. The pKa of IND is ~4.5, and the pKb of ammonia is ~4.75; thus, the equilibrium constant for the neutralization reaction of IND and ammonia is 104.75, which is enough for IND to be ionized in aqueous ammonia. As shown in Figure 1b, the characteristic UV-vis absorbance peaks of 20 μg·mL−1 IND 10 vol% ethanol and 0.1% ammonia solutions are at 320 nm, and the absorptivity of these two solutions are similar. The absorptivity at 320 nm of IND in 50 vol% ethanol is about 10% smaller than that of 10 vol% ethanol and 0.1% ammonia solutions.
IND is a typical poorly water-soluble drug. Its reported aqueous solubility is only 0.94 [44] and 2.3 [45] μg·mL−1 at 298.15 K. The measured aqueous solubility via UV-vis spectroscopy of raw IND is 4.8 ± 0.1 μg·mL−1 at 26 °C (Figure 1c) and increases to 129 ± 21 μg·mL−1 at 100 °C (boiling state). The solubility of IND decreases to 2.6 ± 0.6 μg·mL−1 at 26 °C in the aqueous solution of 1 mg·mL−1 PVP because the polymer solution is weakly acidic (pH ~ 5.0), which inhibits the ionization of IND molecules. The solubility with PVP is 122 ± 9 μg·mL⁻1 at 100 °C similar to that without polymer [46]. A small amount of ammonia can dramatically increase the aqueous solubility of IND (Figure 1d). The IND concentration reaches up to 1.27 ± 0.10 mg·mL−1 in 1000-fold dilute aqueous ammonia (0.1% ammonia water) and increases to 11.9 ± 1.7 mg·mL⁻1 in 1% ammonia water, demonstrating a strong correlation of IND solubility with ammonia concentration. The IND concentration increases to 2.93 ± 0.04 mg·mL−1 in boiling 0.1% ammonia water.

3.1.2. High-Temperature Aqueous Solution Spray Drying

The raw IND used in this work is the most stable γ phase crystals confirmed by the PXRD pattern (Figure 2a). The referenced amorphous IND was prepared by melt-quenching method, because we did not obtain amorphous IND powder via aqueous solution spray drying. The apparent solubility of IND at 100 °C is 129 ± 21 μg·mL⁻1, which is enough to obtain products in the laboratory via high-temperature aqueous solution spray drying. The feed ratio of IND was carried as 50%, 25% and 10%, and IND ASDs with PVP can be obtained in all these conditions (Figure S2). While the IND feeding ratio is 50%, the experimental reproducibility is poor, and the yield of products is low. While the feeding ratio is 10%, the IND content in the final product is relatively low. Thus, to balance the relatively high IND content and yield, the feeding ratio of IND was chosen as 25% for the standard product (IND-PVP-HT). The PXRD pattern of IND-PVP-HT does not show obvious shark diffraction peaks, indicating the amorphous feature. For the selected six proteins (BLG, LAC, BSA, whey protein, soy protein isolate, and corn protein), BLG, LAC, and BSA have good aqueous solubility (exceeding 1 mg·mL−1), while the solubility of whey protein, soy protein isolate, and corn protein is below 10 μg·mL−1. However, all these proteins are insoluble in water at 100 °C, as reported [47]. High-temperature aqueous solution spray drying is not suitable for preparing the ASDs of IND with proteins.

3.1.3. Ammonia-Assisted Aqueous Solution Spray Drying

High-temperature aqueous solution spray drying needs a large mass of aqueous solutions due to the low IND concentration of approximately 0.01 wt.%, which is disadvantageous in industry production. Aqueous solution of IND with high concertation is still required. The increasing ammonia concentration and temperature accelerates the oxidation or degradation of IND [48]. Thus, the condition of 0.1% ammonia water and room temperature were proposed for ammonia-assisted aqueous solution spraying drying preparation of IND ASDs. This ammonia concentration is enough to obtain an apparent IND solubility of 1 mg·mL⁻1 and avoid the degradation of the -CONH- group of IND, and the operation at room temperature can also reduce the oxidation and degradation of IND. Ammonia-assisted aqueous solution spray drying succeeds in preparing the ASDs of IND with various polymers, including synthetic polymers as PVP (IND-PVP-NH3) and proteins as BLG, LAC, and BSA (IND-BLG, IND-LAC, and IND-BSA), confirmed by the PXRD patterns (Figure 2b and Figure S3). The existence of ammonia does not make BLG, LAC, and BSA insoluble.

3.2. Drug Loadings and Morphology of IND ASDs

With the IND feeding ratio of 25%, the experimental IND loading (test details are given in 2.2 Methods part: Drug Loadings Determination) in IND-PVP-HT is only 13%, which is far away from the IND feeding ratio, while those in IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA are 22%, 22%, 21%, and 22%, respectively, which are close to the IND feeding ratio (Figure 3). The temperature of the collector in our spray drying apparatus exceeds the glass transition temperature of amorphous IND (~45 °C) [49,50], which might cause IND molecules to escape with the hot airflow and make the IND loadings of the product less than the IND feeding ratio. The gasification of IND in an ammonia-assisted aqueous solution spray drying process is not obvious, and that in high temperature aqueous solution spray drying is unacceptable.
The morphology of raw IND is irregular microcrystals (Figure 4a). All the aqueous solution spray drying products have the morphology of micrometer-sized spherical particles, which is the characteristic morphology associated with the spray drying method [40]. The size of the particles is mostly in the range of 1 to 3 μm. IND-PVP-HT adheres to smooth microspheres (Figure 4b), and IND-PVP-NH3 is dispersed in rough microspheres, whose morphology is similar to golf balls (Figure 4c). The morphology of IND-BLG (Figure 4d) is dispersed crumpled rough microspheres. IND-LAC (Figure 4e) is composed of dispersed rough and smooth microspheres. The morphology of IND-BSA (Figure 4f) is similar to IND-BLG, crumpled rough microspheres. The rough surfaces of the product obtained by the ammonia-assisted aqueous solution spray drying method can increase the specific surface area, which is beneficial for dissolution performances. Considering the IND loading and morphology of the products, the ammonia-assisted method is better than high temperature aqueous solution spray drying method.

3.3. Spectroscopy Analysis of IND ASDs

Vibrational spectroscopy analysis is used here to confirm the formations of IND ASDs and the existence form of IND molecules. Raman spectroscopy is a powerful tool to determine the molecular structure, molecular conformation, intermolecular interaction, and molecular packing pattern, all of which are strongly related to the short-range orders of organic molecules. Low-frequency Raman spectra (LFRS, ≤300 cm−1) can be used to distinguish different polymorphs of organic molecules [51,52,53,54], as Raman peaks below 300 cm−1 are phonon modes contributed to the unit cell motions (lattice vibrational frequencies) [55]. Mid-frequency Raman spectra (MFRS, in the range of 300–1800 cm−1) provide access to the molecular vibrations that are sensitive to the local functional group environment. The LFRS (in the range of 50–300 cm−1) of the products obtained via the ammonia-assisted method has no obvious Raman bands (Figure S4), indicating that the products obtained via the ammonia-assisted method are ASDs [41]. After carefully comparing the products’ MFRS (Figure S5, Table S1), Raman bands at 1695 cm−1 of γ phase, 1678 cm−1 of amorphous IND, and 1667 cm−1 of IND ammonia solution (IND anion) are chosen as characteristic bands, which corresponds to υ(C=O) [56,57], for further comparison (Figure 5a). The Raman activities of polymers are not high and do not interface with the Raman signals of IND. The characteristic band at 1674 cm−1 of IND-PVP-NH3, 1677 cm−1 of IND-BLG, and 1682 cm−1 of IND-BSA (Figure 5b) are close to that band at 1678 cm−1 of amorphous IND, indicating that IND-PVP-NH3, IND-BLG, and IND-BSA are ASDs mainly composed of neutral IND molecules. The IR spectra of γ phase, amorphous IND, and ammonia solution are very different (Figure S5, Table S2), which is beneficial for comparison. For example, the IR peaks corresponding to δ(CH) [56,57] at 1306 cm−1 of γ phase, 1313 cm−1 of amorphous IND and 1327 cm−1 of IND ammonia solution and the IR peaks corresponding to δ(CH) at 1187 cm−1 of γ phase, 1175 cm−1 of amorphous IND and 1184 cm−1 of IND ammonia solution can be used to compare (Figure 5c). The IR peak of PVP at 1317 cm−1 interferes with the signal of IND (Figure S6), which is not suitable for being used in comparison. The peak at 1174 cm−1 of IND-PVP-NH3, 1170 cm−1 of IND-BLG, 1171 cm⁻1 of IND-LAC, and 1171 cm−1 of IND-BSA are close to the peak at 1175 cm−1 of amorphous IND, and the peak at 1312 cm−1 of IND-BLG, 1312 cm−1 of IND-LAC and 1312 cm−1 of IND-BSA are close to the peak at 1313 cm−1 of amorphous IND (Figure 5d), indicating that IND-PVP-NH3, IND-BLG, IND-LAC and IND-BSA are ASDs mainly composed of neutral IND molecules. Both Raman and IR spectra only observed the existence of IND molecules; however, we cannot exclude the existence of a small amount of IND salt using current methods. Thus, we can conclude from the Raman and IR spectra that the ASDs prepared via ammonia-assisted aqueous solution spray drying are mainly composed of neutral IND molecules.

3.4. Dissolution Profiles of IND ASDs

The dissolution concentration of raw IND (γ phase) is very low and only 4 μg·mL−1 after 24 h in pure water at 37 °C (Figure 6a). Then, the concentration of γ phase remains at 4–5 μg·mL−1, demonstrating that IND aqueous solutions are stable in the dark environment and γ phase is the stable phase with a poorly soluble characteristic. The dissolution profile of IND-PVP-NH3 in pure water shows that the IND concentration quickly increases to 12 μg·mL−1 within 8 h at the initial stage and up to 17 μg·mL−1 at 24 h and then slowly increases to 27 μg·mL−1 at 96 h. The supersaturated condition of IND-PVP-NH3 can be maintained for a long period, and the final concentration is six times that of γ phase. IND-BLG dissolution profile in pure water shows an IND concentration of 15 μg·mL−1 at 8 h, and the IND concentration rises to 23 μg·mL−1 at 24 h and becomes stable as 30 μg·mL⁻¹ at 48 h and 33 μg·mL⁻1 at 96 h (Figure 6a). The dissolution performance of IND-BLG is slightly better than that of IND-PVP-NH3. IND-LAC shows a dissolution profile in pure water with an IND concentration of 36 μg·mL⁻1 at 4 h and 45 μg·mL−1 at 8 h and maintains 71 μg·mL⁻1 after 24 h. IND-BSA dissolution profile in pure water demonstrates a rapid initial dissolution rate, with an IND concentration of 40 μg·mL−1 at 1 h, and the IND concentration rises to 45 μg·mL−1 at 8 h and 50 μg·mL−1 at 24 h, and gradually increases to 56 μg·mL−1 at 96 h. IND-LAC and IND-BSA exhibit significantly superior dissolution performances compared to other ASDs prepared in this work.
We have also carried out the dissolution experiment in pH 1.2 HCl aqueous solution of the IND samples for studying their dissolution behaviour in media mimicking the GI tract. The dissolution profiles of γ phase, IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA in pH 1.2 HCl aqueous solution at 37 °C are shown in Figure 6b. The dissolution of γ phase in pH 1.2 HCl aqueous solution is inferior to that in pure water, with the dissolution concentration of 0.3 μg·mL−1 at 24 h and 0.9 μg·mL−1 at 96 h, which is only 1/5 of that in pure water. The dissolution of IND-PVP-NH3 is better than that of γ phase, with dissolution concentration gradually increasing and basically stabilizing at 4 μg·mL−1 after 24 h. The dissolution profiles of IND-BLG, IND-LAC, and IND-BSA are similar, showing an obvious parachute effect. For example, the dissolution concentration of IND-BLG quickly reaches 12 μg·mL−1, about 1/3 of the final dissolution concentration in pure water, but soon the sample recrystallization occurs, and the dissolution concentration decreases rapidly and basically stabilizes at 6 μg·mL−1 after 24 h.
Overall, in the media mimicking the GI tract, the dissolution properties of all the IND samples decrease. Compared with the γ phase, IND ASDs still show better dissolution profiles, and IND-BLG prepared using proteins as polymer carriers show a higher final dissolution concentration. However, IND-BLG, IND-LAC, and IND-BSA all face the parachute effect. The current preparations are not suitable for use in the media mimicking the GI tract.

3.5. Storage Stability of IND ASDs

IND ASDs samples are very stable, and the PXRD patterns indicate that they are still totally amorphous after long storage (Figure 7a). The SEM images show that their morphology has changed very little after storage (Figure 7b–e). The changes in their dissolution profiles are also small. For example, the dissolution profile of IND-PVP-NH3 after one year of storage is very similar to that of the fresh sample. The IND concentration is 12 μg·mL−1 at 8 h, 20 μg·mL−1 at 24 h, and 26 μg·mL−1 at 96 h (Figure 7f).

3.6. Method Verification by Additional APIs

Sulfamerazine (SMR) is one widely used antibacterial drug to treat susceptible microbial infections belonging to BCS class II [58,59]. Raw SMR is metastable Form I, which is the most stable phase at high temperatures [60], confirmed by the PXRD pattern (Figure 8a). SMR is a weakly acidic molecule and exhibits a solubility exceeding 1 mg·mL−1 in 0.1% ammonia solution, making it suitable for ammonia-assisted aqueous solution spray drying. SMR-PVP and SMR-BLG are confirmed as ASDs from their PXRD patterns, and the contents of SMR are 22% and 23%, respectively, similar to the feeding ratios of SMR. SMR-LAC and SMR-BSA are poorly crystalline products with weak 2θ peaks corresponding to SMR Form I (Figure S7). The dissolution profile of raw SMR shows a gradual increase in concentration, 0.08 mg·mL−1 at 1 h, 0.20 mg·mL−1 at 4 h, and 0.29 mg·mL−1 at 24 h (Figure 8b). SMR-PVP has a significant solubility enhancement, the concentration reaching 0.37 mg·mL−1 within 1 h and increasing to 0.46 mg·mL−1 at 4 h and 0.68 mg·mL−1 at 24 h. The dissolution profile of SMR-BLG shows a modest solubility enhancement with a concentration of 0.23 mg·mL−1 at 1 h, 0.28 mg·mL−1 at 4 h, and 0.36 mg·mL−1 at 24 h. The dissolution performance of SMR-BLG is not significant, which might be caused by the limited ability of proteins to inhibit the crystallization of amorphous SMR, as LAC and BSA failed to prepare ASDs.
Celecoxib (CEL) is a COX-2 inhibitor used for the treatment of inflammation and pain, belonging to BCS class II [61]. The PXRD pattern of raw CEL corresponds to the most stable Form III (Figure 9a), which is the most usual crystalline form. As a neutral molecule, CEL is insoluble in acidic or alkaline conditions. High-temperature aqueous solution spray drying was used to prepare the ASDs of CEL with PVP. The feeding ratio of CEL is 10% because of the insufficient solubility of CEL in the boiling solution. CEL-PVP is ASDs, confirmed by the PXRD pattern, and the content of CEL is 5.3% faced the risk of gasification of CEL molecules. The dissolution profile of raw CEL at 37 °C shows concentrations of 1.9 ug·mL−1 at 8 h, 2.2 ug·mL−1 at 24 h, and 3.5 ug·mL−1 at 48 h (Figure 9b). CEL-PVP exhibits a significant dissolution improvement, with concentrations of 14 ug·mL−1 at 8 h and 17 ug·mL−1 at both 24 and 48 h. The current aqueous solution spray drying technology is still inadequate for CEL, although the ASDs products can be obtained in the laboratory.

4. Discussion

4.1. Feasibility of Aqueous Solution Spray Drying for ASDs Preparation

The challenge of aqueous solution spray drying of poorly water-soluble drugs is to improve the solubility. We suggest that if the solubility of the poorly water-soluble drug is improved to approximately 0.01% (0.1 mg·mL−1), aqueous solution spray drying can produce the ASDs of the drug in the laboratory; if the solubility increased to around 0.1% (1 mg·mL−1), it is feasible to prepare the ASDs of the drug by aqueous solution spray drying in laboratory, and the preparation process can be considered viable for industrial applications; if the solubility is above 1% (10 mg·mL−1), aqueous solution spray drying will be very suitable for industrial produce.
To increase the solubility of poorly water-soluble drugs, two strategies, including high-temperature and additives are used in our laboratory. In the case of IND, the ammonia-assisted method is better than the high-temperature method. Raman and IR spectra indicate that there are no IND ammonium salts observed. The prepared products are ASDs mainly composed of neutral IND molecules. The polymers are feasible and can be synthetic polymers such as PVP, celluloses such as hydroxypropyl methylcellulose acetate succinate (Figure S8), and proteins such as BLG, LAC, and BSA. Although protein denaturation still happened in the alkaline aqueous solution, the protein denaturation in aqueous solution is still safer than that in organic solvent. The ASDs of IND with proteins show better dissolution profiles than the ASDs of IND with PVP or hydroxypropyl methylcellulose acetate succinate. The development of an aqueous solution spray drying method is beneficial to develop advanced polymeric carriers as proteins for ASDs preparation.
The method is easy to extend for the ASDs preparation of other poorly water-soluble drugs, such as SMR and CEL. One limitation of this method is that the APIs should be stable for a short period of time in a weak alkaline or hot aqueous solution.

4.2. Disadvantages and Prospect of Aqueous Solution Spray Drying

At the current stage, we failed to combine high-temperature and ammonia addition solubilization strategies in the case of IND ASDs preparation because of the instability of IND in a hot alkaline solution, and we failed to prepare the CEL ASDs with a high drug ratio because of the limited aqueous solubility of CEL in high-temperature, we failed to avoid the escape of drug molecules during the spray drying process. The addition of ammonia or other volatile ingredients still faces the pressures of environmental protection, although this is better than adding organic solvents in safety. There are still many challenges in developing the aqueous solution spray drying method. The biggest challenge of aqueous solution spray drying is still to improve the solubility of poorly water-soluble drugs without changing the molecular structure. Hydrothermal conditions [62] can increase the solubility of the poorly water-soluble drugs. The combination with hydrothermal conditions can further make the aqueous solution spray drying method suitable for the preparations of APIs ASDs. Aqueous solution spray drying is a crude method in the current experiments, and this approach offers a unique opportunity to prepare advanced ASDs without the use of organic solvents.

5. Conclusions

Aqueous solution spray drying succeeds in preparing the ASDs of IND with PVP and proteins such as BLG, LAC, and BSA, which are mainly composed of neutral IND molecules. These ASDs show high yields, special morphology of robust microspheres, precise compositions, longtime stabilities, and improved dissolution profiles. The ASDs with proteins, especially LAC and BSA, have excellent dissolution performances, indicating that proteins can possibly be used as advanced carriers for drug ASDs. The disadvantages of proteins as carriers for APIs ASDs include the possibility of protein denaturation and spoilage during the ASDs preparation and storage process, limited protein categories for various drugs, and high costs. Aqueous solution spray drying may help avoid these disadvantages and promote further development of ASDs preparation with protein as carriers. The aqueous solution spray drying method is feasible and easily used for preparing the ASDs of other poorly water-soluble drugs such as SMR and CEL. Avoiding the use of organic solvents and using proteins as carriers in the aqueous solution spray drying method is of significance for the development of advanced and green ASDs preparations in laboratories and industries.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cryst15040323/s1, Figure S1: UV-vis spectra and calibration curves of IND 50 vol% ethanol, 10 vol% ethanol and 0.1% ammonia solutions; Figure S2: PXRD patterns of the high-temperature aqueous solution spray drying products of IND with PVP (IND feeding ratio: 50% and 10%); Figure S3: PXRD patterns of the ammonia-assisted aqueous solution spray drying products of IND with PVP (IND feeding ratio: 50% and 10%); Figure S4: Low-frequency Raman spectra of raw IND, amorphous IND, IND-PVP-NH3, IND-BLG, IND-BSA; Figure S5: Mid-frequency Raman spectra and IR spectra of raw IND, amorphous IND, IND ammonia solution, IND-PVP-NH3, IND-BLG, IND-BSA; Figure S6: IR spectra of PVP, BLG, LAC, and BSA in the range of 400–1800 cm−1 and 1100–1400 cm−1; Figure S7: PXRD patterns of SMR-LAC and SMR-BSA; Figure S8: PXRD pattern and dissolution profile of IND-hydroxypropyl methylcellulose acetate succinate; Table S1: Characteristic mid-frequency Raman spectra bands of IND samples; Table S2: Characteristic IR bands (in the range of 400–1800 cm−1) of IND samples. References [51,52] are cited in the Supplementary Materials.

Author Contributions

Conceptualization, methodology, F.C., R.X. and K.L.; investigation, data curation, W.Z. and J.K.; project administration, validation, W.Z.; resources, supervision, F.C., and R.X.; funding acquisition, visualization, writing—original draft preparation, F.C.; writing—review and editing, R.X. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (grant number 22005175) and the Natural Science Foundation of Fujian Province (grant number 2021J011116).

Data Availability Statement

The original contributions presented in the study are included in the article and Supplementary Materials; further inquiries can be directed to the corresponding authors.

Conflicts of Interest

Author Kaerdun Liu was employed by Innovation Development Divison, China Resources Double-crane Pharmaceutical Co., Ltd, Beijing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations

INDIndomethacin
SMRSulfamerazine
CELCelecoxib
PVPPolyvinylpyrrolidone
BLGβ-Lactoglobulin
LACLactalbumin Hydrolysate
BSABovine Serum Albumin
ASDsAmorphous Solid Dispersions
IND-polymerASDs of IND (25 %) and polymer
PXRDPowder X-Ray Diffraction
SEMScanning Electron Microscope

References

  1. Bhujbal, S.V.; Mitra, B.; Jain, U.; Gong, Y.; Agrawal, A.; Karki, S.; Taylor, L.S.; Kumar, S.; Zhou, Q. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. Acta Pharm. Sin. B 2021, 11, 2505–2536. [Google Scholar] [CrossRef] [PubMed]
  2. Pisay, M.; Padya, S.; Mutalik, S.; Koteshwara, K.B. Stability challenges of amorphous solid dispersions of drugs: A critical review on mechanistic aspects. Crit. Rev. Ther. Drug Carrier Syst. 2024, 41, 45–94. [Google Scholar] [CrossRef] [PubMed]
  3. Moseson, D.E.; Tran, T.B.; Karunakaran, B.; Ambardekar, R.; Hiew, T.N. Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023. Int. J. Pharm. X 2024, 7, 100259. [Google Scholar] [CrossRef] [PubMed]
  4. Chen, W.; Yan, A.; Sun, T.; Wang, X.; Sun, W.; Pan, B. Self-nanomicellizing solid dispersion: A promising platform for oral drug delivery. Colloids Surf. B 2024, 241, 114057. [Google Scholar] [CrossRef] [PubMed]
  5. Singh, A.; Van den Mooter, G. Spray drying formulation of amorphous solid dispersions. Adv. Drug Deliv. Rev. 2016, 100, 27–50. [Google Scholar] [CrossRef]
  6. Patil, H.; Vemula, S.K.; Narala, S.; Lakkala, P.; Munnangi, S.R.; Narala, N.; Jara, M.O.; Williams, R.O.; Terefe, H.; Repka, M.A. Hot-melt extrusion: From theory to application in pharmaceutical formulation where are we now? AAPS PharmSciTech 2024, 25, 37. [Google Scholar] [CrossRef]
  7. Ramachandran, R.P.; Nadimi, M.; Cenkowski, S.; Paliwal, J. Advancement and Innovations in Drying of Biopharmaceuticals, Nutraceuticals, and Functional Foods. Food Eng. Rev. 2024, 16, 540–566. [Google Scholar] [CrossRef]
  8. Dedroog, S.; Adriaensens, P.; Van den Mooter, G. Gaining Insight into the Role of the Solvent during Spray Drying of Amorphous Solid Dispersions by Studying Evaporation Kinetics. Mol. Pharm. 2022, 19, 1604–1618. [Google Scholar] [CrossRef]
  9. Li, N.; Cape, J.L.; Mankani, B.R.; Zemlyanov, D.Y.; Shepard, K.B.; Morgen, M.M.; Taylor, L.S. Water-induced phase separation of spray-dried amorphous solid dispersions. Mol. Pharm. 2020, 17, 4004–4017. [Google Scholar] [CrossRef]
  10. Shepard, K.B.; Dower, A.M.; Ekdahl, A.M.; Morgen, M.M.; Baumann, J.M.; Vodak, D.T. Solvent-assisted secondary drying of spray-dried polymers. Pharm. Res. 2020, 37, 156. [Google Scholar] [CrossRef]
  11. Luebbert, C.; Real, D.; Sadowski, G. Choosing Appropriate Solvents for ASD Preparation. Mol. Pharm. 2018, 15, 5397–5409. [Google Scholar] [CrossRef] [PubMed]
  12. Zhuo, X.; Foderà, V.; Larsson, P.; Schaal, Z.; Bergström, C.A.S.; Löbmann, K.; Kabedev, A. Analysis of stabilization mechanisms in β-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches. Eur. J. Pharm. Sci. 2024, 192, 106639. [Google Scholar] [CrossRef] [PubMed]
  13. Zhuo, X.; Tozzetti, M.; Arnous, A.; Leng, D.; Foderà, V.; Löbmann, K. Investigating the influence of protein secondary structure on the dissolution behavior of β-lactoglobulin-based amorphous solid dispersions. Int. J. Pharm. 2024, 653, 123887. [Google Scholar] [CrossRef] [PubMed]
  14. Zhuo, X.; Jasiukenaite, I.; Löbmann, K. β-Lactoglobulin-based amorphous solid dispersions: A graphical review on the state-of-the-art. Eur. J. Pharm. Biopharm. 2024, 202, 114396. [Google Scholar] [CrossRef]
  15. Ren, S.; Nian, F.; Chen, X.; Xue, R.; Chen, F. Routes of theophylline monohydrate dehydration process proposed by mid-frequency raman difference spectra. J. Pharm. Sci. 2023, 112, 2863–2868. [Google Scholar] [CrossRef]
  16. Mazák, K.; Noszál, B. Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters. J. Pharm. Biomed. Anal. 2016, 130, 390–403. [Google Scholar] [CrossRef]
  17. Avdeef, A.; Sugano, K. Salt Solubility and Disproportionation—Uses and Limitations of Equations for pHmax and the In-silico Prediction of pHmax. J. Pharm. Sci. 2022, 111, 225–246. [Google Scholar] [CrossRef]
  18. Yan, H.; Zhong, X.; Liu, Y. Improving the Solubility, Stability, and Bioavailability of Albendazole through Synthetic Salts. Molecules 2024, 29, 3571. [Google Scholar] [CrossRef]
  19. Di Martino, P.; Scoppa, M.; Joiris, E.; Palmieri, G.F.; Andres, C.; Pourcelot, Y.; Martelli, S. The spray drying of acetazolamide as method to modify crystal properties and to improve compression behaviour. Int. J. Pharm. 2001, 213, 209–221. [Google Scholar] [CrossRef]
  20. Lu, H. Fabrication and characterization of porous silver powder prepared by spray drying and calcining technology. Powder Technol. 2010, 203, 176–179. [Google Scholar] [CrossRef]
  21. Long, B.; Walker, G.M.; Ryan, K.M.; Padrela, L. Controlling polymorphism of carbamazepine nanoparticles in a continuous supercritical-CO2-assisted spray drying process. Cryst. Growth Des. 2019, 19, 3755–3767. [Google Scholar] [CrossRef]
  22. Nuchuchua, O.; Every, H.A.; Jiskoot, W. Critical processing parameters of carbon dioxide spray drying for the production of dried protein formulations: A study with myoglobin. Eur. J. Pharm. Biopharm. 2016, 103, 200–209. [Google Scholar] [CrossRef]
  23. Zhuo, X.; Ochner, J.; Leng, D.; Foderà, V.; Löbmann, K. Exploring the effect of protein secondary structure on the solid state and physical stability of protein-based amorphous solid dispersions. Eur. J. Pharm. Biopharm. 2024, 198, 114274. [Google Scholar] [CrossRef]
  24. Hou, A.; Li, L.; Huang, Y.; Singh, V.; Zhu, C.; Pan, X.; Quan, G.; Wu, C. Fragmented particles containing octreotide acetate prepared by spray drying technique for dry powder inhalation. Drug Delivery Transl. Res. 2018, 8, 693–701. [Google Scholar] [CrossRef]
  25. Zhang, X.; Yue, X.; Cui, Y.; Zhao, Z.; Huang, Y.; Cai, S.; Wang, G.; Wang, W.; Hugh, S.; Pan, X.; et al. A systematic safety evaluation of nanoporous mannitol material as a dry-powder inhalation carrier system. J. Pharm. Sci. 2020, 109, 1692–1702. [Google Scholar] [CrossRef]
  26. Anita, C.; Munira, M.; Mural, Q.; Shaily, L. Topical nanocarriers for management of Rheumatoid Arthritis: A review. Biomed. Pharmacother. 2021, 141, 111880. [Google Scholar] [CrossRef]
  27. Gogic, A.; Vesovic, M.; Nedeljkovic, N.; Nikolic, M.; Jurisevic, M.; Zdravkovic, N.; Zivanovic, A. Indomethacin Derivatives as Potential Anticancer Agents-Daybreak of New Epoch. ChemistrySelect 2024, 9, e202402050. [Google Scholar] [CrossRef]
  28. Leung, H.W.; Copley, R.C.B.; Lampronti, G.I.; Day, S.J.; Saunders, L.K.; Johnstone, D.N.; Midgley, P.A. From formulation to structure: 3D electron diffraction for the structure solution of a new indomethacin polymorph from an amorphous solid dispersion. IUCrJ 2024, 11, 744–748. [Google Scholar] [CrossRef]
  29. Keßler, L.; Mishra, R.; Hietala, S.; Lammens, M.; Peltonen, L.; Rades, T.; van Veen, B.; Juppo, A.; Laaksonen, T.; Strachan, C.; et al. Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion. Eur. J. Pharm. Sci. 2025, 204, 106960. [Google Scholar] [CrossRef]
  30. Autzen Virtanen, A.; Myślińska, M.; Healy, A.M.; Power, E.; Madi, A.; Sivén, M. The challenge of downstream processing of spray dried amorphous solid dispersions into minitablets designed for the paediatric population—A sustainable product development approach. Eur. J. Pharm. Sci. 2024, 196, 106752. [Google Scholar] [CrossRef]
  31. Zhuo, X.; Sener, Z.; Kabedev, A.; Zhao, M.; Arnous, A.; Leng, D.; Foderà, V.; Löbmann, K. Mechanisms of drug solubility enhancement induced by β-lactoglobulin-based amorphous solid dispersions. Mol. Pharm. 2023, 20, 5206–5213. [Google Scholar] [CrossRef] [PubMed]
  32. Wu, J.; Mooter, G.V.D. The influence of hydrogen bonding between different crystallization tendency drugs and PVPVA on the stability of amorphous solid dispersions. Int. J. Pharm. 2023, 646, 123440. [Google Scholar] [CrossRef] [PubMed]
  33. Hermeling, M.; Nueboldt, C.; Heumann, R.; Hoheisel, W.; Breitkreutz, J. Nano-Dry-Melting: A novel technology for manufacturing of pharmaceutical amorphous solid dispersions. Pharmaceutics 2022, 14, 2145. [Google Scholar] [CrossRef]
  34. Kabedev, A.; Zhuo, X.; Leng, D.; Fodera, V.; Zhao, M.; Larsson, P.; Bergstrom, C.A.S.; Lobmann, K. Stabilizing mechanisms of beta-lactoglobulin in amorphous solid dispersions of indomethacin. Mol. Pharm. 2022, 19, 3922–3933. [Google Scholar] [CrossRef]
  35. Dedroog, S.; Boel, E.; Kindts, C.; Appeltans, B.; Van den Mooter, G. The underestimated contribution of the solvent to the phase behavior of highly drug loaded amorphous solid dispersions. Int. J. Pharm. 2021, 609, 121201. [Google Scholar] [CrossRef]
  36. Holzapfel, K.; Rades, T.; Leopold, C.S. Co-amorphous systems consisting of indomethacin and the chiral co-former tryptophan: Solid-state properties and molecular mobilities. Int. J. Pharm. 2023, 636, 122840. [Google Scholar] [CrossRef]
  37. Rathod, V.; Gajera, B.; Pinninti, A.; Mohammed, I.A.; Dave, R.H. Strategizing spray drying process optimization for the manufacture of redispersible indomethacin nanoparticles using quality-by-design principles. AAPS PharmSciTech 2023, 24, 133. [Google Scholar] [CrossRef]
  38. Méndez Cañellas, F.; Geertman, R.; Tajber, L.; Padrela, L. Sorbitol-coated indomethacin and naproxen particles produced by supercritical CO2-assisted spray drying. J. Supercrit. Fluids 2023, 199, 105969. [Google Scholar] [CrossRef]
  39. Li, J.; Zordan, C.; Ponce, S.; Lu, X. Impact of swelling of spray dried dispersions in dissolution media on their dissolution: An investigation based on UV imaging. J. Pharm. Sci. 2022, 111, 1761–1769. [Google Scholar] [CrossRef]
  40. Nguyen, T.T.; Saipul Bahri, N.S.N.; Rahmatika, A.M.; Cao, K.L.A.; Hirano, T.; Ogi, T. Rapid indomethacin release from porous pectin particles as a colon-targeted drug delivery system. ACS Appl. Bio Mater. 2023, 6, 2725–2737. [Google Scholar] [CrossRef]
  41. Larkin, P.J.; Wasylyk, J.; Raglione, M. Application of low- and mid-frequency Raman spectroscopy to characterize the amorphous-crystalline transformation of indomethacin. Appl. Spectrosc. 2015, 69, 1217–1228. [Google Scholar] [CrossRef] [PubMed]
  42. Shen, P.; Zhang, C.; Hu, E.; Pang, Z.; Gao, Y.; Qian, S.; Zhang, J.; Wei, Y.; Heng, W. Gelation switch of polyamorphic indomethacin depending on the thermal procedure. Eur. J. Pharm. Biopharm. 2022, 177, 249–259. [Google Scholar] [CrossRef] [PubMed]
  43. Dunn, C.; Perrier, J.; Khadra, I.; Wilson, C.G.; Halbert, G.W. Topography of simulated intestinal equilibrium solubility. Mol. Pharm. 2019, 16, 1890–1905. [Google Scholar] [CrossRef] [PubMed]
  44. Shakeel, F.; Alanazi, F.K.; Alsarra, I.A.; Haq, N. Solubility prediction of indomethacin in PEG 400+water mixtures at various temperatures. J. Mol. Liq. 2013, 188, 28–32. [Google Scholar] [CrossRef]
  45. Alsalhi, M.S.; Chan, K.L.A. Amino acid hydrotropes to increase the solubility of indomethacin and carbamazepine in aqueous solution. Int. J. Pharm. 2022, 617, 121591. [Google Scholar] [CrossRef]
  46. Bolten, D.; Lietzow, R.; Türk, M. Solubility of ibuprofen, phytosterol, salicylic acid, and naproxen in aqueous solutions. Chem. Eng. Technol. 2013, 36, 426–434. [Google Scholar] [CrossRef]
  47. Xin, X.; Xu, Y.; Shi, H.; Liu, X. General method to stabilize mesophilic proteins in hyperthermal water. iScience 2021, 24, 102503. [Google Scholar] [CrossRef]
  48. Jiménez-Rodríguez, A.; Heredia-Olea, E.; Barba-Dávila, B.A.; Gutiérrez-Uribe, J.A.; Antunes-Ricardo, M. Polysaccharides from Agave salmiana bagasse improves the storage stability and the cellular uptake of indomethacin nanoemulsions. Food Bioprod. Process. 2021, 127, 114–127. [Google Scholar] [CrossRef]
  49. Li, Y.; Yu, J.; Tan, X.; Yu, L. Surface Mobility of Amorphous Indomethacin Containing Moisture and a Surfactant: A Concentration–Temperature Superposition Principle. Mol. Pharm. 2022, 19, 2962–2970. [Google Scholar] [CrossRef]
  50. Thayumanasundaram, S.; Venkatesan, T.R.; Ousset, A.; Van Hollebeke, K.; Aerts, L.; Wübbenhorst, M.; Van den Mooter, G. Complementarity of mDSC, DMA, and DRS Techniques in the Study of Tg and Sub-Tg Transitions in Amorphous Solids: PVPVA, Indomethacin, and Amorphous Solid Dispersions Based on Indomethacin/PVPVA. Mol. Pharm. 2022, 19, 2299–2315. [Google Scholar] [CrossRef]
  51. Bērziņš, K.; Fraser-Miller, S.J.; Rades, T.; Gordon, K.C. Low-frequency Raman spectroscopic study on compression-induced destabilization in melt-quenched amorphous celecoxib. Mol. Pharm. 2019, 16, 3678–3686. [Google Scholar] [CrossRef]
  52. Bērziņš, K.r.; Sutton, J.J.; Fraser-Miller, S.J.; Rades, T.; Korter, T.M.; Gordon, K.C. Solving the computational puzzle: Toward a pragmatic pathway for modeling low-energy vibrational modes of pharmaceutical crystals. Cryst. Growth Des. 2020, 20, 6947–6955. [Google Scholar] [CrossRef]
  53. Bērziņš, K.r.; Fraser-Miller, S.J.; Gordon, K.C. A new frontier for nondestructive spatial analysis of pharmaceutical solid dosage forms: Spatially offset low-frequency raman spectroscopy. Anal. Chem. 2021, 93, 3698–3705. [Google Scholar] [CrossRef]
  54. Bērziņš, K.r.; Fraser-Miller, S.J.; Gordon, K.C. Pseudo-3D subsurface imaging of pharmaceutical solid dosage forms using micro-spatially offset low-frequency Raman spectroscopy. Anal. Chem. 2021, 93, 8986–8993. [Google Scholar] [CrossRef]
  55. Jantschke, A.; Pinkas, I.; Hirsch, A.; Elad, N.; Schertel, A.; Addadi, L.; Weiner, S. Anhydrous β-guanine crystals in a marine dinoflagellate: Structure and suggested function. J. Struct. Biol. 2019, 207, 12–20. [Google Scholar] [CrossRef]
  56. Ali, H.R.H.; Alhalaweh, A.; Velaga, S.P. Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin. Drug Dev. Ind. Pharm. 2013, 39, 625–634. [Google Scholar] [CrossRef]
  57. Badawi, H.M.; Förner, W. Analysis of the molecular structure and vibrational spectra of the indole based analgesic drug indomethacin. Spectrochim. Acta Part A 2014, 123, 447–454. [Google Scholar] [CrossRef]
  58. Aitipamula, S.; Chow, P.S.; Tan, R.B.H. The solvates of sulfamerazine: Structural, thermochemical, and desolvation studies. CrystEngComm 2012, 14, 691–699. [Google Scholar] [CrossRef]
  59. Hossain, G.M.G. Sulfamerazine tetrahydrofuran monosolvate. IUCrData 2016, 1, x160596. [Google Scholar] [CrossRef]
  60. Zhang, G.G.Z.; Gu, C.; Zell, M.T.; Burkhardt, R.T.; Munson, E.J.; Grant, D.J.W. Crystallization and Transitions of Sulfamerazine Polymorphs. J. Pharm. Sci. 2002, 91, 1089–1100. [Google Scholar] [CrossRef]
  61. Hyun, S.-M.; Lee, B.J.; Abuzar, S.M.; Lee, S.; Joo, Y.; Hong, S.-H.; Kang, H.; Kwon, K.-A.; Velaga, S.; Hwang, S.-J. Preparation, characterization, and evaluation of celecoxib eutectic mixtures with adipic acid/saccharin for improvement of wettability and dissolution rate. Int. J. Pharm. 2019, 554, 61–71. [Google Scholar] [CrossRef]
  62. Feng, P.; Yang, W.; Xu, D.; Ma, M.; Guo, Y.; Jing, Z. Characteristics, mechanisms and measurement methods of dissolution and deposition of inorganic salts in sub-/supercritical water. Water Res. 2022, 225, 119167. [Google Scholar] [CrossRef]
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Figure 1. Indomethacin (IND) solubility. (a) Molecular structure of IND and IND anion, (b) UV-vis spectra of 20 μg·mL−1 IND 50 vol% ethanol, 10 vol% ethanol and 0.1% ammonia solutions, (c) the solubilities of raw IND in pure water and aqueous solution of 1 mg·mL−1 PVP at 26, 60, 90 and 100 °C (boiling state), (d) the solubilities of raw IND in diluted 1000 times and 100 times aqueous ammonia solutions.
Figure 1. Indomethacin (IND) solubility. (a) Molecular structure of IND and IND anion, (b) UV-vis spectra of 20 μg·mL−1 IND 50 vol% ethanol, 10 vol% ethanol and 0.1% ammonia solutions, (c) the solubilities of raw IND in pure water and aqueous solution of 1 mg·mL−1 PVP at 26, 60, 90 and 100 °C (boiling state), (d) the solubilities of raw IND in diluted 1000 times and 100 times aqueous ammonia solutions.
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Figure 2. Preparation of ASDs of IND via aqueous solution spray drying method. PXRD patterns of (a) raw IND, amorphous IND, and high-temperature aqueous solution spray drying products (IND-PVP-HT with the feeding ratio of 25% IND) and (b) ammonia solution spray drying products (IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA with the feeding ratio of 25% IND).
Figure 2. Preparation of ASDs of IND via aqueous solution spray drying method. PXRD patterns of (a) raw IND, amorphous IND, and high-temperature aqueous solution spray drying products (IND-PVP-HT with the feeding ratio of 25% IND) and (b) ammonia solution spray drying products (IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA with the feeding ratio of 25% IND).
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Figure 3. Experimental IND loadings (square) in ASDs prepared via aqueous solution spray drying. The red line is used to mark 25 wt.%, corresponding to the IND feed ratio.
Figure 3. Experimental IND loadings (square) in ASDs prepared via aqueous solution spray drying. The red line is used to mark 25 wt.%, corresponding to the IND feed ratio.
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Figure 4. SEM images of products via aqueous solution spray drying. (a) raw IND, (b) IND-PVP-HT, (c) IND-PVP-NH3, (d) IND-BLG, (e) IND-LAC, (f) IND-BSA.
Figure 4. SEM images of products via aqueous solution spray drying. (a) raw IND, (b) IND-PVP-HT, (c) IND-PVP-NH3, (d) IND-BLG, (e) IND-LAC, (f) IND-BSA.
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Figure 5. Vibrational spectroscopy analysis of ASDs via ammonia-assisted aqueous solution spray drying. Raman spectra of (a) raw IND (γ phase), amorphous IND, IND ammonia solution, (b) IND-PVP-NH3, IND-BLG, IND-BSA in the range of 1500–1800 cm−1, IR spectra of (c) γ phase, amorphous IND, IND ammonia solution, (d) IND-PVP-NH3, IND-BLG, IND-LAC, IND-BSA in the range of 1100–1400 cm−1. The IND aqueous ammonia solution was prepared by dissolving 100 mg of IND in 1 mL of ammonia solution diluted 10 times. Raman spectra of IND-LAC were not obtained due to the fluorescence interface.
Figure 5. Vibrational spectroscopy analysis of ASDs via ammonia-assisted aqueous solution spray drying. Raman spectra of (a) raw IND (γ phase), amorphous IND, IND ammonia solution, (b) IND-PVP-NH3, IND-BLG, IND-BSA in the range of 1500–1800 cm−1, IR spectra of (c) γ phase, amorphous IND, IND ammonia solution, (d) IND-PVP-NH3, IND-BLG, IND-LAC, IND-BSA in the range of 1100–1400 cm−1. The IND aqueous ammonia solution was prepared by dissolving 100 mg of IND in 1 mL of ammonia solution diluted 10 times. Raman spectra of IND-LAC were not obtained due to the fluorescence interface.
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Figure 6. Dissolution profiles at 37 °C in (a) pure water and (b) pH 1.2 HCl aqueous solution of γ phase, IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA.
Figure 6. Dissolution profiles at 37 °C in (a) pure water and (b) pH 1.2 HCl aqueous solution of γ phase, IND-PVP-NH3, IND-BLG, IND-LAC, and IND-BSA.
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Figure 7. Storage stability of IND ASDs. (a) PXRD patterns, (b–e) SEM images, and (f) dissolution profiles in pure water at 37 °C of IND ASDs after a long storage (b: IND-PVP-NH3, c: IND-BLG, d: IND-LAC, and e: IND-BSA).
Figure 7. Storage stability of IND ASDs. (a) PXRD patterns, (b–e) SEM images, and (f) dissolution profiles in pure water at 37 °C of IND ASDs after a long storage (b: IND-PVP-NH3, c: IND-BLG, d: IND-LAC, and e: IND-BSA).
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Figure 8. Preparation of the ASDs of sulfamerazine (SMR) via ammonia-assisted aqueous solution spray drying. (a) PXRD patterns and (b) dissolution profiles of raw SMR, SMR-PVP, and SMR-BLG with SMR feeding ratio of 25%.
Figure 8. Preparation of the ASDs of sulfamerazine (SMR) via ammonia-assisted aqueous solution spray drying. (a) PXRD patterns and (b) dissolution profiles of raw SMR, SMR-PVP, and SMR-BLG with SMR feeding ratio of 25%.
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Figure 9. Preparation of the ASDs of celecoxib (CEL) via high temperature aqueous solution spray drying. (a) PXRD patterns and (b) dissolution profiles of raw CEL and CEL-PVP with a CEL feeding ratio of 10%.
Figure 9. Preparation of the ASDs of celecoxib (CEL) via high temperature aqueous solution spray drying. (a) PXRD patterns and (b) dissolution profiles of raw CEL and CEL-PVP with a CEL feeding ratio of 10%.
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Table 1. Reported spray drying solutions of indomethacin (IND) in recent years.
Table 1. Reported spray drying solutions of indomethacin (IND) in recent years.
FormSolutionsRef.
ASDsA mixed solution of water, acetic acid, and ethanol with a v/v% ratio of 10%: 5%: 85%. Briefly, indomethacin (1.5 g) was dissolved in 425 mL ethanol, β-lactoglobulin (3.5 g) was dissolved in 50 mL water and 25 mL acetic acid.[31]
Drug and poly (vinylpyrrolidone-co-vinyl acetate) 64 were dissolved in dichloromethane with a 10% w/v solid concentration.[32]
Nano-Dry-Melting process. An aqueous drug slurry in a wet-stirred media mill was nano-milled and spray-dried.[33]
A mixed solution of acetic acid (5%) and ethanol (95%). Indomethacin was dissolved in 190 mL ethanol, and β-lactoglobulin was dissolved in 10 mL acetic acid with a total of 1 g solid.[34]
Indomethacin (2% w/v) and poly(vinylpyrrolidone-co-vinyl acetate) 64 were dissolved in one of seven solvents (methanol, ethanol, 2-propanol, acetone, dichloromethane, acetonitrile, ethyl acetate).[35]
co-amorphousIndomethacin and tryptophan were dissolved in a mixture of acetone and water (70:30 v/v) with a 1.0% or 0.5% w/v solid concentration.[36]
crystalsAqueous nanosuspension prepared using the wet media milling technique.[37]
partially crystallineSupercritical CO2-assisted spray drying. 400 mg indomethacin and 400 mg sorbitol were dissolved in 20 mL methanol.[38]
not mentioned10 g of indomethacin and polymers were dissolved in 300 mL acetone (hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate) or methanol (polyvinylpyrrolidone).[39]
loading0.1 wt.% indomethacin, 1.0 wt.% pectin and 0.5–12 wt.% CaCO3 aqueous dispersions.[40]
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Zheng, W.; Ke, J.; Liu, K.; Xue, R.; Chen, F. Aqueous Solution Spray Drying Preparations of Binary Amorphous Solid Dispersions. Crystals 2025, 15, 323. https://doi.org/10.3390/cryst15040323

AMA Style

Zheng W, Ke J, Liu K, Xue R, Chen F. Aqueous Solution Spray Drying Preparations of Binary Amorphous Solid Dispersions. Crystals. 2025; 15(4):323. https://doi.org/10.3390/cryst15040323

Chicago/Turabian Style

Zheng, Wenling, Junni Ke, Kaerdun Liu, Rongrong Xue, and Fenghua Chen. 2025. "Aqueous Solution Spray Drying Preparations of Binary Amorphous Solid Dispersions" Crystals 15, no. 4: 323. https://doi.org/10.3390/cryst15040323

APA Style

Zheng, W., Ke, J., Liu, K., Xue, R., & Chen, F. (2025). Aqueous Solution Spray Drying Preparations of Binary Amorphous Solid Dispersions. Crystals, 15(4), 323. https://doi.org/10.3390/cryst15040323

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