(M1530-07-46) Spray Drying of Poorly Water-Soluble Drugs Without any Organic Solvent Using the Acid-Base Supersolubilization (ABS) Principle

Purpose: Over two-thirds of drugs under development in the pharmaceutical industry are poorly soluble and fall into BCS Class II or IV. This poses significant drug formulation and delivery challenges, often requiring various solubilization strategies. Amorphous solid dispersions (ASDs) have emerged as one of the most effective approaches for enhancing the bioavailability of poorly water-soluble drugs. Currently marketed ASD products like Sporanox^® (itraconazole), Norvir^® (ritonavir), and Kaletra^® (lopinavir/ritonavir) demonstrate the clinical success of this technology. However, conventional spray drying techniques for preparing ASDs typically rely on large volumes of organic solvents such as dichloromethane, acetone, methanol, or tetrahydrofuran, which raise environmental, safety, and cost concerns. This is because not many organic solvents can dissolve both the hydrophobic drug and the hydrophilic polymer simultaneously. Therefore, the solvent-to-drug ratio can be very high, creating significant waste and an environmental burden. The acid-base supersolubilization (ABS) principle offers an alternative approach to using organic solvents. When a strong base like sodium hydroxide increases the pH of an acidic drug suspension in water, the solubility increases until the pH of maximum solubility (pH_max) is reached, after which salt precipitation occurs, limiting further solubility enhancement(Figure 1). However, a weaker base is used, such as tromethamine, pH_max may never be reached, and the solubility can continue increasing according to the Henderson-Hasselbalch equation without any salt formation, leading to remarkably high solubility. Our laboratory has previously demonstrated the ABS principle with several poor water soluble compounds: indomethacin solubility increased from < 1 mg/mL to >240 mg/mL with tromethamine; flurbiprofen solubility increased from 0.011 mg/mL to >358 mg/mL with meglumine; haloperidol solubility increased from ~1 μg/mL to >300 mg/g of solution with malic acid and glutaric acid; and itraconazole solubility significantly improved with citric acid. In our previous research, we successfully prepared ASDs of these drugs using hot-melt extrusion (HME). The present study extends the application of the ABS principle to develop ASDs through spray drying using only water as a solvent, thereby eliminating the need for organic solvents while maintaining the solubility enhancement and dissolution benefits.

Methods: The aqueous solubility of indomethacin with the weak base tromethamine was determined using the shake-flask method at 25°C. Tromethamine was added gradually to increase pH and thereby increase the solubility of indomethacin. Aqueous solutions containing indomethacin (10% w/w), tromethamine (3.8% w/w) in a 1:2 molar ratio, and Poloxamer 407 (20% w/w) with remaining Kollidon VA64 (66.2% w/w) were prepared in distilled water without any organic solvents by using the ABS principle. These solutions were then spray-dried at 2% w/v solid concentration, processed using a Buchi Mini B-90 spray dryer under optimized conditions (inlet temperature: 95-105°C, pump rate: 15-20%, aspirator: 100%, outlet temperature: 50°C). An identical formulation previously prepared by hot-melt extrusion (HME) at 80°C was used for comparison. The spray-dried powders were characterized using DSC, PXRD, and in vitro dissolution testing. A step dissolution test was conducted where formulation-filled capsules (equivalent to 25 mg of indomethacin) were first placed in 250 mL of 0.1M HCl (pH 1) for 2 hours, followed by pH adjustment to 6.8 using approximately 80 mL of pre-heated (37°C) 0.2 M trisodium phosphate solution. In the future, further studies were conducted by spray drying formulations of flurbiprofen with meglumine, itraconazole with citric acid, haloperidol with glutaric and malic acid, and the results are compared with previous studies on the hot melt extrusion of such formulations.

Results: The representative results with the indomethacin-tromethamine system demonstrated supersolubilization of indomethacin with tromethamine, increasing from < 1 mg/mL to >240 mg/mL. The spray drying successfully produced amorphous powders similar to hot melt extrusion (Figure 2). Dissolution studies in acidic media (pH 1) showed that spray-dried ASD exhibited faster initial dissolution than HME formulations, achieving >85% drug release within 15 minutes versus 80% after 45 minutes for HME products (Figure 3). Faster release in spray-dried formulation was due to the powder properties, such as consistent particle size, compared to the HME formulation. However, some precipitation occurred after 60 minutes with spray-dried ASD, resulting in ~65% drug remaining in solution at 120 minutes, while the HME formulation maintained a more consistent 80% drug in solution. Upon pH transition to 6.8, both formulations rapidly dissolved and maintained complete dissolution. Similarly, high dissolution rates were also observed with the spray-dried formulations of other drugs.

Conclusion: The ABS principle successfully enabled spray drying of indomethacin and other poorly water-soluble drugs using only water as solvent, eliminating the need for organic solvents typically required for preparing ASDs. This environmentally friendly approach enhances drug solubility and performs excellent dissolution, particularly in the initial phase. The approach offers significant advantages, including elimination of organic solvents, simplified manufacturing, reduced environmental impact, and avoiding residual solvent issues while effectively addressing the challenge of poor drug solubility. This methodology represents a promising green technology for the sustainable pharmaceutical development of poorly water-soluble drugs.


Figure 1: Illustration of acid-base supersolubilization (ABS) principle, where Graph A (Left) represents a pH versus solubility profile showing the increase in solubility of an acidic compound with increasing the pH by the addition of a base (line A to B) until pHmax (point B) is reached. Above pHmax, the salt precipitates out. The solubility of salt is represented by line B to C. Graph B (right) represents the pH versus solubility profile where the weak base is added to increase pH that does not form a salt, and the solubility keeps on increasing by the extension of line A to B upward to provide supersolubilization. (C) With the weak base tromethamine, indomethacin showed a remarkable increase in solubility of >240mg/mL, showing acid-base supersolubilization.


Figure 2 Solid-state characterization of indomethacin formulations. (A) PXRD patterns of pure indomethacin, tromethamine, Kollidon VA64 polymer, Poloxamer 407, and the final formulations prepared by hot-melt extrusion (HME) and spray drying. The absence of characteristic crystalline peaks in both final formulations confirms their amorphous nature. (B) DSC thermograms showing the thermal behavior of individual components and final formulations. Pure indomethacin exhibits a sharp melting endotherm at approximately 160°C, and tromethamine shows thermal events around 140°C and 180°C. Both spray-dried and HME final formulations lack these characteristic melting endotherms, further confirming the successful formation of amorphous solid dispersions using both manufacturing techniques.


Figure 3 Dissolution profiles of indomethacin formulations in pH 1 (0-120 min) followed by pH 6.8 (120-240 min). Spray-dried ASD (triangles) shows rapid initial release followed by partial precipitation, while hot-melt extruded ASD (squares) demonstrates more sustained release in acidic medium. Both ABS-based formulations achieve complete dissolution after pH transition, whereas the conventional ASD without tromethamine(circles) shows negligible release throughout.