(W0930-01-06) Application of Acid-Base Supersolubilization (ABS) Principle to Increase Aqueous Solubility of Weakly Acidic Drug Indomethacin and Its Dissolution from ASD Prepared by Hot-Melt Extrusion

Purpose: Over two-thirds of drugs under development in the pharmaceutical industry are extremely insoluble in aqueous media and fall into BCS Class II or IV. This research explores how the aqueous solubility of a poorly water-soluble, weakly acidic drug, indomethacin, can be greatly improved, and its dissolution rate from amorphous solid dispersions(ASD) can be enhanced by applying a novel physicochemical principle called acid-base supersolubilization(ABS). According to the classical pH-solubility theory, solubility of free acid and its salt with a basic counterion described by two independent curves as shown in Fig.1 where free base is the equilibrium species and the other where the salt is the equilibrium species; the point where the two curves intersect is the pH of maximum solubility(pH_max). As shown in Fig. 1-A, when a base is used to increase the pH of the suspension of an acidic drug in water, the solubility of the drug increases until pH_max is reached, and upon further increasing of pH to >pH_max, phase transition of the drug occurs, resulting in the crystallization of its salt form. In this case, bases used to adjust the pH of the suspensions must be strong enough to increase the pH above pH_max; If relatively weaker bases used, pH_max may never be reached, and solubility of drug in aqueous medium keeps increasing according to Handerson-Hasselbach equation without salt precipitation until a very high solubility is attained (Fig. 1-B). The ABS principle's importance has been previously proven for weak basic drug haloperidol using weak acids. It has been reported that, while aqueous solubilities of free base form and HCl salts of haloperidol are ~1µg/mL and 2mg/mL, respectively, the solubility of the compound could be increased to >300mg per gram of solution ( >300,000 times) by adjusting pH with such weak acids as malic acid, succinic acid, and citric acid, which did not form haloperidol salts. Although ABS principle has previously been used for basic drugs, no study on its application to improve solubility and dissolution rates of acidic drugs have been reported. Present study was conducted to apply the ABS principle to increase the aqueous solubility of a weakly acidic drug, indomethacin (IND), by interaction with a weak base tromethamine. Furthermore, the acid-base interaction was applied to lower the processing temperature of hot melt extrusion (HME) and the formation of amorphous solid dispersion of IND.

Methods: The aqueous solubility of IND, with the weak base tromethamine, was determined using the shake-flask method at 25^oC, and samples were analyzed using HPLC. Amorphous solid dispersions(ASD) were prepared using hot melt extrusion (HME)(Thermo Scientific Process11mm extruder). Rheology as function of temperature, hot-stage microscopy, DSC, and PXRD were performed to determine HME experimental conditions and characterize ASDs. In vitro dissolution testing of 25-mg IND equivalent was performed in 250mL 0.1M HCl (pH 1.2) using USP II apparatus at 50 RPM and 37^oC.

Results: Solubility of IND as a function of increasing concentration of weak base tromethamine showed acid-base supersolubilization(ABS) at pH ~8, increasing the solubility of IND to >240mg/ml, but relatively stronger bases, such as sodium hydroxide and sodium bicarbonate, formed sodium salt above pH7.2, causing limited solubility of IND. Amorphous solid dispersion(ASD) was formed when such a concentrated aqueous solution was dried. In the present investigation, a similar solid ASD was formed by the solvent-free HME process, where IND-tromethamine mixture at 1:2 molar ratio (Indomethacin 10%w/w and tromethamine 3.8w/w) was extruded along with surfactant Poloxamer 407(P407), at 10 and 20% levels and remaining of the polymer KollidonVA64 (KVA64). Although the HME of IND with only KVA64 requires 140⁰C to extrude, the mixture could be extruded at a low temperature of 80⁰C in presence of tromethamine, thus avoiding any potential degradation of IND at high temperatures. Physically and chemically stable ASDs were formed in all cases. Drug release in the 250mL of 0.1M HCl (pH~1) showed that < 5% IND dissolved when ASD was produced using 10% (w/w) IND in KVA64 alone, and the addition of P407 could increase drug release to ~40%, which subsequently precipitated out of solution. Contrastingly, formulation prepared with tromethamine according to the ABS principle greatly improved drug release to >80% and prolonged supersaturation of dissolution media.

Conclusion: The application of acid-base supersolubilization (ABS) principle greatly increased solubility of indomethacin in water from <1mg/mL to >240mg/mL by interaction with tromethamine. There was also exceptionally high drug release of >80% under gastric pH conditions from its ASDs in the presence of tromethamine, in contrast to the literature reports that the release of IND from ASDs at low pH is very limited (usually < 10-15%). In addition to the drug dissolution, the solvent-free method of hot melt extrusion could be easily employed at a relatively low temperature of 80^oC because of ABS, resulting in good processibility and avoiding the potential degradation of IND.

References: 1. Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D. and Serajuddin, A.T., 2013. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharmaceutical Research, 30, pp.1561-1573.
2. Shah, A. and Serajuddin, A.T., 2014. Supersolubilization by using nonsalt-forming Acid-Base interaction. Amorphous Solid Dispersions: Theory and Practice, pp.595-611.
3. Kramer, S.F. and Flynn, G.L., 1972. Solubility of organic hydrochlorides. Journal of Pharmaceutical Sciences, 61(12), pp.1896-1904.
4. Parikh, T. and Serajuddin, A.T., 2018. Development of fast-dissolving amorphous solid dispersion of itraconazole by melt extrusion of its mixture with weak organic carboxylic acid and polymer. Pharmaceutical Research, 35, pp.1-10.


Figure 1: Illustration of acid-base supersolubilization (ABS) principle, where Graph A (Left) represents a theoretical 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 theoretical 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 experimentally.


Figure 2: (A) In Vitro drug release of capsules filled with powdered extrudates with dose equivalent to 25 mg of indomethacin in 250mL of 0.1M HCl (pH~1). All the dotted lines show drug release from the extrudates without the weak base- tromethamine. All the solid lines show release from the extrudates with the tromethamine. (B)1 The cloudy dissolution media suggest undissolved or precipitated indomethacin for the extrudates of indomethacin-Kollidon VA64. (B)2 Clear media suggest completely dissolved indomethacin (particle analysis shows particle size of 46nm ± 5nm) for the batch containing Indomethacin +Tromethamine Kollidon VA64 + 20% P407.


Figure 3: Hot stage microscopy of (A) indomethacin (showing melting at 160 oC) (B) tromethamine (showing a first change in crystalline structure at 140 oC and melting at 180 oC) (C) Physical mixture of indomethacin and tromethamine in ratio 1:2 (started melting at 120 oC and complete melting at 130 oC) (D) Major events of the melting from 125 oC till 130 oC, at various time points.