(M1030-01-06) Supersolubilization and Amorphization of a Weakly Acidic Drug, Flurbiprofen, by Applying Acid-Base Supersolubilization (ABS) Principle

Purpose: Acid-base supersolubilization (ABS) is a novel approach that helps in increasing the solubility of weakly ionic drugs. Earlier work on the interaction of weakly basic drugs with weak acids protonated the drug molecule without reducing the pH below the pH of maximum solubility (pHmax). It also prevented the formation of crystalline salt and instead resulted in a highly soluble form of the drug in solution. (Singh et al., 2013) (Serajuddin, 2007a) These solutions on drying formed amorphous solid dispersion (ASD). Similarly, ASDs were obtained by melting drugs with weak acids. In the current investigation, the application of the ABS principle to a weakly acidic drug, flurbiprofen, by use of weak bases was explored. Flurbiprofen (FBP) was chosen as a model drug due to its physicochemical property having a low intrinsic solubility of 0.005 to 0.010 mg/mL in the gastrointestinal pH range. (Munir et al., 2022) Different weak bases such as meglumine, lysine, and tromethamine were used; along with sodium hydroxide as the salt-forming reference base.

Methods: The solubility of flurbiprofen (FBP) was determined as a function of pH by adjusting pH with different bases to determine the pHmax for individual bases. Based on this information, a separate study was conducted where weighed amounts of bases were added to water and the solubility of FBP was determined by the shake flask method. Different molar ratios of flurbiprofen and individual bases were mixed in water and solutions were dried to obtain dry solids. These dry solids were characterized for crystallinity using DSC and PXRD. In vitro dissolution testing was conducted using the USP II apparatus, at 50 RPM and 37° C. About 50 mg drug equivalent solids were evaluated in 250 mL in pH 2 medium for 2 hours followed by pH adjustment to 6.8. Particle size was measured to characterize any precipitation during the dissolution testing. Further, a ternary system of FBP, meglumine, and Kollidon ® VA64 was developed by hot melt extrusion and evaluated for drug release.

Results: pH-solubility study of FBP as a function of base showed that the solubility of FBP increased to >399 mg/mL with lysine and >358 mg/mL with meglumine producing supersolubilization. Tromethamine and sodium hydroxide formed crystalline salts, resulting in relatively lower solubility. The second study, involving the solubility of FBP with increasing base concentration showed a higher solubility of 347 mg/g of solution with meglumine and 420mg/g of solution with lysine. Dried aqueous formulations of flurbiprofen-meglumine mixtures formed amorphous solids, as confirmed by DSC and PXRD analyses. It can be hypothesized from pH-solubility considerations that the amorphous materials produced by drying the flurbiprofen-meglumine concentrated solutions would be physically stable. Since flurbiprofen does not form salts with the meglumine, there will not be any conversion of the solids into crystalline form. Additionally, conversion to its free base form may also be insignificant as the microenvironmental pH of the system would be high. In dissolution studies, flurbiprofen-meglumine and flurbiprofen-lysine solids exhibited rapid dissolution in acidic media but could not sustain supersaturation as shown in Figure 3A. Although both showed precipitation over time, particle size measurements of flurbiprofen-lysine samples were relatively bigger in the micron range and settled at the bottoms of the dissolution vessel shown in Figure 3B. Whereas flurbiprofen-meglumine samples did not crystallize out as salt and precipitate out as nanometer-range particles. The nanosized particles tend to undergo redissolution over time. On the other hand, dissolution evaluation of the 20% loaded flurbiprofen with polymer helped in maintaining supersaturation in acidic media showing more than 80% FBP release in the presence of meglumine (Formulation F4) in comparison to the absence of meglumine (Formulation F2) as shown in Figure 3C. These results demonstrate the potential of the ABS principle using meglumine to enhance solubility, and dissolution rate and produce amorphous solids for weakly acidic drugs.

Conclusion: ABS is a promising approach for weakly acidic drugs flurbiprofen by using weak bases such as meglumine similar to its prior success with basic drugs. The ABS principle offers a potential advantage for developing amorphous solid dispersions (ASDs) with high drug loading and improved dissolution rates, without the risk of crystallization or salt formation.

References: Munir, M.U., Ikraam, M., Nadeem, M., Khalid, S.H., Asghar, S., Khalid, I., Irfan, M., Islam, N., Ajaz, N., Khan, I.U., 2022. Fabrication, In Vitro and In Vivo Evaluation of Non-Ordered Mesoporous Silica-Based Ternary Solid Dispersions for Enhanced Solubility of Flurbiprofen. Pharmaceuticals 15, 856. https://doi.org/10.3390/ph15070856
Serajuddin, A.T.M., 2007a. Salt formation to improve drug solubility. Adv. Drug Deliv. Rev. 59, 603–616. https://doi.org/10.1016/j.addr.2007.05.010
Serajuddin, A.T.M., 2007b. Salt formation to improve drug solubility. Adv. Drug Deliv. Rev. 59, 603–616. https://doi.org/10.1016/j.addr.2007.05.010
Singh, S., Parikh, T., Sandhu, H.K., Shah, N.H., Malick, A.W., Singhal, D., Serajuddin, A.T.M., 2013. Supersolubilization and amorphization of a model basic drug, haloperidol, by interaction with weak acids. Pharm. Res. 30, 1561–1573. https://doi.org/10.1007/s11095-013-0994-7


Fig. 1. Schematic representation of the interrelationship between the solubility of acid and its salt form as a function of pH. In (A), line AB represents free acid as equilibrium species below the pHmax and line BC represents salt as equilibrium species above the pHmax (reprinted with permission from (Serajuddin, 2007b)). In (B), different species formed at pH above and below the pHmax are shown, when the pH of the suspension of an acidic drug, A, is lowered by the addition of a base, X+. The subscript ‘s’ in [AH]s and [A-]s indicates saturation. Subfigure (C) represents pH vs solubility profile where bases added to increase pH is so weak that no salt forms and the solubility keeps on increasing by the extension of line upward to provide supersolubilization.


Fig. 2. DSC scans (A) and PXRD patterns (B) of flurbiprofen and meglumine mixtures at 1:3, 1:2, 1:1, and 2:1 molar ratios (scans 1, 2, 3, and 4, respectively). DSC scans and PXRD patterns of meglumine and flurbiprofen alone are also shown as scans 5 and 6 for comparison.


Fig. 3. 3A. Comparative step dissolution profiles of amorphous flurbiprofen- meglumine and flurbiprofen lysine at 1:1 ratios with pure flurbiprofen API. 3B. Particle size evaluation of dissolution samples of amorphous flurbiprofen-meglumine and flurbiprofen lysine dry mixtures at 1:1 molar ratio during acid phase of dissolution. 3C. Step dissolution profiles of flurbiprofen-Kollidon ® VA64 extrudates with and without meglumine 3D. Particle size evaluation of dissolution samples flurbiprofen-Kollidon ® VA64 extrudates with and without meglumine at 20% drug loading. Each data point represents an average of 3 determinations.