Supersolubilization and Amorphization of a Weakly Acidic Drug, Flurbiprofen, by applying Acid-Base supersolubilization (ABS) principle

Abstract

Improvement in drug solubility is a major challenge for developing pharmaceutical products. It was demonstrated earlier that aqueous solubilities of weakly basic drugs could be increased greatly by interaction with weak acids that would not form salts with the drugs, and the highly concentrated solutions thus produced converted to amorphous solids upon drying. The technique was called acid-base supersolubilization (ABS). The current investigation explored whether the ABS principle could also be applied to weakly acidic drugs. By taking flurbiprofen (pK_a 4.09; free acid solubility 0.011 mg/mL) as the model weakly acidic drug and tromethamine, lysine, meglumine, and NaOH as bases, it was studied which of the bases would result in ABS. While in the presence of NaOH and tromethamine, flurbiprofen converted to salts having aqueous solubility of 11–19 mg/mL, the solubility increased to > 399 mg/mL with lysine and > 358 mg/mL with meglumine, producing supersolubilization. However, crystallization of lysine salt was observed with time, followed by some decrease in solubility after reaching maximum solubility with lysine. In contrast, the supersolubilization was maintained with meglumine, and no crystallization of meglumine salt was observed. Upon drying, flurbiprofen-meglumine solutions produced amorphous materials that dissolved rapidly and produced high drug concentrations in aqueous media. Thus, the ABS principle also applies to acidic drugs depending on the weak base used.

Introduction

The development of most new chemical entities (NCE) into bioavailable oral dosage forms is challenging because of their poor aqueous solubility (Alqahtani et al., 2021, Li et al., 2005a). Liu (2017) estimated that almost 90 % of NCEs synthesized and 75 % of compounds under development in the pharmaceutical industry fall into the category of low aqueous solubility. The United States Pharmacopeia (USP) considers a compound to be insoluble or practically insoluble if its solubility in water is < 0.1 mg/mL, i.e., <100 µg/mL. However, the drug solubility of even less than 0.001 mg/mL (1 µg/mL) is common. For example, it has been reported that the solubility of itraconazole under intestinal pH conditions is as low as 4 ng/mL (Brewster and Loftsson, 2007) and even 0.2 ng/mL (Glomme et al., 2005). The definition of poor aqueous solubility of drugs was further refined in the Biopharmaceutical Classification System (BCS) developed by Amidon et al. (1995), which was later adapted by the US Food and Drug Administration (Purdie FP, FDA, CDER, 2017). According to the BCS, the highest dosage strength of a drug must dissolve in 250 mL of an aqueous medium within the pH range of 1 to 6.8 at 37 °C for it to be called water-soluble, and, if not, it is considered to have low water solubility. As an example, if a drug has a dose of 100 mg and a water solubility of 1 µg/mL (0.001 mg/mL), which is common for NCEs, the aqueous medium required to dissolve the dose will be 100 L, i.e., 400 times higher than 250 mL of aqueous medium recommended by BCS. The volume of liquid will further increase if the solubility is lower, or the dose is higher. For a drug like itraconazole with a usual dose of 200 mg and an aqueous solubility of ∼ 4 ng/mL, an exorbitantly large volume of 50,000 L of water will be required to dissolve the dose.

Clearly, conventional dosage forms may not be able to resolve bioavailability issues with poorly water-soluble drugs, and alternative novel dosage forms are required to increase their dissolution rate and bioavailability (Alqahtani et al., 2021, Raines et al., 2023, Williams et al., 2013). In 2023, the University of Maryland Center for Excellence in Regulatory Science and Innovation (M−CERSI) in the USA organized an international conference on ‘Drug Dissolution in Oral Drug Absorption’, where leading academic, industrial, and regulatory scientists from the USA, Europe, and Asia participated (Raines et al., 2023). In this conference, amorphous solid dispersion (ASD) emerged as the most viable option for the development of poorly water-soluble drugs. However, many issues with the development of ASDs still remain; some of the issues are (a) relatively low drug loading in ASDs due to low drug-polymer miscibility, (b) the risk of crystallization of drugs from ASD drug products, (c) incomplete drug dissolution from dosage forms, (d) precipitation of drugs from supersaturated solutions after dissolution, and (e) complexation or binding of drugs with polymers and other excipients that could limit drug absorption even after dissolution.

One of the strategies to increase the solubility and dissolution rates of drugs in ASDs discussed in the above-mentioned conference is a novel approach called acid-base supersolubilization (ABS). According to the ABS principle developed by Singh et al. (2013), the solubility of basic drugs in aqueous media can be increased greatly by interaction with weak acids, and amorphous solid dispersions (ASDs) are formed when such highly concentrated solutions are dried. They explained the ABS principle using the classical pH vs. solubility theory (Kramer and Flynn, 1972, Serajuddin and Jarowski, 1985). In general, the solubility of a basic drug increases when an acid is used to reduce the pH of its solutions in aqueous media. However, the solubility of the basic drug increases until the pH is lowered to the pHmax, which is the pH of maximum solubility in water. Upon further lowering of pH below the pHmax, salt of the basic drug with the added acid would be formed. However, for salt to form, the added acid must be both strong and soluble enough to reduce the pH below pHmax. If the acid is weak and cannot lower pH below pHmax, no salt would be formed. Instead, the drug’s solubility would keep increasing until a very high solubility is reached. This is the basis of the acid-base supersolubilization (ABS) principle. As an example, while the intrinsic or free base solubility of the basic drug haloperidol in aqueous media is 1–2.5 µg/mL (Avdeef et al., 2016, Li et al., 2005b) and the solubilities of phosphate and HCl salts of haloperidol were 1 and 4 mg/mL, respectively, the solubility increased to > 300 mg per gram of solution when the pH was adjusted by adding weak acids like malic acid, succinic acid, and citric acid that did not form salts with haloperidol (Singh et al., 2013). ASDs were formed when the concentrated solutions of haloperidol with these acids were dried, which were physically stable and neither converted to crystalline salts nor reverted to the crystalline base. The ASDs could, however, be in the form of viscous semisolid that could be solidified into free-flowing powders by adsorbing them onto silicas (Shah and Serajuddin, 2015, Shah and Serajuddin, 2014). In addition to haloperidol, the ABS principle was successfully applied to develop ASDs of itraconazole with increased drug loads and high dissolution rates (Parikh et al., 2016). The itraconazole ASDs could also be prepared by hot melt extrusion (HME) without using any water to dissolve the drug and acid (Parikh and Serajuddin, 2018). Later, Patel and Serajuddin, 2021, Patel and Serajuddin, 2023 applied the ABS principle to prepare ASD filaments by HME with as much as 50 % drug content to develop rapidly dissolving 3D-printed tablets. The filaments and the tablets were physically stable, as there was no crystallization of the drug (Serajuddin, 2023).

As described above, acid-base super solubilization (ABS) is a novel strategy to increase drug loading in ASDs and increase their dissolution rates. However, it has so far been used only for basic drugs like haloperidol and itraconazole. There are no studies on applying the ABS principle to poorly water-soluble acidic drugs to increase drug solubility and convert supersolubilized systems into ASDs.

The present investigation aims to study the acid-base supersolubilization (ABS) of an acidic drug, for which we selected flurbiprofen as the model drug. Flurbiprofen is a non-steroidal anti-inflammatory drug (NSAID) with additional antipyretic and analgesic properties. It has a pKa of 4.09 and a molecular weight of 244.265 g·mol−1, and it exhibits pH-dependent solubility with the reported low solubility of 5–8 µg/mL at 22⁰C under gastric pH conditions (Baek et al., 2011). Therefore, it is a BCS II drug. Although the solubility increases under intestinal pH conditions, the drug exhibits much intra- and inter-subject variations in absorption rate and bioavailability. Various formulation strategies to improve the dissolution rate and bioavailability of flurbiprofen such as dry elixir (Kim et al., 1995), inclusion complex (Tokumura et al., 2009), salt formation (Anderson and Conradi, 1985), and solid dispersion (Habib et al., 1998) have been reported in the literature.

In the present investigation, we first used sodium hydroxide (pKa ∼ 15.7) to study the pH vs. solubility profile of flurbiprofen since the salt formation with such a strong base was expected; this would determine where the pHmax lies in the pH-solubility profile before the formation of sodium salt. Then, three relatively weaker bases, namely, tromethamine (pKa 8.12), lysine (pKa 2.22, 9.18, 10.71), and meglumine (pKa 9.62), were used to determine which of them, if any, would lead to acid-base supersolubilization and form amorphous solids.