Poor biopharmaceutical performance of Biopharmaceutical Classification System (BCS) class II drug molecules is a major hurdle in the design and development of pharmaceutical formulations. Anisotropic surface chemistry of different facets in crystalline material affects physicochemical properties, such as wettability, of drugs. In the present investigation, a molecule-centered approach is presented toward crystal habit modification of celecoxib (CEL) and its effect on oral bioavailability. Two crystal habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal habit (CEL-P), were obtained by recrystallization from toluene at 25 and 60 °C, respectively. Compared to CEL-A, CEL-P exhibited significantly faster dissolution kinetics in aqueous media and significantly higher C max and shorter T max in an oral bioavailability study. The significant enhancement in dissolution and biopharmaceutical performance of CEL-P was attributed to its more abundant hydrophilic surfaces compared to CEL-A. This conclusion was supported by wettability and surface free energy determination from contact angle measurements and surface chemistry determination by X-ray photoelectron spectroscopy (XPS), crystal structure modeling, and crystal face indexation.

Berberine is a drug with an intense bitter taste. The high aqueous solubility of its chloride salt, which is commonly used in commercial drug products of berberine, worsens the challenge of taste masking. We have approached this drug delivery challenge by forming salts with the sweeteners acesulfame and saccharine, through the anion exchange reaction. In addition to the intrinsic sweetness of the two counterions, both salts also exhibit reduced aqueous solubility, which further alleviates the problem of bitter taste of the drug by limiting dissolution of berberine. Moreover, both salts exhibit good tableting performance. They are also non-hygroscopic and stable against high humidity and temperature. The stability against humidity variations makes the two sweet salts more amenable for tablet development over the chloride salt, which undergoes complex hydration/ dehydration phase changes when relative humidity varies. Collectively, the two novel solid phases of berberine are sweet and exhibit superior properties for developing pharmaceutically elegant drug products.

Cytosine, a nucleobase, can exhibit two protonated states, cytosinium and hemicytosinium. The controlled synthesis of structures containing these ions is highly desired but not yet achieved. Herein, we report strategies for robust synthesis of both structures by controlling the strength of an acid used for protonation and its concentration. The duplex structure is always obtained by using an acid with a pK a > 4.2, which is incapable of disrupting the relatively stable duplex structure. When stronger acids (pK a < 4.19) are used, the duplex structure is obtained by controlling acid concentration to protonate a half of cytosine in solution, and the cytosinium structure is obtained with excess acid. These strategies are successfully applied to synthesize both forms of 5-fluorocytosine, an antifungal drug. The hemicytosinium structure exhibits superior physicochemical properties than the parent drug and the cytosinium salt. These strategies may be useful to prepare materials important to various branches of science, ranging from biology to nanodevice fabrication and to pharmaceuticals.

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