Design and Preparation of a 4:1 Lamivudine–Oxalic Acid CAB Cocrystal for Improving the Lamivudine Purification Process

Lamivudine (LMV), a cytosine derivative and a reverse transcriptase inhibitor, faces the challenge of inefficient purification after its chemical synthesis. Currently available methods of purification involve salt formation (salicylate or oxalate) followed by treatment with a toxic base, triethyl amine (TEA), to neutralize the protonated LMV. Any reduction in the use of TEA will make the purification process greener and more economical. In this context, we designed and successfully isolated a new and elusive 4:1 CAB cocrystal between LMV and oxalic acid (OXA) that has the potential to significantly improve the efficiency of the LMV purification process. The new CAB cocrystal of LMV was efficiently produced by carefully controlling the ratio of LMV to OXA in the crystallization medium. Compared to salts currently used for purification, much less TEA is required for the 4:1 CAB cocrystal (LMV/LMVH⁺/OXA^2– at 2:2:1 mole ratio) because only half of the LMV is protonated that requires TEA treatment

Design, Synthesis, and Characterization of New 5‑Fluorocytosine Salts

5-Fluorocytosine (FC), an antifungal drug and a cytosine derivative, has a complex solid-state landscape that challenges its development into a drug product. A total of eight new FC salts, both cytosinium and hemicytosinium, with four strong acids were prepared by controlling acid concentration in the crystallization medium. The pharmaceutically acceptable saccharin salt of FC exhibits superior phase stability and, hence, has the potential to address the instability problem of FC associated with hydration

Protonation of Cytosine: Cytosinium vs Hemicytosinium Duplexes

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 p<i>K</i>_a > 4.2, which is incapable of disrupting the relatively stable duplex structure. When stronger acids (p<i>K</i>_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

Impact of Crystal Habit on Biopharmaceutical Performance of Celecoxib

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 <i>C</i>_max and shorter <i>T</i>_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