4 research outputs found
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<sup>+</sup>/OXA<sup>2–</sup> 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><sub>a</sub> > 4.2, which is incapable of disrupting
the
relatively stable duplex structure. When stronger acids (p<i>K</i><sub>a</sub> < 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
Probing Interfaces between Pharmaceutical Crystals and Polymers by Neutron Reflectometry
Pharmaceutical powder engineering often involves forming
interfaces
between the drug and a suitable polymer. The structure at the interface
plays a critical role in the properties and performance of the composite.
However, interface structures have not been well understood due to
a lack of suitable characterization tool. In this work, we have used
ellipsometry and neutron reflectometry to characterize the structure
of such interfaces in detail. Ellipsometry provided a quick estimate
of the number of layers and their thicknesses, whereas neutron reflectometry
provided richer structural information such as density, thickness,
roughness, and intermixing of different layers. The combined information
allowed us to develop an accurate model about the layered structure
and provided information about intermixing of different layer components.
Systematic use of these characterization techniques on several model
systems suggests that the nature of the polymer had a small effect
on the interfacial structure, while the solvent used in polymer coating
had a large effect. These results provide useful information on the
efforts of engineering particle properties through the control of
the interfacial chemistry