Salts and Salt Cocrystals of the Antibacterial Drug Pefloxacin

Abstract

Pefloxacin (PEF) is an amphoteric, antibacterial drug which exists as a neutral molecule in the crystal structure stabilized by C–H···O and C–H···F interactions. The design of multicomponent solids using crystal engineering was undertaken in a cocrystal/salt screen of PEF with generally recognized as safe (GRAS) dicarboxylic acids to improve the solubility and phase stability of the drug. Ten multicomponent forms, namely, five salts, two salt hydrates, and three salt cocrystals, were prepared by liquid-assisted grinding followed by crystallization. In some cases, salt and salt cocrystals were obtained concomitantly during solution evaporative crystallization. Single crystal X-ray diffraction showed that the structures are stabilized by N+–H···O–, O–H···O, C–H···O, C–H···F, and π–π stacking interactions. The bulk phase purity of multicomponent forms was characterized by powder X-ray diffraction, spectroscopy, and thermal techniques. The salt/salt cocrystal forms exhibit a faster dissolution rate and higher solubility compared to pure PEF in pH 1.2 (acidic, like gastric environment) and pH 7 phosphate buffer media (neutral, like intestinal passage). Specifically the PEF+–SA– salt (SA = succinic acid) showed remarkably high solubility, dissolution rate, and stability compared to the other multicomponent forms and PEF neutral form. The drug formulation compatible pefloxacin succinate is a promising soluble and stable PEF salt.

Neutral, Zwitterion, Ionic Forms of 5‐Aminoisophthalic Acid in Cocrystals, Salts and Their Optical Properties

“…[20][21][22][23][24] The electrostatic interactions in the noncovalent self-assemblies of inorganic complexes are common. [25][26][27][28] Among many examples of organic salts forming cocrystals the salts of active pharmaceutical ingredients, [25] carboxylic acid, [20][21][22][23][24] quaternary ammonium [29] and heterocycle containing oximes [30] are well studied. Depending on the reactivity of a base dicarboxylic acids form salts with different stoichiometries.…”

“…Charge‐assisted hydrogen bonds have definite scopes in the synthesis of non‐covalent assemblies . The electrostatic interactions in the non‐covalent self‐assemblies of inorganic complexes are common . Among many examples of organic salts forming cocrystals the salts of active pharmaceutical ingredients, carboxylic acid, quaternary ammonium and heterocycle containing oximes are well studied.…”

Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study

“…It is expected to have a combined benefit of the salt and cocrystal properties, such as improved stability, solubility, dissolution, as well as enhanced the bioavailability [ 12 , 13 , 14 , 15 , 16 ]. As previously reported, salt cocrystal niclosamide and salt cocrystal pefloxacin can enhance solubility and dissolution [ 17 , 18 ]. Moreover, our previous research has shown that a salt cocrystal can be made from saccharine sodium salt with theophylline, as well as acidic saccharine with a similar excipient [ 19 ].…”

“…This study aimed to discover salt cocrystals of NDH with LP (abbreviated NDP) to obtain the drug’s superior properties, namely, stability, solubility, and dissolution [ 3 , 4 , 5 , 6 , 7 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Considering that ND was unstable, we initially arranged a cocrystal from NDH to develop a suitable and practical method, which can be performed readily even under the ambient conditions.…”

Structure of Imidazolium-N-phthalolylglycinate Salt Hydrate: Combined Experimental and Quantum Chemical Calculations Studies

“…A shift in the vibrational frequency of the multi-component molecular crystal with respect to the individual molecular entities denotes the formation of new hydrogen bonds and other weak noncovalent forces [38][39][40]. As depicted in Figure S1, from the IR spectrum of NPG, carbonyl stretching frequencies of the carboxylic acid are observed at 1724.17 and 1415.18 cm −1 .…”