title: Characterization of polymorphic ampicillin forms.
abstract: In this work polymorphs of α-aminobenzylpenicillin (ampicillin), a β-lactamic antibiotic, were prepared and investigated by several experimental and theoretical methods. Amorphous monohydrate and three crystalline forms, the trihydrate, the crystal form I and the crystal form II, were investigated by FT-IR and micro-Raman. Also data obtained by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) and hot-stage Raman spectroscopy are reported. Finally, quantum mechanical calculations were performed by density functional theory (DFT) to assist the assignment of spectroscopic experimental bands. For the first time, the ampicillin molecule in its zwitterionic form was studied at the B3LYP/aug-cc-pVDZ level and the corresponding theoretical vibrational spectra were computed. In fact, ampicillin in the crystal is in zwitterionic form and concentrations of this same form are quite relevant in solutions at physiological pH. Experimental and theoretical results allowed identification of specific features for polymorph characterization. Bands typical of the different polymorphs are identified both in IR and Raman spectra: in particular in the NH stretching region (IR), in the amide I+δNH region (both techniques), in the 1520-1490cm(-1) region (IR), in the 1320-1300cm(-1) and 1280-1220cm(-1) (IR), in the 1200-1170cm(-1) (Raman), in the amide V region (IR), and, finally, in the 715-640cm(-1) and 220-200cm(-1) (Raman). Interconversion among different polymorphs was investigated by hot-stage Raman spectroscopy and thermal analysis, clarifying the complex pattern of transformations undergone as a function of temperature and heating rate. In particular, DSC scans show how the trihydrate crystals transform into anhydrous forms on heating. Finally, stability tests demonstrated, after a two years period, that no transformation or degradation of the polymorphs occurred.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi n.183, 41125 Modena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Baraldi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, via Belmeloro 8/2, 40126 Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tinti
authors.affiliation: Istituto per la Sintesi Organica e la Fotoreattività, ISOF-CNR, via P. Gobetti 101, 40129 Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ottani
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi n.183, 41125 Modena, Italy. Electronic address: mariacristina.gamberini@unimore.it.
authors.forename: M C
authors.initials: MC
authors.lastname: Gamberini
mesh_terms: D000667:Ampicillin / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006358:Hot Temperature; D015394:Molecular Structure; D044367:Phase Transition; D033362:Powder Diffraction; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin
keywords: Ampicillin; DFT calculations; FTIR/ATR spectroscopy; Raman microscopy; Thermal analysis; X-ray powder diffraction