title: Influence of pH and method of crystallization on the solid physical form of indomethacin.
abstract: The purpose of this study was to investigate the effect of pH and method of crystallization on the solid physical form of indomethacin (IDM). IDM, a non steroidal anti-inflammatory drug poorly soluble in water, underwent two different crystallization methods: crystallization by solvent evaporation under reduced pressure at 50.0°C (method A), and crystallization by cooling of solution from 50.0 to 5.0°C (method B). In both cases, several aqueous ethanolic solutions of IDM of different pHs were prepared. pHs were adjusted by adding acidic solutions (HCl 2M) or alkali (NaOH or NH4OH 2M) to an aqueous ethanolic solution of IDM. Thus, several batches were recovered after crystallization. The chemical stability of IDM was verified through (1)H NMR and mass spectroscopy (FIA-ESI-MS), that revealed that IDM degraded in strong alkali media (pH ≥ 12). Crystals obtained under different crystallization conditions at pHs of 1.0, 4.5, 7.0, 8.0, 10.0 and chemically stable were thus characterized for crystal habit by scanning electron microscopy, for thermal behaviour by differential scanning calorimetry, and thermogravimetry, and for solid state by X-ray powder diffractometry. Under the Method A, IDM always crystallized into pure metastable alpha form when solutions were acidified or alkalized respectively with HCl and NH4OH. On the contrary, in presence of NaOH, IDM crystallized under a mixture of alpha and sodium trihydrate form, because the presence of the sodium counter ion orientates the crystallization towards the formation of the trihydrate salt. Under the method B, at pH of 1.0, IDM crystallized under the alpha form; at pH 4.5, IDM crystallized under the form alpha in presence of some nuclei of gamma form; at pH 7.0, 8.0, and 10.0 for NH4OH, IDM crystallized under the most stable polymorph gamma form, whereas in presence of NaOH, a mix of alpha, and salt forms was formed whatever the pH of the solution.
authors: University of Camerino, School of Pharmacy, Via S. Agostino, Camerino, Italy.
authors: Alessandra
authors: A
authors: Dubbini
authors: University of Camerino, School of Pharmacy, Via S. Agostino, Camerino, Italy.
authors: Roberta
authors: R
authors: Censi
authors: University of Camerino, School of Pharmacy, Via S. Agostino, Camerino, Italy.
authors: Valentina
authors: V
authors: Martena
authors: University of Medicine, Tirana, Faculty of Pharmacy, Street of Dibra, Tirana, Albania.
authors: Ela
authors: E
authors: Hoti
authors: University of Camerino, School of Pharmacy, Via S. Agostino, Camerino, Italy.
authors: Massimo
authors: M
authors: Ricciutelli
authors: University of Medicine, Tirana, Faculty of Pharmacy, Street of Dibra, Tirana, Albania.
authors: Ledjan
authors: L
authors: Malaj
authors: University of Camerino, School of Pharmacy, Via S. Agostino, Camerino, Italy. Electronic address: piera.dimartino@unicam.it.
authors: Piera
authors: P
authors: Di Martino
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D033362:Powder Diffraction; D011312:Pressure; D012996:Solutions; D013818:Thermogravimetry; D014961:X-Ray Diffraction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012996:Solutions; D007213:Indomethacin
keywords: Crystallization; Indomethacin; Polymorphism; pH