Formas sólidas de cetoprofeno: obtenção, caracterização e avaliação da influência na qualidade de ingredientes farmacêuticos ativos

Abstract

Ketoprofen is an Active Pharmaceutical Ingredient (API) that has low solubility in aqueous solvents. Furthermore, it presents other challenges related to its pharmacological properties, such as: the need to reduce gastrointestinal side effects and short elimination half-life. Various formulation strategies have been used to deal with these problems, like injectable preparations for rapid release, suppositories, and enteric coatings to decrease gastrointestinal effects, and controlled-release dosage forms to circumvent short elimination half-life problems. On the other hand, the use of salts and co-crystals of ketoprofen has always attracted substantial interest, due to the possibilities of improvements obtained regarding tolerability and solubility, with rate and extent of absorption increase, and onset of the therapeutic effect reduction. Therefore, the aims of this research were to carry out studies of ketoprofen solid-state obtention, characterization, accelerated stability and solubility. Initially, two analytical methods were validated for application in the study: a spectrophotometric method and a HPLC method. The HPLC method showed better results in selectivity, precision, and accuracy, which was chosen for the other tests. Two solid forms with crystal structures not reported in the Cambridge Structural Database (CSD) were obtained: the sodium salt of ketoprofen (CETNa) and a cocrystal of ketoprofen and saccharin 1:2 (CET_SMPT_SAC_5). The samples were characterized by X-ray powder diffraction (XRDP), infrared spectroscopy (IR) and thermal analysis (TG and DSC) studies. In addition, accelerated stability and solubility tests were performed. However, although the cocrystal of ketoprofen and saccharin 1:2 has been characterized, its achievement was not reproducible, making it impossible to carry out solubility studies in the sample. Solubility studies in CETNa demonstrated that its solubility in water was about 80 times greater. Nevertheless, CETNa presented stability problems compared to CETMP, where CETNa had a lower content after 3 months of testing under the experimental accelerated stability conditions. It also showed amorphization in stability studies and after sieving, which are disadvantageous factors. Therefore, it was not possible to propose a solid pharmaceutical form for oral use for this salt. However, characterization studies of different solid forms of APIs are fundamental to contribute to aspects related to the quality, safety and efficacy of medicines.