Estudo estrutural e físico-químico de formas sólidas da buclizina

Abstract

The search for Active Pharmaceutical Ingredients (APIs) with greater solubility has motivated several studies involving Crystal Engineering of drug molecules. Approximately half of the solid formulations have the API in salt form due to the low solubility that their free acids and bases normally exhibits. In this context, the studied drug in this dissertation is Buclizine (BCZ), which has antihistaminic, antimuscarinic, antiemetic and orexigenic activities. The presence of the piperazine ring in its chemical structure allows the BCZ to be present in solution or in the solid state as neutral species (BCZ free base), monoacid (BCZH+) or diacid (BCZH22+). Although it has been marketed for more than 60 years as the chloride salt of its diacid species (BCZH2Cl2). There is so far no determined structure for any solid form of BCZ; and neither classification in the Biopharmaceutical Classification Sy3stem (BSC), being the BCZ only referred as a low solubility API. Therefore, the objective of this work was to elucidate the crystalline structure of BCZH2Cl2, as well as other crystalline variations of BCZ, including its monocomponent form (anhydrous free base), multicomponent forms (salts, cocrystals, hydrates / solvates) and polymorphs. Additionally, we aimed to correlate the structures of the forms obtained with properties of pharmaceutical interest, such as solubility, dissolution profile and stability. Three solid pH-dependent variations of BCZ were obtained: the free base BCZ (BCZ-FB), the BCZ monohydrochloride (BCZHCl) and the BCZ dihydrochloride (BCZH2Cl2). The three forms were systematically characterized by Powder X-ray diffraction (PXRD), Infrared spectroscopy (IR), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) techniques. Moreover, the structures of BCZHCl and BCZH2Cl2 were determined using the Single crystal X-ray diffraction technique (SCXRD). The results of the crystallographic determination allowed to conclude that the two salts obtained crystallize as a physical mixture of their optical isomers R and S and not as racemic crystals. Tablets containing BCZ-BL, BCZHCl and BCZH2Cl2 were individually produced and their quality was evaluated according the hardness, friability, average weight, assay and uniformity. For the quantification of BCZ in the assays of uniformity, stability, solubility and dissolution profile, were used a previously developed high performance liquid chromatography (HPLC) method partially validated in this dissertation. The solubility equilibrium in ultrapure water and pH 4.5 buffer showed that BCZH2Cl2 is more soluble than BCZHCl, followed by BCZ-FB, reversing the trend observed in the media HCl 0.1 and 0.01 mol L -1. Above pH 4.5, all the forms were insoluble. Dissolution profiles performed in acetate buffer pH 4.5 + 1.0% sodium lauryl sulfate showed differences between the formulations. The stability study carried out at 40 ° C and 75% relative humidity showed that the content of BCZ in the tablets, with the different crystalline forms prepared in this work, remained stable.