IMPROVEMENT OF PHYSICOCHEMICAL AND TECHNOLOGY PROPERTIES OF DESLORATADINE VIA MULTICOMPONENT CRYSTAL ENGINEERING

• Main Author: Ainurofiq, Ahmad
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/34311
• Institution: Institut Teknologi Bandung

Active pharmaceutical ingredients are challenged by commercialization and development due to unfavorable physicochemical and physicomechanical properties. Desloratadine (DES) is used to treat allergic rhinitis, urticaria and generally as an important anti-histamine drug, and it has unsatisfactory mechanical properties and a low solubility. Especially, DES mechanical properties manifested by capping occur during the tableting process. Crystal engineering through multicomponent crystal manufacturing is known to improve the deficiency of mechanical properties, this is due to the role of molecular manipulation in the crystal lattice which have an important role in the design of materials for easy tabletation. To date, no crystal engineering approach has been reported to address the unfavorable problems of DES. The purpose of this study is to obtain multicomponent crystals from DES with various coformers, whose synthesis is able to overcome poor tabletability, low solubility, and improve dissolution rates. In addition, this research is also to find out the phenomenon of co-amorphization to improve dissolution rates, solubility, and stability of DES. This research is also to find out the effect of treatment that usually occurs during manufacturing including: the effect of solvent, grinding, heating, and compression pressure on some possible changes in the physicochemical properties of DES and multicomponent crystals, especially polymorphic transformations. Multicomponent crystal synthesis was carried out between DES and 26 coformers at a 1: 1 molar ratio using the solvent evaporation method and 12 types of solvents used. The results of multicomponent crystal manufacturing are evaluated by a polarized light microscopy, if a new crystal habit is formed which is different from DES and the coformer, it shows the prediction of the formation a new multicomponent crystal compound. This possibly newly formed component is soon characterized using: powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and stability evaluation. Determination of multicomponent crystal structures is done using single crystal X-ray diffraction (SCXRD), which is then evaluated of its physicochemical properties which includes solubility and dissolution rate. The physicomechanical properties are evaluated for its tabletability (tensile strength), flowability and compressibility (Carr index and Hausner ratio), elasticity (elastic recovery), and the determination of the slip plane. In this study, a co-amorphous substance from DES and benzoic acid (BA) using melt-quenching method was prepared and characterized using DSC, FTIR, PXRD, and a polarized light microscopy. Dissolution profile, solubility, and physical stability of the DES-BA co-amorphous substance were determined. Further studies are held to evaluate DES and multicomponent crystals from the effect of solvents, grinding, heating, and compression pressure on physicochemical properties characterized by PXRD, FTIR, DSC, SEM, and solubility evaluation. The results of examination of DES raw materials showed form I polymorph based on the confirmation results of FTIR, XRD, and DSC. Only one coformer, benzoic acid (BA) successfully formed a multicomponent crystal. The results of all DES- BA characterizations indicate the formation of a new solid crystalline phase, which is different from the individual DES and BA components which ensure the formation of multicomponent crystals. The stability of multicomponent crystals observed with PXRD and FTIR in accelerated conditions for 4 months at a temperature of 40 ° C / RH 75% showed a stable result with no pattern changes compared to its condition before experimentation. Single crystal structure analysis revealed that this new multicomponent crystal was categorized as salt because of the transfer of protons from BA to DES molecules. With the formation of multicomponent salt crystals, it has been shown that the tabletability and plasticity of multicomponent crystals increases and is different from the parent drug. In addition, the tendency of capping and lamination was not observed in DES-BA multicomponent crystals. The existence of layered structures and slip plane from multicomponent crystals is associated with improvements in tabletability, which is not present in DES. DES-BA in this case showed increased solubility in water and 0.1 N HCl, and has better dissolution profile. Analysis proved that DES-BA co-amorphous substance has been formed perfectly and homogeneously. The DSC experiment showed that the glass transition temperature (Tg) of the co-amorphous DES-BA had a higher single Tg than the amorphous DES. FTIR revealed strong interactions, especially in salt formation. The dissolution rate and solubility of co-amorphous DES-BA (1: 1) is greater than that of DES crystals. Physical stability examination for 3 months at 40 ° C with 75% RH showed that co-amorphous DES-BA was more stable than a single form of amorphous DES. The effect of compression pressure on physicochemical and physicomechanical characteristics shows relatively small changes of DES crystallinity and multicomponent crystals which are represented by degree of crystallinity, crystallite size, and FWHM. The value of changes in crystanillity in DES is greater than that of multicomponent crystals with increasing compression pressure. ATR-FTIR spectra show the same pattern, it proves the effect of the compression pressure is not significant enough to change the crystallinity of DES and multicomponent crystals. Compression does not cause polymorphic transformation. SEM observations showed a tendency for inter-particle attachment to DES, which did not occur in multicomponent crystals. Tabletability of DES and multicomponent crystals, when linked, are more influenced by internal factors in the form of slip plane, while external factors in the form of relative compression pressure do not affect the results of tabletability. Polymorphic transformation occurs in DES, but does not occur in multicomponent crystals. Multicomponent crystals are stable from the effects of solvent, heating, grinding and compression. The DES transformation process is triggered by the effect of recrystallization with different solvents producing different polymorphs, and evaporation of the solvent accompanied by heating also causes polymorphic transformation. The grinding process has induced polymorph I transformation to polymorph II. The effect of heating has initiated the formation of polymorph II from polymorph I, although the result is a mixture of both polymorphs. The final result shows that DES-BA multicomponent crystals can improve tabletability, solubility, and have good stability. Meanwhile, the formation of coamorphous DES-BA has shown the potential to improve stability, improve solubility and dissolution. However, in comparison, multicomponent crystals are more stable. Evaluation of the grinding, solvent, heating and compression pressure processes showed that multicomponent crystals does not undergo polymorphic transformation, while DES does. This study shows that DES-BA multicomponent crystals can be developed in the direction of formulations that are physicochemical and physicomechanical feasible.