CRYSTALLOGRAPHIC STUDY ON DRUGS MIXTURE OF LOPINAVIR AND RITONAVIR

• Main Author: Budi Setianto, Arif
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/34190
• Institution: Institut Teknologi Bandung

The physical treatment of active pharmaceutical ingredient and its mixture, either in a form of milling, melting, or drying is often intentionally carried out during formulation process of a dosage form in order to enhance the solubility and compactibility of the drugs. Lopinavir (LPV) and ritonavir (RTV) are anti-viral drugs and frequently used in combinations. Formulation of these combinations with exipient (copovidone, PEG, sodium stearyl fumarat) can be made by using hot melt extrusion (HME). HME consists of blending, milling, melting and reducing the particle size processes in one direction. This research challenges to reveal the interaction between LPV and RTV due to melting, milling and compacting processes. It also revealed the phase transformation between LPV- RTV and LPV with various coformer: cysteine, taurine, orotic acid, barbituric acid in acetone, ethyl acetate, diethyl eter, and cyclohexane solvent. The first step to reveal the interaction between LPV-RTV is through the mixing of LPV-RTV (1:1). Their mixture in various molar fractions are recognized using differential thermal analysis (DTA), powder X-ray diffraction (PXRD), and scanning electron microscope (SEM). The next step is grounding LPV, RTV, and their mixture (1:1) using mortar grinder for 5-60 minutes. The other batch is compressed at 37.5 - 187.5 MPa pressure. The presence of phase transformations in LPV, RTV, and their mixtures (1:1) was identified and analyzed by PXRD, Differential Scanning Calorimetric (DSC), SEM, Fourier Transfer Infrared (FT- IR), and Raman spectroscopy. After grinding more than 5 minutes produces amorphous LPV, but RTV remains crystalline, while the mixture of LPV-RTV is an amorphous and crystalline mixture as observed from the X-ray diffraction. The DSC thermogram on the LPV has melted and showed two endothermic peaks (81.13 and 99.35 o C) whereas the RTV is only a sharp endothermic peak (124.7 o C). The result of the recrystallization of melting of both in molar fractions 1:1 is above the melting temperatures, there is no phase transformation. Based on their phase diagram profile, there is no interaction between the LPV-RTV. In the grinding of the LPV, RTV powder and their mixture, there is a decrease in melting temperature except for RTV. However, the thermogram compressed mixture did not change in endothermic peaks. The 60-minute grinding of the LPV was resulted wavenumber peaks spectra IR (3374 and 1661 cm -1 ) and the broadening Raman (1664 cm -1 ) showed an amorphous pattern. While the 60 minute grinding of the RTV vibration iv do not broadening peaks on both IR and Raman spectrum. The 60 minute grinding on a mixture of LPV and RTV has the IR and Raman spectrum which belong to the combined spectra after treatment of each component. After compress strong vibrations appears at 1703 cm -1 (IR LPV), 1659 cm -1 (IR RTV) and 3357, 3329 cm -1 (IR LPV-RTV) in LPV, RTV and LPV-RTV spectrum respectively. While on the Raman spectra, there is no change observed in the spectra due to compression. The morphological changes of LPV powder, RTV, and the both mixtures were clearly shown by SEM photomicrograph after grinding over 5 min. The LPV powder surfaces that are compressed look more solid than others. Based on the above phenomenon, it shows that between LPV and RTV did not interact one to another. Therefore it was followed up with crystal engineering technic, LPV is mixed with coformer as the substitute of RTV. The mixing process is through wet mixing mechanism among the LPV with coformer. Unfortunately, the result generates a phase transformation of LPV solvate from the solvent medium. The resulting LPV solvates (LPV-acetone, -ethylacetate, -cyclohexane and -diethyl ether) were characterized using single crystal XRD and simultaneous XRD-DSC setup. They also performed compression on the solvates to determine the tabletability. The outcome of a single crystal XRD (SCXRD) characterization yields a complete crystal structure information as shown in the cif (crystallographic information file) file/data. From this cif data can be known space group and crystal system. The entrapped solvent in the LPV solvate is very difficult to remove using simple evaporation process, and was verified through the simultaneous XRD-DSC measurement except the LPV hydrate. The tabletability of LPV, RTV, the mixed of LPV-RTV, and LPV solvates vary from one to another. LPV and LPV-RTV mixtures have higher tensile strength at the same compression pressure than RTV. Incressingly of tabletability of solvate begin from LPV acetone,followed by -cyclohexane, -diethyl ether, -hydrate, and the largest was -ethyl acetate. At 30 minutes grinding, both LPV and LPV-RTV have the largest DE120. But all of DE120 from dissolution rate test were below 50% (LPV pure state, LPV- RTV, and solvate form).