THE EFFECT OF CO-FORMER AND TABLET EXCIPIENT ON SOLUBILITY AND DISSOLUTION OF NIMODIPINE

• Main Author: Novita, Gressy
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/33146
• Institution: Institut Teknologi Bandung

Nimodipine (NMP) belongs to class II Biopharmaceutics Classification System (BCS) with the typical characteristics of high permeability and poor solubility. The poor dissolution behavior of nimodipine was considered as the substantial factor limiting its oral absorption and will affect the bioavailability. NMP exists into two polymorphic forms known as modification I and II (mod I and II). Mod I, available on the market, is a metastable form. Mod II is the stable form. Solid state transformation can occur in formulations due to processing, such as solvent recrystallization, milling, heating, and compression. Phase transformation could affect the physical properties such as internal structure, melting point, solubility, dissolution, and compressibility. For the active ingredients available in the form of metastable polymorphs and belonging to BCS Class II it is necessary to observe the occurrence of polymorphic transformation to ensure the quality of the final product. Efforts to increase solubility can be done by crystal engineering method. Crystal engineering through the cocrystallization process between the active ingredients with cocrystal former. Cocrystal compounds reported to improving its solubility, dissolution rate, stability, bioavailability, and compressibility properties of the active ingredients. The selection of coformer compounds and their method of manufacture greatly influences the success of the formation of cocrystal compounds. The existence of excipients and mechanical energy caused by the manufacturing process can affect the solubility and dissolution rate of the active ingredient. The rate of NMP dissolution has been reported differently for each batch of production. For problematic ingredients in the tablet dissolution is necessary to study the effect of excipients on the dissolution rate. The aim of this study was to reveal the physical phenomena that occur in an effort to improve solubility and dissolution of NMP through crystal engineering techniques using pharmaceutical coformer compounds and with the addition of excipients as diluent. This research was a multi-stage process that consisting of NMP characterization and the effect of solvent crystallization, study of thermal and mechanical energy on NMP, crystal engineering for solubility improvement starting with coformer selection, screening, and characterization of interaction, and dissolution test, the influence of excipients which function as diluent to increase solubility and dissolution rate of NMP. NMP was characterized by the matching of PXRD diffractogram, DSC thermogram, and FTIR, compared with the reference. Then the solids were subjected to the treatment of milling, heating, recrystallization at solvent, and compression. The results were characterized by PXRD, DSC, FTIR, polarization microscope, and SEM. The grinding process for 15, 30, 60, and 120 minutes does not cause polymorphic transformation in NMP solids. Solubility and dissolution rate were not significantly different. The one-hour heating process at 60, 125, and 150ºC did not result in polymorphic transformation. The process of recrystallizing through 60-minute dissolution with the aid of magnetic stirrer in organic solvents (ethanol, methanol, and acetone) leads to partial modification of polymorphic modifications I to II. The compression process of single NMP with various pressure from 4.9 to 29.4 kN did not result in polymorphic transformation, but sintering (loss of surface boundary due to particle joining) occurs on the surface and tablet fracture. The greater the compression strength, the larger the sintering occurance. As a result of this sintering, the water molecules can not penetrate the surface of the tablet so that the tablet does not disintegrate in the disintegration test. Efforts to increase NMP solubility are made through crystalline engineering for the formation of cocrystal compounds between NMP and coformers. Selection of coformer based on sinton owned. Several selected coformers were followed by a cold contact method and their PXRD measurements. From the results of screening and characterization performed, the crystals can only form between NMP with isonikotinamide (INA). The pattern of PXRD diffractogram of NMP and INA differs from the original compound. The binary phase diagram between NMP and INA shows the crystals formed at a 1: 1 molar ratio. The DSC thermogram shows a 112ºC cocrystal melting point, lower than the second melting point of the starting compound. However, the solubility test showed no significant solubility change. Based on the characterization due to compression treatment of NMP causing sintering and dissolution rate difference, a study of the effect of the existence of excipients as a filler to the rate of NMP dissolution. Preferred excipients are ?- lactose monohydrate and microcrystalline cellulose (MCC) with ratio NMP: excipients 10:90, 20:80, and 30:70 w/w. Tests for NMP:excipients were performed on a physical mixture, the mixture was milled, the mixture compressed into tablets, and the powder tablet. NMP and excipient mixtures were characterized by PXRD and SEM as well as dissolution tests. Diffractogram PXRD mixture showed no change or diffraction peak shift. Dissolution tests show that the greater the number of excipients used the higher the number of NMPs it isolates. Treatment in the form of milling, compression, or compression and milling combined affects the number of deformed. In general, ?-lactose monohydrate increases dissolution rate better than MCC in all treatments. This study has revealed the phenomenon that occurs due to the various effects of manufacturing processes on the physical properties of NMP solids. In an effort to increase the NMP solubility through crystal engineering formed between NMP- INA crystals but not yet able to improve solubility and NMP dissolution. The addition of excipient and the effect of mechanical energy to the NMP-excipient mixture can increase solubility and NMP dissolution even closer to the dissolution of innovator tablets.