#TITLE_ALTERNATIVE#

• Main Author: NOVITA NIM: 30712010, GRESSY
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/27583
• Institution: Institut Teknologi Bandung

Nimodipine (NMP) belongs to class II Biopharmaceutics Classification System <br /> <br /> (BCS) with the typical characteristics of high permeability and poor solubility. <br /> <br /> The poor dissolution behavior of nimodipine was considered as the substantial <br /> <br /> factor limiting its oral absorption and will affect the bioavailability. NMP exists <br /> <br /> into two polymorphic forms known as modification I and II (mod I and II). Mod I, <br /> <br /> available on the market, is a metastable form. Mod II is the stable form. Solid <br /> <br /> state transformation can occur in formulations due to processing, such as solvent <br /> <br /> recrystallization, milling, heating, and compression. Phase transformation could <br /> <br /> affect the physical properties such as internal structure, melting point, solubility, <br /> <br /> dissolution, and compressibility. For the active ingredients available in the form <br /> <br /> of metastable polymorphs and belonging to BCS Class II it is necessary to <br /> <br /> observe the occurrence of polymorphic transformation to ensure the quality of the <br /> <br /> final product. <br /> <br /> Efforts to increase solubility can be done by crystal engineering method. Crystal <br /> <br /> engineering through the cocrystallization process between the active ingredients <br /> <br /> with cocrystal former. Cocrystal compounds reported to improving its solubility, <br /> <br /> dissolution rate, stability, bioavailability, and compressibility properties of the <br /> <br /> active ingredients. The selection of coformer compounds and their method of <br /> <br /> manufacture greatly influences the success of the formation of cocrystal <br /> <br /> compounds. <br /> <br /> The existence of excipients and mechanical energy caused by the manufacturing <br /> <br /> process can affect the solubility and dissolution rate of the active ingredient. The <br /> <br /> rate of NMP dissolution has been reported differently for each batch of <br /> <br /> production. For problematic ingredients in the tablet dissolution is necessary to <br /> <br /> study the effect of excipients on the dissolution rate. <br /> <br /> The aim of this study was to reveal the physical phenomena that occur in an effort <br /> <br /> to improve solubility and dissolution of NMP through crystal engineering <br /> <br /> techniques using pharmaceutical coformer compounds and with the addition of <br /> <br /> excipients as diluent. <br /> <br /> This research was a multi-stage process that consisting of NMP characterization <br /> <br /> and the effect of solvent crystallization, study of thermal and mechanical energy <br /> <br /> on NMP, crystal engineering for solubility improvement starting with coformer <br /> <br /> selection, screening, and characterization of interaction, and dissolution test, the <br /> <br /> influence of excipients which function as diluent to increase solubility and <br /> <br /> dissolution rate of NMP. <br /> <br /> NMP was characterized by the matching of PXRD diffractogram, DSC <br /> <br /> thermogram, and FTIR, compared with the reference. Then the solids were <br /> <br /> subjected to the treatment of milling, heating, recrystallization at solvent, and <br /> <br /> compression. The results were characterized by PXRD, DSC, FTIR, polarization <br /> <br /> microscope, and SEM. The grinding process for 15, 30, 60, and 120 minutes does <br /> <br /> not cause polymorphic transformation in NMP solids. Solubility and dissolution <br /> <br /> rate were not significantly different. The one-hour heating process at 60, 125, and <br /> <br /> 150ºC did not result in polymorphic transformation. The process of recrystallizing <br /> <br /> through 60-minute dissolution with the aid of magnetic stirrer in organic solvents <br /> <br /> (ethanol, methanol, and acetone) leads to partial modification of polymorphic <br /> <br /> modifications I to II. <br /> <br /> The compression process of single NMP with various pressure from 4.9 to 29.4 <br /> <br /> kN did not result in polymorphic transformation, but sintering (loss of surface <br /> <br /> boundary due to particle joining) occurs on the surface and tablet fracture. The <br /> <br /> greater the compression strength, the larger the sintering occurance. As a result of <br /> <br /> this sintering, the water molecules can not penetrate the surface of the tablet so <br /> <br /> that the tablet does not disintegrate in the disintegration test. <br /> <br /> Efforts to increase NMP solubility are made through crystalline engineering for <br /> <br /> the formation of cocrystal compounds between NMP and coformers. Selection of <br /> <br /> coformer based on sinton owned. Several selected coformers were followed by a <br /> <br /> cold contact method and their PXRD measurements. From the results of screening <br /> <br /> and characterization performed, the crystals can only form between NMP with <br /> <br /> isonikotinamide (INA). The pattern of PXRD diffractogram of NMP and INA <br /> <br /> differs from the original compound. The binary phase diagram between NMP and <br /> <br /> INA shows the crystals formed at a 1: 1 molar ratio. The DSC thermogram shows <br /> <br /> a 112ºC cocrystal melting point, lower than the second melting point of the <br /> <br /> starting compound. However, the solubility test showed no significant solubility <br /> <br /> change. <br /> <br /> Based on the characterization due to compression treatment of NMP causing <br /> <br /> sintering and dissolution rate difference, a study of the effect of the existence of <br /> <br /> excipients as a filler to the rate of NMP dissolution. Preferred excipients are &#945;- <br /> <br /> lactose monohydrate and microcrystalline cellulose (MCC) with ratio NMP: <br /> <br /> excipients 10:90, 20:80, and 30:70 w/w. Tests for NMP:excipients were <br /> <br /> performed on a physical mixture, the mixture was milled, the mixture compressed <br /> <br /> into tablets, and the powder tablet. NMP and excipient mixtures were <br /> <br /> characterized by PXRD and SEM as well as dissolution tests. Diffractogram <br /> <br /> PXRD mixture showed no change or diffraction peak shift. Dissolution tests show <br /> <br /> that the greater the number of excipients used the higher the number of NMPs it <br /> <br /> isolates. Treatment in the form of milling, compression, or compression and <br /> <br /> milling combined affects the number of deformed. In general, &#945;-lactose <br /> <br /> monohydrate increases dissolution rate better than MCC in all treatments. <br /> <br /> This study has revealed the phenomenon that occurs due to the various effects of <br /> <br /> manufacturing processes on the physical properties of NMP solids. In an effort to <br /> <br /> increase the NMP solubility through crystal engineering formed between NMP- <br /> <br /> INA crystals but not yet able to improve solubility and NMP dissolution. The <br /> <br /> addition of excipient and the effect of mechanical energy to the NMP-excipient <br /> <br /> mixture can increase solubility and NMP dissolution even closer to the dissolution <br /> <br /> of innovator tablets. <br />