#TITLE_ALTERNATIVE#

• Main Author: UTAMI NIM : 30713006, DWI
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/26799
• Institution: Institut Teknologi Bandung

Non-steroidal anti-inflammatory drug (NSAID) is classified as second class of <br /> <br /> the Biopharmaceutics Classification System (BCS), which have low solubility and <br /> <br /> high permeability, therefore their bioavailability is limited. Diclofenac acid <br /> <br /> (DFA) and mefenamic acid (MFA) are two types of NSAID that are widely used in <br /> <br /> Indonesia, in addition to phenylbutason. The cocrystals formation can improve <br /> <br /> the solubility and stability of both NSAID. Based on the design strategy of homo <br /> <br /> and heterosynthon formation on DFA and MFA, both can form hydrogen bonds <br /> <br /> with nicotinamide (NIC), basic tris (TRIS) and L-proline (PRO) coformers. The <br /> <br /> cocrystals formation is expected to improve the solubility of the drug substance. <br /> <br /> This research was aimed to form the cocrystals of DFA and MFA with NIC <br /> <br /> coformers, TRIS and PRO and improve the solubility of the drug. This study was <br /> <br /> initiated by preliminary study of the cocrystal formation of the DFA and MFA <br /> <br /> with the coformer by the hydrogen bond formation. The potential interaction to <br /> <br /> formed the cocrystal was determinated its three dimensional structure. <br /> <br /> Futhermore the solubility improvement study was conducted by the aqueous <br /> <br /> solubility test compared to the drug and followed by the stability test toward <br /> <br /> temperature and humidity. In this study also observed the cocrystal formation, in <br /> <br /> order to give the comprehensive consideration, especially on the dynamics of <br /> <br /> hydrogen bond formation as a specific interaction of cocrystal. <br /> <br /> The first step of the research was a preliminary study of cocrystal formation <br /> <br /> against the DFA and MFA with NIC coformer, TRIS and PRO by milling method <br /> <br /> with solvent. The presence of the crystalline formation was characterized by the <br /> <br /> formation of hydrogen bonds determined by Fourier Transform Infra-Red (FT-IR) <br /> <br /> analysis. The result of FT-IR analysis showed four interaction drug –coformer <br /> <br /> that strongly indicated to be formed a new crystalline phase namely: DFA-PRO <br /> <br /> and MFA-NIC as cocrystals and also two salt form, namely: DFA-TRIS and <br /> <br /> MFA-TRIS. The next step was formation, isolation and characterization of drug <br /> <br /> substances - selected coformers as cocrystal. <br /> <br /> The formation and isolation of selected cocrystals was carried out by the solvent <br /> <br /> evaporation method of the mill and melt crystallization to obtain a quality single <br /> <br /> 4 <br /> <br /> crystal. The comprehensive characterization of the cocrystal were performed by <br /> <br /> FT-IR, Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction <br /> <br /> (PXRD), microscopy polarization, and Thin Layer Chromatography (TLC). The <br /> <br /> characterization by FT-IR, DSC and PXRD method indicated that the new <br /> <br /> crystalline phase of the DFA-PRO and MFA-NIC cocrystal were formed. The <br /> <br /> results of crystal isolation yielded a single DFA-PRO qualified crystal that <br /> <br /> defined a three-dimensional structure with Single Crystal X-ray Diffraction <br /> <br /> (SCXRD). <br /> <br /> The determination of a three-dimensional structure showed that DFA-PRO is a <br /> <br /> new zwitterionic cocrystal as monoclinic structure with a P21 space group. The <br /> <br /> packing crystal formed a unique double layer structure between DFA and PRO. <br /> <br /> DFA molecules form neutral molecules, while PRO is formed as zwitterion. The <br /> <br /> hydrogen bonds occured between the carbonyl functional group of carboxylic <br /> <br /> acid of DFA with the hydrogen atom in heterocyclic nitrogen functional group of <br /> <br /> PRO. <br /> <br /> The evolution of the crystalline formation by the grinding method based on PXRD <br /> <br /> analysis was initiated by the occurance of the plane through which the hydrogen <br /> <br /> bond passes. The DFA-PRO cocrystal increased the DFA solubility by 7.65 times <br /> <br /> from the drug, while MFA-NIC resulted in an increase of MFA solubility in the <br /> <br /> form of crystallites by 2.56 times. The intermolecular hydrogen bonding strength <br /> <br /> and layer form interconnect between drug substances with coformer was a factor <br /> <br /> that influenced to solubility improvement. DFA-PRO cocrystal was stable at room <br /> <br /> temperature and dissociated in high humidity. The MFA-NIC crystal was stable <br /> <br /> relatively by moisture and dissociated at high temperatures. <br /> <br /> The study was succesfully in establishing the formation method, the new threedimensional zwitterionic cocrystal structure of DFA-PRO and the improvement of <br /> <br /> the solubility properties of the drug. The study also reveals its stability against <br /> <br /> temperature and humidity as well as the evolution of the formation of cocrystal, <br /> <br /> which would be particularly useful in the development of cocrystal dosage forms. <br /> <br /> The resulting discovery is expected to contribute the development of NSAID drug <br /> <br /> preparations as well as to provide scientific information for the exploration of <br /> <br /> other NSAID drug cocrystal studies. <br />