EFFORT TO IMPROVE MICROMERITIC, MECHANICAL, AND DISSOLUTION BEHAVIOR OF RAMIPRIL THROUGH SPHERICAL COCRYSTALLIZATION TECHNIQUE

• Main Author: Indra
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/81195
• Institution: Institut Teknologi Bandung

Ramipril, a medication prescribed for hypertension and cardiac insufficiency, functions by inhibiting the angiotensin-converting enzyme (ACE). Due to its restricted dissolution in the gastrointestinal tract and inadequate bioavailability (28–35%), its solubility in water is limited to 3.5 µg/mL. Previous approaches, such as Liquid and Solid Self-Emulsifying Drug Delivery Systems (L/S-SNEDDS), exhibited limitations, including degradation, capsule leakage, incompatibility with capsule shells, and the possibility of drug precipitation during the process of manufacture and storage. Consequently, ramipril crystal engineering is gaining traction as a means to improve the standard of pharmaceutical ingredients. Spherical cocrystallization, an approach within the field of crystal and particle engineering, modulates the size and shape of particles in order to enhance the micromeritic and physicochemical characteristics of active pharmaceutical particles. Recognizing and comprehending the principal elements that impact the development of spherical cocrystal aggregates, along with their foundational mechanisms, enables the production of spherical cocrystal aggregates with superior size, form, and density. Consequently, this enhances the flow properties, compressibility, and dissolution rate of the product. This study aims to: (i) evaluate molecular complementarity and hydrogen bonding in coformer screening, (ii) utilize principal component and cluster analysis for identifying RA cocrystals, (iii) examine the impact of stirring speed and solvent volume on spherical RA agglomerate formation, and (iv) develop spherical cocrystallization techniques to improve ramipril's micromeritic and dissolution properties. Concerning molecular complementarity (MC) and hydrogen bonding propensity (HBP), the investigation commenced with coformer screening utilizing Cambridge Structural Database (CSD) software. Spherical agglomerates were generated through the suspension of the precipitate resulting from ramipril interactions in a solvent mixture comprising favorable, unfavorable, and intermediary solvents. The characterization techniques employed encompassed Differential Scanning Calorimetry, polarizing and Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Powder X-ray diffraction, as well as solubility and dissolution tests. The micromeritic and mechanical characteristics of the agglomerates were evaluated by conducting tensile strength tests and analyzing iv particle size distribution, bulk density, tapped density, Carr's Index, and Hausner Ratio. These properties were then compared to those of the raw ramipril. The results of the MC and HBP analyses revealed that the delta propensities of coformers AA, BIP, HIPA, FUM, VA, and BENZ are equal to or greater than zero, suggesting the possibility of cocrystal formation with RA. Additional investigations utilizing PCA and CA on the FTIR spectrum of RA and its cocrystallization products unveiled that RA-AA, RA-VA, and RA-BIP demonstrated cocrystal formation. In contrast, RA-BENZ, RA-FUM, and RA-HPA failed to generate cocrystals. At the same time, RA-AA, RA-VA, and RA-BIP indicated cocrystal formation. This finding was supported by powder X-ray diffraction patterns, DSC-TGA thermograms, and Kofler analysis, all confirming that RA forms cocrystals with coformers AA, VA, and BIP. These cocrystals showed an increase in solubility compared to raw RA. Micromeritic property evaluation of RA-VA and RA-AA spherical cocrystals showed a significant improvement in flow properties, marked by lower and consistent angle of repose values, in line with the particle morphology observed through SEM. Further evaluation revealed that RA-AA cocrystals have a superior tabletability profile compared to standard RA and RA-VA cocrystals. The RA-AA cocrystal tablets exhibit satisfactory tensile strength values (> 2 MPa) when subjected to low compression pressures. The contact angle study indicated that RA-AA cocrystals had significantly reduced, signifying enhanced wettability and hydrophilic characteristics compared to raw RA and RA-VA cocrystals. Furthermore, RA-AA showed superior solubility and dissolution rates, aligning with the observed reduction in contact angles and implying increased hydrophilic interactions and surface-wetting capabilities.