LITERATURE REVIEW OF AMINO ACID AS A POTENTIAL COFORMER AND EXPERIMENT OF PILOT SCALE UP OF SALT COCRYSTAL DICLOFENAC SODIUM PROLINE

• Main Author: Anabella Jessica, Maria
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/56615
• Institution: Institut Teknologi Bandung

The physicochemical properties of active pharmaceutical ingredients (API), especially solubility and permeability, are the important factors that affect the bioavailability of a pharmaceutical preparation. However, most of the API that has been founded has low solubility and/or permeability. Cocrystal preparation is one of the most popular ways to modify the physicochemical properties through noncovalent interactions between API and coformer, without changing its pharmacological properties. This study summarizes the literature review on amino acids as coformers and experiments regarding the scale up of manufacture of diclofenac sodium-L-proline cocrystal (NDP) which previously reported its structure and ability to increase the solubility of diclofenac sodium by more than three times. The literature review aims to observe the development of the use of amino acids as a potential coformer that is safer than other chemical coformers while still providing the desired physicochemical properties modification. Review material is obtained from searches with search engines: Google Scholar, Pubmed, Science Direct, and ACS (American Chemical Society) Publications using the following keywords: amino acids, cocrystal, coformer, and L-proline. The collected journals were selected according to inclusion criteria, which are: national and international journals published in the last 10 years (2010-2020), discussed about cocrystal development using amino acids as coformer and their influence on the physicochemical properties of API. Amino acids are considered promising coformers due to their functional groups that can form strong hydrogen bonds from their zwitterionic groups. From the selected result, 103 journals were obtained for analysis and it was concluded that amino acids, especially L-proline (LP), are a safe coformer and support the concept of the ‘green method’and can increase the solubility, permeability, and stability of API. This is because LP is soluble in water and has a hydrotropic effect, which is the ability to dissolve hydrophobic molecules. In addition, the presence of a pyrrolidine ring causes the LP structure to be stiff which contributes to its superior stabilization ability compared to other coformers. The research was continued with laboratory experiment that aim to develope a pilot scale up method for manufacture of NDP salt cocrystal to obtain products on a bigger scale, which were then observed for their flowability and compressibility properties. Previous studies have shown that NDP can be produced by both the solvent evaporation (SE). However, scaling up using the SE method requires a lot of solvent, so it is less desirable. The solvent-drop grinding (SDG) method is preferred due to less solvent used and can produce cocrystal in a shorter time than neat grinding (NG) or SE. In this experiment, a study of NDP formation was carried out using the SDG method and the scale up was carried out with SDG method using a bender which represents a mixing device used in the medicinal raw material industry. Optimization of the amount of solvent and mixing time of the diclofenac sodium and LP components in a blender was carried out until the NDP salt cocrystal was obtained according to what had been reported. The resulting cocrystal was characterized using Fourier Transformed Infrared (FTIR), Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD), and Scanning Electron Microscope (SEM). The result of the experiment found that the SDG with conventional mortar method can be used to produce NDP salt cocrystal and the SDG-blender method produces NDP salt cocrystal with the optimal amount of ethanol (96%) of 0,5 mL/g in 2 minutes, at a rotating speed of 20000 rpm. The scale up was carried out in stages, starting from 5 g, 10 g, 15 g, and 25 g each production batch. From the various optimizations, 100 g of NDP salt cocrystal had been collected. After the cocrystal is characterized, the cocrystal formed by the SDG with conventional mortar method in small amounts and the SDG-blender method that produce up to 25 g had a melting point, DSC, and PXRD corresponding to the tetrahydrate form, similar to those previously reported. SEM observation showed that those method has the same morphology. Thus, it can be concluded that the SDG-blender method was successfully used for scaling up the formation of NDP cocrystal. The formation of cocrystal shows better flowability and compressibility properties than diclofenac sodium.