THE IMPROVEMENT OF PHYSICAL CHEMICAL PROPERTIES AND TECHNOLOGY OF TELMISARTAN THROUGH CRYSTAL ENGINEERING AND EXCIPIENT ADDITION

• Main Author: Ratih, Hestiary
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/35092
• Institution: Institut Teknologi Bandung

Telmisartan (TMS) is class II drug in Biopharmaceutical Classification System (BCS) which has low solubility and high permeability. Besides having limited solubility and bioavailability, TMS also has a poor flowability which may cause problems in the manufacturing process. The purpose of this study is to obtain TMS multicomponent crystal with various co-crystal former (coformer) which could improve the physical chemical properties (solubility and dissolution) and technology (flowability and tabletability) of TMS. In addition, this study is also aimed to determine the effect of some disintegrants on dissolution and the tabletability of the formed multicomponent crystal with several treatments and compared with pure TMS and Micardis® innovator products. Telmisartan (TMS) was stable against the effects of grinding and heating. The grinding process for 15, 30, 45 and 60 minutes did not cause the TMS polymorphic transformation. The heating of TMS for one hour at 150 ° and 180 °C did not cause polymorphic transformation, while the heating of TMS at 280 °C caused TMS decomposition. The effect of pH on TMS solubility showed that TMS dissolves more easily at pH 1.2 than pH 4.5 and 6.8. The selected coformer is a carboxylic acid derivative that has a hydroxyl group as hydrogen bond donor (HBH) and a carbonyl group as hydrogen bond acceptor (HBA); oxalic acid (OXA), citric acid (CIT), fumaric acid (FUM) and succinic acid (SUC). Powder X-ray diffraction (PXRD) patterns showed that TMS formed multicomponent crystal with oxalic acid (OXA), citric acid (CIT) and fumaric acid (FUM), whereas TMS did not form multicomponent crystal with succinic acid (SUC). After multicomponent crystal formation, the characterization with Fourier Transform Infrared Spectroscopy (FTIR), polarization microscope, and physicochemical properties test such as solubility and dissolution rate were carried out. Multicomponent crystal solubility of TMS-OXA, TMS-CIT and TMS- FUM in water at 25 ° C was 11.4; 2.7; and 4.7 times higher than pure TMS, while the solubility of the TMS-SUC non-multicomponent crystal complex is the same as pure TMS. vi The next research was carried out by selecting TMS-OXA multicomponent crystal for further research. Preparation of the TMS-OXA multicomponent crystal by solvent evaporation (SE) method and Ultrasound assisted Solution Cocrystallization (USSC). The results of the TMS-OXA multicomponent crystal technology properties showed that flowability, tabletability and plasticity of multicomponent crystal prepared by using SE and USSC methods produced better results than pure TMS. The TMS-OXA SE and USSC multicomponent crystal powder could be compressed into tablets in all compression force (4.98 - 29.89 kN). TMS has a tendency of capping at a pressure above14.98 kN. A single crystal X-ray diffraction (SCXRD) was carried out to explain the multicomponent crystal structure and the data showed that the multicomponent system formed was the TMS:OXA:H2O (2:1,5:3) hydrate salt co-crystal (HSC). HSC TMS:OXA:H2O (2:1,5:3) has a triclinic crystal system with space group P - 1. The formation of the HSC TMS:OXA:H2O could cause an increase in solubility, dissolution and tabletability compared with the pure TMS. The capping tendency was not observed in HSC TMS:OXA:H2O tablets. By observing the effect of compression on physicochemical and physicomechanical characteristics, the index of crystallinity, crystallite size, FWHM of TMS and TMS:OXA:H2O HSC (SE and USSC) showed changes with increasing compression pressure. Compression may disrupt the crystal structure and trigger non-crystalline formation. ATR-FTIR spectra show the same pattern which proves that the effect of the compression pressure is not significant enough to change the crystallinity of TMS and TMS:OXA:H2O HSC. Compression did not cause polymorphic transformation. The dissolution test results of TMS tablets and SE and USSC TMS:OXA:H2O HSC tablets in various compression pressures showed that all tablets were not disintegrated on phosphate buffer media in pH 7.5. In dissolution test, sintering on tablets could affect hardness, porosity and wettability and tablet dissolution rate. One of the ways to overcome the sintering of TMS and TMS:OXA:H2O HSC tablets is by adding excipients such as disintegrant. The disintegrants used were Starch 1500 (S1500), sodium starch glycolate (SSG), microcrystalline cellulose (MCC) and croscarmellose sodium (CCS) with a ratio of TMS/HSC: disintegrant (1: 9) and (3: 7) b/b. Evaluation on the mixture of TMS:disintegrant and HSC:disintegrant were carried out in a physical mixture, the milled mixture, the mixture compressed into tablet, and the powder tablets. Characterization includes PXRD and SEM and a dissolution test was carried out and the tensile strength of the mixture of TMS/HSC:disintegrant was determined. The dissolution rate and tabletability of the mixture of HSC:disintegrant (1:9) and (3:7) are higher compared to the mixture of TMS:disintegrant (1:9) and (3:7). The combination of HSC:CCS (1:9) produced the highest dissolution rate and tabletability compared with other disintegrants in all treatments. The milled mixture treatment produced the highest dissolution with DP60 minutes which was 105.90±0.17% and 60 minutes dissolution efficiency (ED60), which was 101.09±0.48%. For the treatment of the mixture compressed into tablet and the powder tablets, the vii dissolution rate of HSC:CCS (1: 9) compared to the Micardis® innovator tablet. HSC:CCS (1:9) produces better dissolution results than innovator tablets. The study has revealed the phenomenon that occurs due to various effects of treatment on the nature of TMS solids. This study also shows that crystal engineering through the formation of TMS:OXA:H2O (2:1,5:3) HSC could improve the solubility, dissolution and tabletability of TMS. The addition of disintegrant excipients to TMS and HSC could increase TMS dissolution rate quite significantly, even HSC:CCS (1:9) provides better ED60 than the Micardis® innovator products. This study is an alternative to the development of TMS tablet formulations without using alkaline substances such as meglumine which has always been used in the formulation of innovator products to improve the dissolution.