Purpose: Only in the United States, at least one in every three people suffer of metabolic syndrome (MetS)  which is defined as a constellation of interconnected risk factors that seems to heighten diabetes and cardiovascular diseases . Therefore, it is common that a patient with MetS will suffer of hypertension, hypercholesterolemia, and diabetes at the same time. The use of combination therapy, with the aim of treating more than one disease simultaneously has emerged as a practical strategy in the formulation of more efficient drugs. Among the drugs that can be selected for the combined treatment of diabetes and cardiovascular diseases, the majority present low solubility .
Currently, there are some strategies followed to increase the solubility of drugs , including the preparation of binary co-amorphous systems [5-6] in which two drugs are combined to produce a stable amorphous formulation. Thus, for the treatment of the metabolic syndrome, this strategy can be exploited to develop a combined therapy. Two drugs widely used in the treatment of these diseases are irbesartan (arterial hypertension) and glimepiride (diabetes), both classified as class II drugs (low solubility and high permeability). Therefore, the objective of this work was to develop a binary co-amorphous system with enhanced solubility prepared by melt-quenching mixtures of irbesartan (IBS) and glimepiride (GMP). Currently, there are no previous reports of a co-amorphous system prepared with these drugs.
Methods: Co-amorphous system IBS-GMP was prepared by melt-quench technique, in mole fractions 0.01, 0.1, 0.3, 0.5 and 0.7. Thermal characterization was performed by differential scanning calorimetry (DSC), stability in the amorphous state as a function of time was analyzed by X-ray diffraction (XRD), and the dissolution profile was studied at pH 1.2 and at 37 °C. IBS and GMP solubilities were determined by high-performance liquid chromatography with SL diode-array detector (HPLC-DAD).
Results: Figure 1a shows the phase transitions of pure drugs and co-amorphous systems. Pure GMP and IBS show one endothermic peak related to melting temperature (Tm) at 215 °C and 182 °C, respectively. Both temperatures agree with melting temperature reported before for glimepiride and irbesartan. In the case of the binary systems, thermograms show the eutectic and liquidus temperatures. The eutectic composition of the system (177 °C) was found near the molar fraction xGMP=0.1. Figure 1b shows the glass transition for pure drugs and co-amorphous systems. Glass transition temperatures (Tg) measured have values higher than 40 °C for all the formulations so that the binary system is an amorphous material at room temperature. Samples were heated up to 220 °C without any signal of crystallization, therefore the co-amorphous samples are stable as a function of temperature.
The analysis of the amorphous materials by XRD as a function of time showed that the formulations were stable and did not present any crystallization signals even after 210 days of storage in a desiccator at room temperature. Figure 2 shows the formulation xGMP = 0.3, which maintains its amorphous state as evidenced by the absence of peaks in the XRD pattern which would indicate crystallization.
Results of irbesartan’s solubility demonstrate an increment of 12 times with respect to the solubility of the crystalline form (see Figure 3).
Conclusion: The results of this work showed that it is possible to obtain miscible binary co-amorphous systems with high Tg values. The stabilization in the amorphous state of different molar compositions was achieved, which were maintained without recrystallization for a long period of time. This work presents an evidence of the increase in solubility for irbesartan by developing of co-amorphous drug systems, where the components of the system not only acting as an amorphous matrix to increase the solubility but also as a drug with a specific combined therapeutic effect, thus providing an alternative treatment of metabolic syndrome. References:  M. Aguilar, et al., Jama, 313 (19). 1973–1974, 2015.  S. M. Grundy, et al., Circulation, 112 (17), 2735–2752, 2005.  G.L. Amidon, et al., Pharm. Res., 12 (3), 413–20, Mar. 1995.  K. T. Savjani, et al., ISRN Pharm., 2012, 195727.  L. M. Martínez, et al., Int. J. Pharm., 477 (1–2) 294–305, 2014.  O. Korhonen, et al., Expert Opin. Drug Deliv., 14 (4), 551–569, 2017.