(M0930-01-05) Investigating Telmisartan Loaded Oral Microparticles Prepared by an Emulsion-Based Approach

Purpose: Solubility enhancement is still one of the main challenges in oral small molecule drug product development. A very high number of new chemical entities emerging from drug discovery are poorly soluble. There are existing manufacturing technologies on the market to formulate poorly soluble drugs [1]. Amorphous solid dispersions (ASDs) are a very successful approach and show the strongest growth among all solubility enhancing technologies [2]. ASDs are mainly produced using hot melt extrusion or spray-drying processes which are well-established manufacturing techniques in the market [3]. However, these processes cannot currently overcome all hurdles, like the low solubility in suitable organic solvents or the need of additional down-streaming processes to increase the flow properties of the drug product. Therefore, new manufacturing techniques are necessary to overcome some of these limitations. In this study we investigated an emulsion-based approach to produce oral microparticles for solubility enhancement of oral small molecules. Telmisartan (melting point 269°C) was used as a model drug. The ASD microparticles were characterized regarding their particle size, physical state and their solubility enhancement performance.

Methods: Preparation of telmisartan ASD microparticles: EUDRAGIT® E PO (Evonik Industries AG, Germany) and telmisartan (Hoelzel Diagnostika Handels GmbH, Germany) were dissolved in dichloromethane, representing the dispersed phase (DP). Poly vinyl alcohol (PVA, Merck KGaA, Darmstadt, Germany) was dissolved in deionized water which was used as continuous phase (CP). The CP and DP solutions were mixed to generate an emulsion using a static mixer. After mixing the solid wet particles were separated from the aqueous phase and dried. Determination of particle size & morphology: The particle size of the prepared telmisartan ASD microparticles was determined using a laser diffraction particle size detector (MasterSizer 3000, Malvern Panalytical Ltd., Malvern, United Kingdom). The microparticle morphology was observed via scanning electron microscopy (SEM) (JEOL JSM IT300, Jeol Ltd., Tokyo, Japan). X-ray powder diffraction: X-ray powder diffraction (XRPD) studies were performed to determine whether the incorporated drug telmisartan was in the amorphous or crystalline state. Analyses were run on a Cubix3 Pharma diffractometer from Malvern Panalytical Ltd. (Malvern, United Kingdom). The intensity (count) of the diffracted X-rays was recorded as a function of the diffraction angle θ and the resulting diffractogram was displayed as intensity (count) against 2θ. In vitro dissolution study: Dissolution experiments were conducted in triplicate with 25 mg telmisartan drug substance or an equivalent amount of ASD using USP apparatus II from ERWEKA GmbH (Langen, Germany). The paddle speed was set to 150 rpm. All experiments were performed in 500 mL of acetate buffer pH 4.0 (Ph. Eur.) at 37 ± 0.5 °C. The test duration was 120 min. All samples were withdrawn by a fraction collector and manually diluted 1:1 (v/v) with acetonitrile, before HPLC analysis.

Results: Uniform round microparticles could be prepared using the emulsion-based process. The final dry powder had a mean particle size of 200 µm (figure 1) and a good flowability. The spherical shape with a smooth surface and the size of the particles, measured via laser diffraction, were confirmed via the SEM measurement (Figure 2). Telmisartan remained in an amorphous state determined via XRPD after processing and three months of stability at 25°C/60%RH and 30°C/65%RH (data not shown). The in vitro dissolution profiles showed no solubility of the telmisartan drug substance, whereas the oral microparticles increased the dissolution rate up to 80% in comparison to the crystalline drug (Figure 3). The results showed that dissolution could not only be increased decisively with the new process compared to the pure crystalline drug after processing, but was also stable after three months of storage at 25°C/60%RH and 30°C/65%RH.

Conclusion: This study illustrates that oral microparticles offer a unique solution to solubility enhancement when it comes to the formulation of challenging APIs. The new process facilitated the solubilization of telmisartan and created a free-flowing powder, as indicated by the SEM measurement. The API was transformed into the amorphous state and the particles were stable over three months of storage at two ICH conditions. Further trials are necessary to investigate the pharmacokinetic properties of these microparticles.

References: [1] P. Tran et al., Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs, Pharmaceutics, 11; 3, 2019

[2] M. Crew, BIOAVAILABILITY ENHANCEMENT – Analysis of the Historical Use of Solubilization Technologies, Drug Development & Delivery, 2014

[3] S.V. Jermain et al., Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update, International Journal of Pharmaceutics 535; 379–392, 2018


Figure 1: Laser diffraction measurement (A) and scanning electron microscopy determination (B, El. Mag: 50) of telmisartan ASD microparticles.


Figure 2: Scanning electron microscopy determination (B, El. Mag: 50) of telmisartan ASD microparticles.


Figure 3: in vitro dissolution profiles of telmisartan drug substance and telmisartan ASD microparticles. 0M=initial measurement; 3M 25°/60%RH or 3M 30°C/65%RH: 3 months of storage at two ICH conditions. Each value designates the mean ± SD (n=3).