(M1530-03-17) Downstreaming Amorphous Solid Dispersions: Direct Compression of Free-Flowing Telmisartan Microparticles

Purpose: Solubility enhancement is still one of the main challenges in oral small molecule drug product development. 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 that are well-established manufacturing techniques in the market.³ However, these processes cannot currently overcome all hurdles. Some Active Pharmaceutical Ingredients (APIs) are sensitive to high temperatures and high mechanical stress, and at the same time, have low solubility in suitable organic solvents. These limitations can lead to low spray solution concentrations. Moreover, poor particle engineering control in these processes results in cohesive powder with inferior flow properties, so that additional down-streaming steps are needed after the formation of the ASD. However, this can stress the amorphous system and risk destabilization of the physical form. Even though spray-dried dispersions, hot-melt extrusion, and solubilizing excipients are the most common techniques for solubility enhancement, the pharmaceutical sector needs further innovations to maximize the benefits of ASDs. The use of oral microparticles offers a potential solution. The objective of this study was to investigate the benefits of ASD microparticles on the down streaming behavior for oral solid dosage formation.

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 freeze-dried.⁴ Manufacturing of tablets - Round bi-convex 10 mm tablets with an API content of 40 mg per tablet were compressed with a compression force of 10.4 kN. Tablets were prepared via a direct compression method and contained the following inactive ingredients: Avicel^® PH 102, Emcompress^® premium, Explotab^® Type A, Aerosil^® 200 Pharma and magnesium stearate. Flowability - Flowability of the microparticles has been measured with a rotational Anton Paar Rheometer MCR 502. For the measurements the samples were placed in the ring and applied with displacement speed. The torque was measured when the sample started to move. In vitro dissolution study - Dissolution experiments were conducted in triplicate 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 HCl solution pH 1.2 and 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: Microparticles showed a bulk density of 0.54 g/mL and a tapped density of 0.70 g/mL, the final tableting blend a bulk density of 0.56 g/mL and a tapped density of 0.70 g/mL. Figure 1 shows the flowability results of the rheological measurement. The data points of the microparticles clearly state that the powder is free flowing. Tablets had a mean weight of 326 mg with a relative standard deviation of 0.49%. Telmisartan remained in an amorphous state determined via XRPD after processing. Results of the dissolution study of the telmisartan tablets are detailed in figures 2 and 3. Dissolution was improved in both media, pH 1.0 and pH 4.0, demonstrating an improved solubility and no recrystallization tendency.

Conclusion: The results demonstrate that by using the new oral microparticle process EUDRATEC^® SoluFlow, it is possible to create free-flowing amorphous dispersions that can directly be pressed into tablets without further need of additional down streaming steps.

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.
4. I. Syed et al., Investigating telmisartan loaded oral microparticles prepared by an emulsion-based approach, Poster AAPS PharmSci 360 2022.


Flowability results of Telmisartan-Eudragit E100 ASD microparticles


Dissolution study of the Telmisartan tablets in 0.1N HCl (pH 1.2)


Dissolution study of the Telmisartan tablets in acetate buffer solution (pH 4.0)