(W0930-03-15) Spray Drying of Directly Compressible Amorphous Solid Dispersions (ASDs): Comparison of Different Polymers

Purpose: Due to their high stability, easy handling and easy dosing, tablets remain the preferred oral solid dosage form. Furthermore, tableting by direct compression (DC) is a fast and “simple” process to produce a high amount of tablets. However, DC of amorphous solid dispersions (ASDs) powders, commonly prepared to increase the bioavailability of poorly water soluble drugs, is in many cases not straightforward, since most of these powders do not exhibit feasible powder/particle characteristics to obtain proper powder compacts. Spray drying (SD) is one of the most used techniques to prepare ASDs industrially. With this technology, particle shape/size can be adjusted by applying varying process parameters, suggesting that SD can be used to target specific particle and powder characteristics. The current study aimed at evaluating the ability to obtain the required powder characteristics for DC via SD, and to compare the tabletability of ASDs produced with different polymers.

Methods: Spray drying: Combinations of an active pharmaceutical ingredient (API) with different enteric (i.e. polymer A or B) or water-soluble polymers (i.e. polymer C, D or E) were prepared at different API/polymer ratios: 1/1, 1/2 or 1/3 (w/w). Materials were dissolved in DCM/MeOH 1/1 (v/v), at a solid load of 8% (w/v).
PROCEPT 4M8-TriX spray dryer was used, equipped with a large cyclone and the ultrasonic nozzle. Dosing speed was fixed at 8g/min and inlet temperature at 70°C. Direct compression: Obtained SD powder was blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate using Turbula blending (Turbula T2F). DC grades of excipients were selected. Blends were compressed with a compaction simulator (STYL’One Evolution, Medelpharm, Lyon, France) equipped with one pair of flat-faced Euro B punches of 11.28mm diameter. Compression tests were carried out at different main compaction pressures with a targeted tablet weight of 400mg. Powder and tablet characterization: Solid state characterization of the powder was evaluated via X-Ray Powder Diffraction (XRPD, PANalytical, Malvern) and modulated differential scanning calorimetry (mDSC, TA Instruments). Particle size distribution and shape/morphology was evaluated via dry powder laser diffraction (RODOS-HELOS, Sympatec) and scanning electron microscopy (SEM, Phenom Pro Suite, Phenom), respectively. Bulk density was determined with a graduated cylinder. Tablet weight and tablet hardness were determined with a hardness tester (Sotax ST 50 hardness tester). Tensile strength was calculated based on tablet hardness.

Results: To evaluate the possibility to form an ASD, polymers were combined with API in different ratios and were spray dried with standard process parameters. For 1/3 API/polymer (w/w) ratio, polymer C showed crystallinity on XRPD (data not shown). Consequently, this polymer was excluded from the study. All other polymers were further evaluated with 1/2 and 1/1 polymer/API ratio (w/w), and were found amorphous and stable. Once the highest API/polymer ratio (i.e. 1/1 (w/w)) was found amorphous, this ratio was selected to improve powder quality (i.e. increase in particle size and powder density) via SD. For all polymers, a relatively high bulk density (i.e. > 0.37g/mL) and large particles (i.e. d50 >36µm) were obtained (Fig.1). In addition, SEM images showed that wrinkled particles were obtained when enteric concepts were used while water-soluble polymers resulted in spherical particles with wrinkled surface. The obtained SD powder was blended prior to tableting with the different DC excipients, and subsequently, poured in a gravimetric feeder. Powder blend was compacted at different compaction pressures to obtain a tensile strength higher than 1.7MPa. While in a first step powder properties were optimized for 1/1 API/polymer ratio concepts, all three ratios were evaluated for tabletability for each polymer (Fig.2). Overall, proper tabletability (i.e. tensile strength >1.7MPa) with the different concepts was found. Enteric polymers resulted in an increased tensile strength for formulations with higher API load. On the other hand, water-soluble polymers showed that the different API/polymer ratios did not profoundly affect tensile strength. When comparing the different polymers at 1/1 API/polymer ratio (Fig.3), the influence of the polymer was proven, with polymer B reaching the highest tensile strength.

Conclusion: Current study demonstrated that specific powder requirements for tableting (i.e. relative large particle size with proper compressibility) can be obtained via spray drying at a high API load. Furthermore, while tablets with good tabletability were achieved by compressing spray-dried ASD, a clear influence of the polymer used on the tabletability was shown. This study reinforced the importance of having a rational selection of polymer in ASD formulation for downstream processing.


Fig. 1: D50, bulk density and morphology for 1/1 API/polymer (w/w) ratio


Fig. 2: Tabletability plot of different API/polymer (w/w) ratios: Δ=1/3; □=1/2; ○=1/1


Fig. 3: Tabletability plot of 1/1 API/polymer (w/w) ratio