(T1530-11-75) Suitable Powder Characteristics of ASDs for Direct Compression Obtained via Spray Drying

Purpose: Globally, tablets remain the preferred route for administration because of their high stability, easy handling and easy dosing. However, direct compression (DC) of powders is in many cases not straightforward, since most of the powders do not exhibit preferred powder/particle characteristics to obtain proper powder compacts. With spray drying (SD), particle shape/size can be adjusted by applying varying process parameters, and amorphous solid dispersions (ASDs) of poorly soluble active pharmaceutical ingredient (API) can be prepared. Therefore, SD can be used to increase the solubility of APIs, and as a particle engineering technology to target specific particle and powder characteristics. The current study aimed at examining the ability to obtain the required powder characteristics for DC via SD.

Methods: For the SD experiments, an API was combined with HPMCAS-MG in different API/polymer-ratios (1/1, 1/2 and 1/3 (w/w)). Pure acetone and DCM/MeOH 1/1 (v/v) were used as solvents. A solid load of 8% (w/v) was applied. For the DC tests, the obtained spray-dried powder was blended with methylcellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate. Direct compression grades of excipients were selected. The PROCEPT 4M8-TriX spray dryer was used for spray drying, equipped with a large cyclone. The dosing speed was fixed at 8g/min. Two nozzle types were used to atomize the liquid feed, i.e. a bi-fluid (BF) with nozzle orifice 0.6mm and an ultrasonic (US) nozzle (25kHz). Additionally, inlet airflow and inlet temperature were fixed at 0.3m³/min and 75°C, respectively, and a cyclone gas flow of 400L/min was applied. Blends with spray-dried powder were compressed with a compaction simulator (STYL’one Evolution, Medelpharm) equipped with one pair of flat-faced Euro B punches of 11.28mm diameter. Compression tests were executed at different main compaction pressures with a targeted tablet weight of 400mg. Particle size distribution (PSD) and shape/morphology were evaluated via dry powder laser diffraction (RODOS-HELOS, Sympatec) and scanning electron microscopy (SEM, Phenom Pro Suite, Phenom), respectively. Solid state was evaluated with modulated differential scanning calorimetry (mDSC, DSC2500, TA instruments) and X-Ray Powder Diffraction (XRPD, Aeris diffractometer, PANalytical). Tablet’s weight and hardness were determined with a hardness tester (Sotax ST 50 hardness tester). Tensile strength was calculated based on tablet hardness.

Results: As a proper powder flowability is required to acquire an adequate die filling, it was targeted to obtain relatively large particles via SD. Therefore, two different nozzle types (i.e. US and BF nozzle), solvents (i.e. acetone and DCM/MeOH 1/1 (v/v)) and API/HMPCAS-MG ratios (i.e. 1/1, 1/2, 1/3 (w/w)) were tested. An overview of the PSD of the different formulations at 1/3 API/HPMCAS-MG (w/w) ratio can be found in Fig.1. In general, the BF nozzle resulted in smaller particles and in a broader PSD compared to the US nozzle. Moreover, it was observed that use of acetone resulted in larger particles. This can potentially be explained by the higher viscosity of the feed solution before SD when using acetone in comparison to DCM/MeOH 1/1 (v/v). SEM images (Fig.2) of the tests show wrinkled particles, regardless the test and some inflated particles were found for test1 (BF – acetone). The test with the highest particle size, i.e. US nozzle using acetone as solvent, was selected for further optimalisation of API content (i.e. 1/1 and 1/2 API/HMPCAS-MG ratios (w/w)). An API/HMPCAS-MG ratio of 1/1 (w/w) showed traces of crystalline material by mDSC analysis, while at 1/2 and 1/3 ratios (w/w) an ASD was formed, with a T_g of 54 and 98 °C, respectively. XRPD analysis were in good agreement with the mDSC results. Furthermore, PSD of both ASD powders was comparable (Fig.1, test3 vs test4), and these powders were used for DC tests. The obtained spray-dried powder (i.e. 1/2 and 1/3 API/HPMCAS-MG (w/w) ratio) was blended with the selected excipients, poured in a gravimetric feeder and compacted at different compaction pressures to obtain a tensile strength ≥ 1.7 mPa (Fig.3). With both formulations it was possible to obtain tablets with proper quality, with 1/3 API/HPMCAS-MG ratio (w/w) presenting higher tensile strength at similar main compression pressure. Further optimalisation of the excipients in the formulation may increase the tensile strength further.

Conclusion: Current study demonstrated that specific powder requirements for tableting (i.e. relative large particle size with proper compressibility) could be obtained by SD, containing ASDs. Formulations with 50% (w/w) ASD were successfully tableted.

Fig. 1: Illustration of PSD with d10, d50, d90 and SPAN values.

Fig. 2: SEM images of different tests.

Fig. 3: Tabletability plot.