(T1230-11-75) Spray Drying (SD) and Hot Melt Extrusion (HME) for the Preparation of Amorphous Solid Dispersions (ASDs)

Purpose: ASDs are the preferred approach to enhance the solubility of active pharmaceutical ingredients (APIs) suffering of poor bioavailability. These systems can be prepared by two main processes: SD (solvent-based) and HME (melt-based). However, to guarantee a successful preparation of an ASD at reasonable cost and timeline, the selection of the optimal manufacturing technique remains imperative.
In current study, use of SD and HME at early stage of drug development for the preparation of ASDs was evaluated.

Methods: For spray drying, an API and PVP VA64 in a 1/1 API/polymer ratio (w/w) were dissolved in DCM/MeOH 3/1 (v/v). A relatively low solid load of 2% (w/w) was evaluated, because of low API solubility in the used solvent. SD was executed on the PROCEPT 4M8-TriX spray dryer equipped with a large cyclone. Liquid dosing was set at 3g/min. A bi-fluid nozzle was used. Additionally, inlet airflow and inlet temperature were fixed at 0.3m³/min and 70°C, respectively. For hot melt extrusion, an API was mixed with PVP VA64 or Soluplus in a 1/5.67 API/polymer ratio (w/w). Small scale HME of the formulations (5g) was executed on the DSM micro-compounder equipped with co-rotating conical screws. An extrusion temperature of 205°C and screw speed of 100rpm were used. A larger batch (40g) was also tested. Solid state characterization was performed by mDSC and XRPD. Samples (≤5mg) were placed in Tzero pan and analyzed with a DSC 2500 (TA instruments) connected to a refrigerated cooling system unit and purged with 50mL/min of inert dry nitrogen gas. The pan was equilibrated at a temperature of 25°C before heating to 210°C at an underlying heating rate of 3°C/min. During the heating, the temperature was modulated over a period of 40s with an amplitude of 0.64°C. XRPD analysis were carried out using an automated Aeris diffractometer (PANalytical, malvern) with a Cu tube (Kα λ=1.5418Å) with the generator of 40kV and 15mA. Samples were applied on spinning zero background sample holders and analyzed in a continuous scan mode from 4° to 40° with 0.0217° step size and 500s per step counting time.

Results: To evaluate the processability of two manufacturing techniques for ASD production, PVP VA64 was chosen due to its high T_g, possibly positively influencing the system stability. First, SD was evaluated as the PROCEPT 4M8-TriX spray dryer can work with small batch sizes (60mg solids), important at an early stage of product development when limited API amount is available. Processing this formulation resulted, according to mDSC and XRPD analysis (Fig.1), in an homogeneous amorphous system with a single T_g. This result showed the ability of SD to prepare ASDs with high API load, reducing the pill burden for the patients. However, due to the low API solubility in the solvent, solely a relatively low solid load was achieved, limiting the process throughput. Therefore, parallel to the SD processing, HME was studied as a continuous manufacturing technique with higher throughput capacity. To allow comparison with SD, the same polymer (PVP VA64) was used, but an additional polymer (Soluplus) was also studied. Solid state analysis (Fig.2) showed that both formulations resulted in a homogeneous amorphous system with a single T_g. Comparing the two polymers, PVP VA64 resulted in an ASD with higher T_g (103°C vs 77°C for Soluplus), potentially increasing stability. This result showed that it was possible to form an ASD via continuous HME. Nevertheless, compared with SD, a lower API load was achieved on the ASD prepared by HME (15% vs 50% (w/w) for SD). Potential drug load increase via HME will be further examined. A larger scale HME production was performed to confirm that the product obtained via the small scale was representative. A 40g batch of the PVP VA64 formulation was extruded with 78% of recovery. Furthermore, similar solid state properties were found for both batches (Fig.3). Scaling-up this formulation to an extruder with higher throughput capacity is currently in development. Nevertheless, based on the data presented, higher ASD throughput can be obtained with HME, decreasing development and processing time – resulting in a faster time-to-market.

Conclusion: This study demonstrated that although SD remains a crucial technique for the preparation of ASDs, especially when very low amounts of API are available, HME presents advantages for further scale-up of the production.

Fig. 1: XRPD analysis of SD sample.

Fig. 2: XRPD analysis of HME samples with different polymers: PVP VA64 (blue) and Soluplus (green).

Fig. 3: mDSC analysis of hot melt extruded samples at different scales: small-scale (5g, blue) and large-scale (40g, green) – reversed heat flow.