(T1030-01-05) Hydrophilic Polymers in Spray Dried Amorphous Dispersions - Exploring Polyvinyl Alcohol

Purpose: Solubility of the Active Pharmaceutical Ingredient (API) is a crucial factor influencing dissolution and bioavailability. The Biopharmaceutical Classification System arranges APIs into four classes by means of solubility and permeability. APIs in class II and IV are prone to solubility issues that can lead to challenges in formulation development. Currently, around 40 % of marketed drugs exhibit solubility issues with an increasing trend: estimations show a rise of solubility issues for New Chemical Entities reaching values of 90 % [1]. This number indicates that addressing solubility issues is not only a challenge we are currently facing but will be more prominent in the future. Solubility can be enhanced by the disruption of the crystalline lattice of the API. This results in a higher energy form, which, on the one hand shows higher solubility but, on the other hand is less stable. The amorphous state of a crystalline drug can be generated by dissolving and rapid drying with auxiliary materials added for further stabilization. Therefore, polymers are widely used to introduce a matrix in which the amorphous state can be stabilized [2]. This kind of product may be obtained by spray drying the respective API with one or more fitting polymers. The pool of polymers to choose from is vast [3]. Polyvinyl alcohol (PVA) is a polymer that is known to significantly increase solubility of poorly soluble APIs and has been intensively studied in Hot Melt Extrusion processes [4]. Here we would like to show the applicability of PVA in spray drying applications. For this, Indomethacin (IND), a BCS II API, is used. A dedicated three-fluid nozzle technology is evaluated to allow the creation of ASDs using rather hydrophilic polymers. This enables a new method of manufacturing and extends available polymers applicable to the process.

Methods: Spray drying: All drug-polymer combinations were spray dried with a Buchi B295, using Nitrogen as the spraying gas (670 l/min), an inlet temperature of 90 °C and outlet of 50 °C with 35 m³/h at 100 % Aspirator rate. The drug loading is 30 % w/w, respectively. Parteck^® MXP 3-82, MXP 4-88, PVP K30, and a PCL-PVAc-PEG grafted co-polymer: Indomethacin (IND) is dissolved in acetone and deionized water in a ratio of 7:3. The polymers are dissolved in water. A three-fluid nozzle is used, the inner feed forwarding IND solution, the outer feed forwarding the polymer solution. HPMC-AS: IND and HMPC-AS are dissolved in acetone and deionized water in a ratio of 7:3. The solution is sprayed using a two-fluid nozzle.Dissolution: Dissolution of 25 mg IND is performed on a SOTAX AT7 smart (SOTAX AG, Germany) in 900 ml SGF at 75 rpm and 37 °C; UV detection is performed at 318 nm.XRPD: Diffractograms of powders were measured using an Miniflex 600 X-ray diffractometer (Rigaku, Japan) with CuKα radiation (λ = 1.54 A). Samples were scanned in reflectance mode from 3˚ to 50˚ 2θ (deg), with a scan speed of 10˚ 2θ (deg)/min and a step size of 0.020˚ 2θ (deg). The acceleration voltage and current are 45 kV and 15 mA.

Results: Dissolution measurements: As seen in the dissolution data presented in Fig. 1 is the release of crystalline IND is severely limited. Only 0.7 mg/l of IND are found in the dissolution medium after 120 minutes whereas the spray dried dispersion using PVA 3-82 shows a tenfold increase in release at the final timepoint followed by PVA 4-88. The maximum peak of drug release from the ASD using PVA 3-82 is reached after 15 minutes with dissolution of 15 mg/l that only gradually decreases over time. XRPD measurements: The amorphous state of IND is determined using XRPD in comparison to the crystalline substance as shown in Fig. 2. While dominant peaks at 19.6, 21.8 and 29.5 °2θ indicate the crystalline state, these sharp signals are not present in the spray dried drug-polymer samples using PVA 3-82, PVA 4-88, grafted co-polymer and HPMC-AS demonstrating the amorphous state. Only the PVP K30 sample shows an incomplete transition from the crystalline to the amorphous state.

Conclusion: This work shows how polyvinyl alcohol can be used as an excipient for the creation of spray dried amorphous solid dispersions. In the dissolution study with the poorly soluble API Indomethacin, PVA 3-82 was able to enhance dissolution, showing a fast onset as well as ensuring high release values of IND over the time of 120 minutes highlighting its application for prolonging the supersaturated state of low soluble compounds in solution.

References: 1. Loftsson, T. and M.E. Brewster, Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol, 62 (11), 1607 – 1621 (2010)
2. Bhujbal, S.V., Mitra, B., Jain, U., Gong, Y., Agrawal, A., Karki, S., Taylor, L.S., Kumar, S., Zhou Q. Pharmaceutical amorphous dispersion: A review of manufacturing strategies. Acta Pharm. Sin B, 11 (8), 2505 – 2536 (2021)
3. Ziaee, A., Albadarin A.B., Padrela, L., Femmer, T., O’Reilly E., Walter, G. Spray drying of pharmaceuticals and biopharmaceuticals: critical parameters and experimental process optimization approaches, 127, 300 – 318 (2019).
4. Shadambikar, G., Kipping, T., Di-Gallo, N., Elia, A.G., Knuettel, A.N., Treffer, D., Repka, M.A., Vacuum Compression Molding as Screening Tool to Investigate Carrier Suitability for Hot-Melt Extrusion Formulations. Pharmaceutics, 12 1019 (2020)

Figure 1. Dissolution of Indomethacin and respective IND-ASDs in SGF with 30 % drug loading

Figure 2. XRPD of Indomethacin and respective IND-ASDs