Section Overview Poor solubility of active pharmaceutical ingredients (APIs) remains a significant hurdle in drug development as it limits bioavailability. Enhancing API solubility can be approached through various methods, such as promoting API dissolution, API processing, and applying advanced formulation strategies such as hot-melt extrusion and spray drying. Need expert guidance? Reach out to our specialists to explore formulation solutions.
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Spray drying is a technique used to enhance the solubility and bioavailability of poorly water-soluble drug substances through the creation of amorphous solid dispersions (ASD). These formulations consist of an API dispersed within a polymer matrix, resulting in a homogeneous amorphous mixture. However, ASDs are inherently unstable and can recrystallize over time, necessitating the maintenance of the amorphous state. Spray drying addresses this challenge by transforming a solution, suspension, or emulsion into a dry powder. During the process, the solvent is rapidly evaporated from the solution containing the API, embedding it within a polymeric carrier matrix. This stabilizes the amorphous state and prevents recrystallization, thereby enhancing the solubility and bioavailability of poorly soluble APIs.1 Figure 1 provides an overview of the spray drying process. The API and polymer can be fed into drying chamber either in a single solvent (a two-fluid nozzle set-up), or via individual solvents in a three-fluid nozzle set-up. In the drying chamber, droplets containing the API and polymer are formed at the tip of the nozzle and are rapidly dried within milliseconds by a stream of hot gas. The resulting dry amorphous solid dispersion is then collected in the collection vessel. The three-fluid nozzle approach provides formulators with the flexibility to use different solvents for the polymer and API, thereby expanding formulation options.2What is Spray Drying?
Figure 1.Schematic of the spray drying process.2
This article describes the advantages of spray drying for enhancing API solubility and highlights the use of Parteck® MXP polyvinyl alcohol (PVA) polymers (Parteck® MXP 4-88 and Parteck® MXP 3-82 excipients) in the process. It also provides examples demonstrating how these polymers can improve the solubility of both small and large drug molecules. Spray drying is a versatile and efficient formulation strategy offering a range of benefits for pharmaceutical applications including: Similar to other solid dispersion applications, polymers are used to form a matrix during the spray drying process, in which the API is molecularly dispersed. Common polymers used in this process include cellulose derivatives, polyacrylates and polymethacrylates, polyethylene glycols, and polyvinyl pyrrolidone (PVP). Recently, PVA has been highlighted as being well-suited for spray drying due to its amphiphilic nature, stable high drug loads, and optimized hydrolysis grade.2 PVA, a synthetic, chemically defined polymer widely used in biopharmaceutical formulations, is well-suited for use in spray drying applications. It is produced through the polymerization of polyvinyl acetate followed by partial hydrolysis, resulting in a polymer with both hydrophilic (hydroxyl) and hydrophobic (acetate) groups (Figure 2). By fine-tuning the degree of hydrolysis, the amphiphilic nature of PVA can be optimized for specific applications. Its GRAS (Generally Recognized as Safe) status and long history of use in the biopharmaceutical industry provide further assurance of safety and compliance. These properties minimize risks in drug development and manufacturing while supporting formulation flexibility, particularly in controlling dissolution kinetics.Advantages of Spray Drying
Polymers for Spray Drying
Polyvinyl Alcohol (PVA) as a Spray Drying Polymer
Figure 2.PVA is produced by the polymerization of vinyl acetate and the subsequent partial hydrolysis of the polyvinyl acetate to polyvinyl alcohol.
While the Parteck® MXP series of PVA polymers was originally designed for HME applications, they have proven to be exceptionally well-suited for spray drying processes as well. This versatility highlights their effectiveness and adaptability in various formulation techniques with the following key characteristics for each Parteck® MXP grade. Spray drying processes rely heavily on the viscosity of polymer solutions. Low-viscosity polymer solutions allow for a broad processing range and high drug-loading capacities. PVA provides low viscosities even at high concentrations, in contrast to other polymers such as cellulose derivatives, which can show a concentration-dependent viscosity increase (Figure 3A). Scanning electron microscopy (SEM) highlights the morphological advantages of Parteck® MXP excipients. At 15% polymer concentration, Parteck® MXP 3-82 PVA forms homogeneous particles with excellent flowability and compressibility, essential for efficient downstream manufacturing (Figure 3B).Viscosity in Correlation to Polymer Concentration
Figure 3.Comparison of various polymers suitable for spray-drying applications: A) Viscosity profiles at 0–15% (w/w) polymer concentration and B) SEM images of polymer particles manufactured using a 15% (w/w) concentration.
Learn more about the use and advantages of PVA for spray drying in the webinar: Unleashing the Potential for Polyvinyl Alcohol in Spray Drying for Oral Solid Dosage Forms
Case Study: Enhancing the Solubility of Small Molecules with Spray Drying
With use of either Parteck® MXP 3-82 excipient or Parteck® 4-88 excipient in the spray drying process, small molecules are not only stabilized in the ASD but also exhibit improved solubility in solution. This dual benefit makes PVA an ideal choice for formulating challenging small molecule drugs. Indomethacin, a small molecule drug with low solubility in the gastric environment was used to demonstrate the benefit of spray drying with PVA.Parteck® MXP 3-82 and 4-88 as well as PVP K30 and the grafted copolymer are dissolved in distilled water. The API is dissolved in Acetone. The two solutions are spray dried separately using a three fluid nozzle. HPMC-AS and the API were dissolved together in methanol. The solution is spray dried using a two fluid nozzle. X-ray powder diffractograms shown in Figure 4 include the crystalline API (pink trace) and spray-dried dispersions with Parteck® 3-82 and Parteck® 4-88 excipients, and other commercially available polymers suitable for the spray drying process, all with a 30% drug load. All spray-dried dispersions were amorphous, except for those with PVP K30, which retained some crystallinity. In simulated gastric fluid, the API showed almost no dissolution. In contrast, the spray-dried dispersions, especially those made with PVAs, demonstrated significant solubility enhancement. The Parteck® MXP 3-82 excipient formulation, in particular, exhibited a pronounced "spring-and-parachute" effect, characterized by rapid dissolution onset and sustained stabilization of solubilized material.Improving the Solubility of Indomethacin
Figure 4.A) The dissolution profile and B) X-ray powder diffraction (XRPD) of 30% indomethacin in different polymeric matrices in acidic conditions.
Method description: Buchi B-290 (Büchi Labortechnik AG, Flawil, Switzerland); 90 °C inlet temp; 50 °C outlet temp; drying air flow 35 m3/h; atomization air flow 670 L/min (N2: 55 mm); Dissolution method: paddle apparatus, SGF, 75 rpm, 318 nm)
Figure 5 shows the dissolution behavior of ketoconazole, a small molecule drug with low solubility mainly in the intestinal environment. Parteck® MXP 3-82 and 4-88 as well as PVP K30 and the grafted copolymer are dissolved in distilled water. The API is dissolved in Methanol. The two solutions are spray dried separately using a three fluid nozzle. HPMC-AS and the API were dissolved together in methanol. The solution is spray dried using a two fluid nozzle. Based on the X-ray diffractogram, spray-drying led to amorphization for all of the spray-dried dispersions, except PVP K30. Dissolution in fasted state simulated intestinal fluid (FaSSIF) demonstrated solubility improvement with spray-drying and a fast onset for all polymers and stabilization of the supersaturated state. Dissolution enhancement at an intestinal pH was most pronounced with HPMC-AS.Improving the Solubility of Ketoconazole
Figure 5.Dissolution profile of 30% ketoconazole in different polymeric matrices in physiological conditions.
Method description: Buchi B-290 (Büchi Labortechnik AG, Flawil, Switzerland); 90 °C inlet temp; 50 °C outlet temp; drying air flow 35 m3/h; atomization air flow 670 L/min (N2: 55 mm); Dissolution method: paddle apparatus, FaSSIF, 50 rpm, 291 nm.
By taking a closer look and mimicking the transition from the gastric to the intestinal environment with a pH shift from 1 to 6.8, only Parteck® MXP 3-82 excipient inhibited recrystallization and improved solubility (Figure 6). HPMC-AS resulted in lower concentrations of dissolved API overall, even compared to the pure crystalline API, and a rapid decrease to zero following the pH shift, probably due to recrystallization.
Figure 6.Dissolution profile of 30% ketoconazole in Parteck® MXP and HPMC-AS matrix mimicking the intestinal environment.
Additional studies presented in the spray drying webinar include an assessment of the amorphous stability of the marketed drug ritonavir. The dissolution behavior of ritonavir was studied in spray-dried dispersions of Parteck® MXP 3-82 excipient with drug loads ranging from 30% to 70%. At all drug loadings, PVA-based spray-dried dispersions exhibited improved dissolution profiles compared to the crystalline drug (Figure 7). The greatest dissolution enhancement occurred at a 40% drug load, which is very high compared to marketed formulations. While higher drug loadings led to a slight decrease in dissolution enhancement, notable improvements were observed, with spray-dried dispersions achieving dissolution at drug loads as high as 60–70%.Improving the Solubility of Ritonavir
Figure 7.Dissolution of Ritonavir with different drug loading concentrations in combination with Parteck® MXP 3-82 excipient.
Method description: Buchi B-290 (Büchi Labortechnik AG, Flawil, Switzerland); 100 °C inlet temp; 60 °C outlet temp; drying air flow 35 m3/h; atomization air flow 670 L/min (N2: 55 mm); Dissolution method: paddle apparatus, FaSSIF, 50 rpm, 215 nm
While other polymers have also been shown to support high drug loadings of spray-dried dispersions, Parteck® 4-88 and specifically MXP 3-82 polyvinyl alcohols deliver the strongest dissolution enhancements, with a superior performance at high drug loadings paired with high processing yields and good stability compared to other polymers.
The dissolution profile of a spray-dried ritonavir dispersion with Parteck® MXP 3-82 excipient was also compared to a marketed ritonavir formulation. Both displayed rapid dissolution onset; however, only the spray-dried Parteck® MXP 3-82 dispersion exhibited prolonged supersaturation and long-term stabilization, demonstrating the benefits of the spray-drying process.Summary
Case Study: Enhancing the Solubility of Novel Therapeutic Modalities
Spray drying also offers significant advantages for formulation of large biomolecules, addressing key challenges such as solubility and stability. PVA enhances solubility and effectively stabilizes these molecules within amorphous solid dispersions, ensuring their structural integrity and functional activity. One novel application of spray drying that may have great potential is for molecules designed for targeted protein degradation such as proteolysis-targeting chimeras (PROTACs). PROTACs are heterobifunctional molecules with the potential to address undruggable targets. They typically have a molecular size of approximately 500 – 1,500 Dalton, can be orally dosed, and can have unfavorable properties such as low solubility or low permeability. PROTACs continue to gain traction among drug developers due to their potential for addressing what have been considered to be undruggable targets. The case studies summarized below describe the use of spray drying with Parteck® MXP 3-82 excipient as an innovative formulation strategy to improve and optimize delivery and efficacy of PROTACs, paving the way for their successful application in clinical settings. Arvinas-110 (ARV-110) is a PROTAC currently in clinical trials for castration-resistant prostate cancer and has low solubility in a physiological environment. The dissolution behavior of ARV-110 was studied in spray-dried dispersions of Parteck® MXP 3-82 PVA was dissolved in water and the ARV-110 was dissolved in a solvent mixture of Dichlormethan and Methanol (40:60) using a three fluid nozzle. This spray-dried dispersion was compared to the crystalline PROTAC and a physical mixture of PVA and the PROTAC. As shown in Figure 8, dissolution performance and solid-state profile were stable for a minimum of four weeks at both cold (5 °C) and ambient conditions (25 °C/60% rH). Dissolution studies in phosphate buffer (pH 6.8) revealed limited dissolution for the ARV-110 while the physical mixture with Parteck® MXP 3-82 excipient exhibited a slight improvement, highlighting the inherent ability of PVA to enhance solubility.Improving the Solubility of ARV-110
Figure 8.Dissolution and stability of 30% PROTAC ARV-110 in Parteck® MXP 3-82.
Method description: Buchi B-290 (Büchi Labortechnik AG, Flawil, Switzerland); 85 °C inlet temp; 45 °C outlet temp; drying air flow 35 m3/h; atomization air flow 670 L/min (N2: 55 mm); Dissolution in phosphate buffer pH 6.8).
SelDeg51 is a PROTAC that targets the degradation of FK506-binding protein 51, a key regulator of the glucocorticoid receptor. It exists in an initial amorphous state and has low aqueous solubility. The dissolution behavior of SelDeg51 was studied in spray-dried dispersions of Parteck® MXP 3-82 excipient with a 30% drug load in methanol. SelDeg51 is a PROTAC that targets the degradation of FK506-binding protein 51, a key regulator of the glucocorticoid receptor. It exists in an initial amorphous state and has low aqueous solubility. The dissolution behavior of SelDeg51 was studied in spray-dried dispersions of Parteck® MXP 3-82 excipient dissolved in water and SelDeg51 dissolved in methanol with a 30% drug load. A three fluid nozzle was used for spray drying.
The spray-dried dispersion was also evaluated in media mimicking gastric-to-intestinal transport. (data not shown).3,4 ARV-110 exhibited low solubility, while a physical mixture with PVA showed slight improvement. However, the spray-dried dispersion with Parteck® MXP 3-82 demonstrated a pronounced solubility enhancement.Improving the Solubility of SelDeg51
Figure 9.Dissolution and stability of 30% PROTAC SelDeg51 in Parteck® MXP 3-82 excipient.
Method description: Buchi B-290 (Büchi Labortechnik AG, Flawil, Switzerland); 90 °C inlet temp; 55 °C outlet temp; drying air flow 35 m3/h; atomization air flow 670 L/min (N2: 55 mm); Dissolution method: Mini dissolution, Phosphate buffer pH 6.8, 100 rpm, 220 nm.
The potential impact of the spray drying process on SelDeg51's activity was also evaluated and showed that the protein degradation activity of the PROTAC remained consistent when spray-dried with no negative impact on its interaction with EG ligase.3,4
Spray drying is a versatile and powerful technique for enhancing the solubility of both small molecules and complex large-molecule therapeutics. It will continue to be an indispensable option in the formulation toolbox for overcoming the solubility challenges presented by a wide range of drug candidates, including new modalities. In doing so, spray drying can help unlock even more opportunities for innovative therapeutic solutions. As described above, spray drying is already being successfully applied to the development of PROTACs, supporting the advancement of these promising molecules into viable drug candidates. As the field of novel modalities continues to evolve, spray drying will continue to be an essential formulation tool for unlocking the full potential of PROTAC-based therapies and other novel therapeutic classes. Central to the success of this technology is the careful selection of polymers, which play a critical role in determining both process efficiency and the performance of the final formulation. PVA stands out as an exceptional polymer in spray drying applications, offering a unique combination of benefits. Its low viscosity allows for high drug loadings, while its ability to stabilize amorphous dispersions ensures long-term stability. Furthermore, PVA significantly enhances dissolution profiles, delivering superior solubility compared to crystalline drugs or other polymers. These attributes make PVA a valuable excipient for tackling solubility and stability challenges in drug development.Conclusion
Need expert guidance? Reach out to our specialists to explore formulation solutions.
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References
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Mueller LK, Halstenberg L, Di Gallo N, Kipping T. Evaluation of a Three-Fluid Nozzle Spraying Process for Facilitating Spray Drying of Hydrophilic Polymers for the Creation of Amorphous Solid Dispersions. Pharmaceutics. 15(11):2542. https://doi.org/10.3390/pharmaceutics15112542
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Ziaee A, Albadarin AB, Padrela L, Femmer T, O'Reilly E, Walker G. 2019. Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches. European Journal of Pharmaceutical Sciences. 127300-318. https://doi.org/10.1016/j.ejps.2018.10.026
3.
Webinar. Unleashing the Potential for Polyvinyl Alcohol in Spray Drying for Oral Solid Dosage Forms. [Internet]. Available from: https://event.on24.com/wcc/r/4480203/57D1DF9B04A30008B2D24900AC9F8F57
4.
Mareczek L, Mueller LK, Halstenberg L, Geiger TM, Walz M, Zheng M, Hausch F. Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras. Pharmaceutics. 16(7):924. https://doi.org/10.3390/pharmaceutics16070924
