Comparative Assessment of Spray Drying and Hot Melt Extrusion as Manufacturing Processes for Amorphous Solid Dispersions

• ExxPharma Therapeutics LLC

Amorphous solid dispersions of poorly soluble drug substances were prepared using a variety of technologies, the most popular of which are spray drying and hot melt extrusion. As a result, a majority of the oral dosage forms of poorly soluble drug substances in the market consist of amorphous solid dispersions manufactured by spray drying or melt extrusion. In this and subsequent articles, an attempt will be made to compare and contrast the two technologies, including their pros and cons, in five parts, i.e., (1) Historical Perspective, (2) Manufacturing Processing Conditions, (3) Scale up and Equipment Considerations, (4) Quality, Cost and Regulatory Implications, and (5) Downstream Process Interfacing.

Part I: Historical Perspective

Amorphous Solid Dispersions

Oral dosage forms are the most preferred drug delivery systems for many reasons including ease of administration, high patient compliance, handling convenience, relative product stability, dosage form flexibility and cost considerations. While development of dosage forms of many drug substances is straightforward, development of poorly soluble drug substances is challenging, particularly as related to bioavailability. Oral bioavailability of poorly soluble drug substances depends on several factors, such as solubility, permeability, first-pass metabolism, pre-systemic metabolism and susceptibility to efflux mechanisms. The most prominent causes of poor bioavailability are poor solubility and low permeability. The advent of high throughput screening tools in drug discovery has led to the emergence of increasingly lipophilic and high molecular weight compounds. Approximately 90% of new molecular entities coming out of companies’ pipelines are poorly soluble, poorly permeable or both. Similarly, about 40% of marketed products, which initially were developed and approved based on unoptimized formulations or alternative dosage forms, have low solubility, low permeability or both.^1-3 As a result, formulation development of poorly soluble drug substances has been a persistent problem that continues to negatively impact the clinical viability of many promising molecules, thereby potentially preventing or delaying important life-saving medicines from reaching the patients.

To address the bioavailability issues, many pharmaceutical companies have developed or acquired various solubility enhancement technologies that employ different formulation approaches, such as particle size reduction (e.g., micronization and nano-milling), salts, co-crystals, self-emulsifying excipients and solid dispersions to enhance the solubility of poorly soluble drug substances.⁴ Solid dispersions have many advantages over other solubility enhancement methods, particularly with respect to manufacturing efficiency. These advantages, in turn, have enabled solid dispersions to become the most preferred formulation components of oral dosage forms of poorly soluble drug substances whether the drugs are highly crystalline or lipophilic.

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A solid dispersion can be defined as a dispersion of one or more active ingredients in an inert polymeric matrix in the solid state which is prepared by a melt or fusion method, a solvent method or a combination of the fusion and solvent methods.⁵ In 1961 Sekiguchi and Obi prepared two types of solid dispersions containing crystalline polymeric carriers: eutectic mixtures, where the drug was crystalline, and monotectic mixtures, where the drug was amorphous.6 In the 1970’s, crystalline polymeric matrices were replaced by amorphous polymeric carriers to generate three types of solid dispersions based on the physical state of the drug substance in the matrix; (a) glassy suspension if the dispersed drug exists in an amorphous state, (b) crystalline suspension if the drug exists as fine crystalline particles and (c) glassy solution if the drug exists as a molecular dispersion in the matrix. During the past three decades or so, glassy suspensions and glassy solutions, collectively known as amorphous solid dispersions, have become the most widely used solubility enhancement tools during the development and manufacturing of poorly soluble drug substances.

A review of the literature indicates that around 3451 articles and 1076 patent applications that deal with the development and manufacturing of solid dispersions were published between 1980 and 2015. The number of published articles and patent applications increased annually with more than 70% of them published between 2005 and 2015.⁷ The numbers illustrate that amorphous solid dispersions are increasingly becoming critical components of dosage forms of poorly soluble and poorly bioavailable drug substances.

Amorphous solid dispersions (ASDs) manufacturing processes are: (a) solvent-based heat-free processes, which include spray drying, spray coating, coprecipitation, freeze drying, electrospinning, supercritical fluid-based technologies and micro-precipitation; and (b) solventfree, melt-based processes, which comprise size reduction, ultrasonic assisted compaction, melt granulation, melt extrusion, generally known as HME, and Kinetisol.⁸ Out of the two groups, the most popular and commercially-proven manufacturing technologies are spray drying and hot melt extrusion, and will be discussed further.

Spray Drying

Spray drying, which has its origin in the United States, was first patented by Percy on April 9, 1872, under the title of “Improvement in Drying and Concentrating Liquid Substances by Atomizing”.⁹ Significant industrial use of spray drying was demonstrated in the 1920s when the technology was initially used to improve shelf-life and facilitate handling of powder detergents, and later as a drying process for the manufacture of powdered milk. During World War II, the need for reduced weight and volume of food and other materials during transport led to the surge of interest in spray drying technology. This was followed by further expansion of the application of the technology to a wide range of industrial manufacturing operations, including powdered soaps and detergents, instant coffee, corn starch, fertilizers, powdered polymer resins, mineral ores, and clays. In the 1940s, Bullock et.al. explored the application of spray drying as a drying process for pharmaceuticals during the preparation of infusions for reconstitution, extracts, inorganic medicinal salts and antibiotics. Since then, spray-drying has been used in diverse pharmaceutical applications, such as the preparation of free-flowing tablet excipients, biotherapeutic particles for pulmonary inhalations and amorphous solid dispersions as well as to dry or encapsulate crystalline active pharmaceutical ingredients.^10-12

Application of spray drying technology in the preparation of  amorphous solid dispersions of poorly water-soluble compounds can be traced back to 1965, when Tachibana, et.al. prepared an amorphous solid dispersion of β-carotene in polyvinylpyrrolidone (PVP) by first dissolving β-carotene and PVP in methanol and then spray drying the solution to generate the dispersion.¹³ In 1975, Kawashima, et.al., applied spray drying to improve the solubility and dissolution rate of salicylic acid, a poorly water‐soluble drug substance.¹⁴ In 1978, Sato, et.al., used spray drying to prepare stable amorphous macrolide antibiotic solids. The macrolide antibiotic and a cellulose polymer, selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose were dissolved in a volatile organic solvent, selected from the group consisting of dichloromethane, 1,1,1-trichloroethane and chloroform, and the resulting solution was spray dried.¹⁵ In 1986, Panoz, et.al. described the preparation of amorphous solid dispersion by a spray drying process.¹⁶ Since then, many products which comprise spray dried amorphous solid dispersions have been developed and approved (Table 1).

Hot Melt Extrusion

Hot melt extrusion is a manufacturing process that utilizes continuous, small mass mixers called extruders. There are two types of extruders: single-screw extruders and twin-screw extruders. The earliest singlescrew extruder was designed by Sturges in 1871 while the earliest twinscrew extruders were designed by Wiegardin and Pfleiderer in 1879 and 1882, respectively.^17-19 Industrial use of single-screw extruders was first demonstrated in the early 1930s when the extruders were used to extrude thermoplastic materials. Commercial twin-screw extruders were introduced in the 1940s. Currently, more than half of all plastic products, including plastic bags, sheets, and pipes, are manufactured using twin screw extrusion processes. Even though the technology has had a wide application in the manufacture of food, natural rubber and plastics for almost a century, it only started to get attention in the pharma industry and academia as a drug product manufacturing tool in the 1980s.^20,21

Since the early 1980’s, application of melt extrusion in the development and manufacture of pharmaceutical products has increased steadily.^22-26 During this period, the technology has proven to be a convenient and cost-effective manufacturing process for the preparation of granules, pellets, modified release tablets, transdermal and transmucosal drug delivery systems, amorphous solid dispersions, and abuse deterrent formulations. The technology has also been used commercially to manufacture combination drug products, such as contraceptive rings, subcutaneous implantable rods, ophthalmic implants, etc.

The application of a twin-screw extrusion process to prepare solid dispersions of poorly soluble drug substances was first introduced in the pharma industry in 1992 by Ghebre-Sellassie et.al. The formulation and process were subsequently used to develop Rezulin™ tablets (troglitazone), the first drug product, that consisted of melt-extruded amorphous solid dispersions, to be approved by the FDA for marketing authorization in 1997.^23,24

It took another eight years before the second product, Kaletra® tablets (Lopinavir/Ritonavir), that comprised melt extrusion-based amorphous solid dispersion, was approved by the FDA. Since then, as is apparent from Table 1, hot melt extrusion appears to be gaining momentum as the preferred manufacturing process for amorphous solid dispersions. Based on the advantages hot melt extrusion offers, the trend is expected to continue unabated for the foreseeable future.

Having addressed the historical origins of spray drying and hot melt extrusion as manufacturing processes for amorphous solid dispersions and their current status in the pharma industry, an attempt will be made in Part II to assess and discuss the operational characteristics of the two technologies, robustness and limitations of the manufacturing processes and the effect of the various processing conditions.

References

1. Savjani K T, Gajjar A K and Savjani J K. Review Article Drug Solubility: Importance and Enhancement Techniques, ISRN Pharmaceutics, Volume 2012, Article ID 195727, doi:10.5402/2012/19572.
2. Aungst B J, Novel Formulation Strategies for Improving Oral Bioavailability of Drugs with Poor Membrane Permeation or Presystemic Metabolism, J. Pharm. Sciences, 1993;82(10):979-987.
3. Patel N, Jain S, Solubility and dissolution enhancement strategies: Current understanding and recent trends Drug Development and Industrial Pharmacy. 2014;41(6):875-87.
4. Zhang X, Xing H, Zhao Y, Ma Z, Review: Pharmaceutical Dispersion Techniques for Dissolution and Bioavailability Enhancement of Poorly Water-Soluble Drugs, Pharmaceutics. 2018;10(3):1-33
5. Chio W L, Riegelman S. Pharmaceutical application of solid dispersion systems. J. Pharm. Sciences. 1971;60(9):1281-1302
6. Sekiguchi K, Obi N. Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull. 1961; 9:866–872
7. Zhang J, Han R, Chen W, et.al., Analysis of the Literature and Patents on Solid Dispersion from 1980 to 2015, Molecules. 2018, 23(7), 1697.
8. Sandhu H, Shah N Chokshi H, Malick A W. Overview of amorphous solid dispersion technologies. In: Shah N, Sandhu H, Choi D S, Chokshi, A H. Malick, eds. Amorphous Solid Dispersions Theory and Practice, New York Heidelberg Dordrecht London: Springer; 2014:91-122.
9. Samuel R. P, Improvement in Drying and Concentrating Liquid Substances by Atomizing, US Patent No. 125,406, April 9, 1872.
10. Parikh D, Spray drying as a granulation Technique; In: Handbook of Pharmaceutical Granulation Technology, Drugs and the Pharmaceutical Sciences. New York, Marcel Dekker.1997; 75-96.
11. Gaspar F, Spray drying in the pharmaceutical industry, European Pharmaceutical Review, 2014; Issue 5. Available at https://www.europeanpharmaceuticalreview.com/article/27923/issue-5-2014-digital-edition.
12. Seville C P, Li, H, Learoyd P T. Spray-Dried Powders for Pulmonary Drug Delivery, Critical Reviews in Therapeutic Drug Carrier Systems. 2007;24(4):307-360.
13. Tachibana, T, Nakamura A. A method for preparing an aqueous colloidal dispersion of organic materials by using water-soluble polymers: Dispersion of B-carotene by polyvinylpyrrolidone. A. Kolloid-Z.u.Z.Polymere. 1965; 203(2):130–133. Available at httpe://doi.org/10.1007/BF01507758.
14. Kawashima Y, Saito M, Takenaka H. Improvement of solubility and dissolution rate of poorly water‐soluble salicylic acid by a spray‐drying technique, Journal of Pharmacy and Pharmacology, 1975;27(1):1-5.
15. Sato T, Kobayashi T, Mayama T, Okada A. Process for Preparation of Stable Amorphous Macrolide Antibiotic Solids, US Patent No. 4,127,647, November 28, 1978.
16. Panoz E D, Athlone, Corrigan O I. Medicaments with a High Degree of Solubility and Method for their Production, US patent No. 4,610,875, September 9, 1986.
17. Sturges J D. Improvement in apparatus for cooling and mixing soap. US Patent 114063,1877.
18. Wiegand SL. Machines for sheeting dough. US Patent 155602, 1879.
19. Pfleiderer, P., Innovations on kneading and mixing machines of Freyburger type. German Patent 18797, 1882.
20. Maniruzzaman M, Boateng JS, Snowden MJ, Douroumis D. A Review of Hot-Melt Extrusion: Process Technology to Pharmaceutical Products, ISRN Pharmaceutics Volume 2012, Article ID 436763, 9 pages doi:10.5402/2012/436763
21. Crowley M M, Zhang F, Repka A M, et. al., Pharmaceutical Applications of Hot-Melt Extrusion, Drug Development and Industrial Pharmacy, 2007;33(9):909–926.
22. Schiraldi T M, Perl M M, Rubin H, Rockaway, Bio-adhesive Extruded Film for Intra-Oral Drug Delivery and Process, US Patent No. 4,713,243, Dec. 15, 1987.
23. Martin E M. Twin-screw extruders for pharmaceutical products from technical and historical perspective. In: Ghebre-Sellassie I, Martin E M, Zhang F, DiNunzio J, eds. Pharmaceutical Extrusion Technology, 2nd ed, Boca Raton, FL: Tylor & Francis Group, 2018:1-35.
24. Terefe H. The Origin of Hot Melt Extrusion, American Pharmaceutical Review. 2017;20(5):36-43.