FUNCTIONAL EXCIPIENTS – Improving the Water Solubility of Oral Drugs With Amorphous Solid Dispersions (ASDs)
In 2020, more than 40% of new drug approvals in the US, Europe, and Japan were for oral administration and more than half of these were oral tablets.1 Oral solid dosage forms are one of the most popular drug delivery methods due to the ease involved in self-administration, handling, and transportation.2 These factors provide desired convenience to patients, thus patient compliance, when compared to some other routes of administration.
Despite the large number of drugs in development and the obvious advantages of oral dosage forms, the growth of this segment is hindered by the fact that nearly 90% of the drugs in the pipeline have poor solubility. The improvement of drug solubility and subsequent oral bioavailability remains one of most challenging aspects of the drug development process. One method that is becoming increasingly popular to address oral drug solubility issues is the use of amorphous solid dispersions (ASDs).
WHAT ARE ASDS?
An ASD is a solid dispersion in which the API is dispersed within an excipient matrix in a substantially amorphous form. Developments throughout the past few decades in synthetic polymers have enabled ASDs to emerge as an effective oral delivery strategy for overcoming poor drug solubility in aqueous environments. The polymer carrier stabilizes the drug in amorphous form, enabling long-term storage stability and improved dissolution when compared to the crystalline or pure amorphous drug forms.3-5
Drug-polymer ASDs can be prepared using hot-melt extrusion and spray-drying. In hot-melt extrusion, the drug and the polymer carrier are heated up to their melting point and mixed. Upon cooling of the melt, the drug is trapped within the carrier matrix in an amorphous state. In spray-drying, the drug, polymer carrier, and any other excipients are dissolved in a suitable solvent to form a liquid feedstock. In a continuous process, the liquid feedstock is sprayed into a heated air stream. Due to fast solvent evaporation, the liquid feedstock droplets rapidly dry, entrapping the amorphous drug in the polymer matrix in the form of a solid powder.
WHAT ARE THE ADVANTAGES OF USING ASDS OVER OTHER DELIVERY METHODS?
There are many approaches to enhance the delivery of poorly water-soluble drugs intended for oral solid dosage. Many of these formulation strategies have distinct disadvantages. Lipid-based formulations can be associated with low drug loading, causing stability problems.6,7 Solubilization in micelles is frequently associated with colloidal instability when introduced to bile salts in the stomach.6 Self-emulsifying drugs are often poorly tolerated in the long-term due to the surfactants used.8 Micronized suspensions are often associated with slow and incomplete dissolution.9
ASDs provide an attractive alternative approach to these formulation methods. In a study examining 40 research papers, 82% of ASD formulations were found to increase or maintain bioavailability of a drug in vivo.10 With the right polymer choice, many crystalline drugs can be stabilized in an amorphous form through ASDs. Depending on the drug-polymer system, a much higher drug load could be achieved using ASD delivery methods compared with other solubilization techniques. In addition, the development and manufacturing of ASDs rely on pharmaceutical processes that are well understood and easily scalable, including hot-melt extrusion and spray-drying.
ACHIEVING THE FULL POTENTIAL OF ASDS
Despite the advantages ASDs can provide for oral solid drug delivery, they account for only ~0.6% of drug products on the market today.10,11 This suggests ASDs’ potential has not been fully explored in today’s drug development.
One challenge that must be overcome when developing and manufacturing ASDs is preventing recrystallization of APIs to increase their long-term stability.
Studies have shown that the addition of specialized polymers can help stabilize ASDs against crystalization.12 Linear polyacrylic acid (PAA), for example, is a polymer that has been shown to both stabilize ASDs and increase the API solubility when prepared using solvent evaporation techniques, such as spray drying.13-15
An example of a speciality polymer currently available is the Apinovex™ polymer manufactured by LLS Health. This high molecular weight linear polyacrylic acid excipient can effectively enable physically stable, spray-dried ASDs, allowing for flexibility in drug loading of up to 80% API.
With such polymers, it is possible for drug formulators to take full advantage of the benefits of ASDs, enabling them to overcome formulation challenges to deliver more effective novel drug products capable of transforming the lives of patients.
- GLOBAL REPORT – 2020 Global Drug Delivery & Formulation Report
- Sohail Arshad M, Zafar S, Yousef B, et al. A Drug Development & Delivery January/February 2023 Vol 23 No 1 review of emerging technologies enabling improved solid oral dosage form manufacturing and processing [published online ahead of print, 2021 Jun 18]. Adv Drug Deliv Rev. 2021;113840.
- T Loftsson, ME. Brewster. Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol, 62 (2010), pp. 1607-1621.
- Kanaujia, et al. 2015. Amorphous formulations for dissolution and bioavailability enhancement of poorly soluble APIs. Powder Technology, Pharmaceutical Particle Technology 285, 2-15.
- Pandi P, et al. Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products. Int J Pharm. 2020;586:119560.
- Boyd BJ, et al. Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems. Eur J Pharm Sci. 2019;137:104967.
- Chen XQ, Gudmundsson OS, Hageman MJ. Application of lipid-based formulations in drug discovery. J Med Chem. 2012;55(18):7945-7956. doi:10.1021/jm3006433.
- Gupta S, et al. Formulation strategies to improve the bioavailability of poorly absorbed drugs with special emphasis on self-emulsifying systems. ISRN Pharm. 2013;2013:848043. Published 2013 Dec 26.
- He Y, Ho C. Amorphous Solid Dispersions: Utilization and Challenges in Drug Discovery and Development. J Pharm Sci. 2015;104(10):3237-3258.
- Newman A, Knipp G, Zografi G. (2012). Assessing the performance of amorphous solid dispersions. J Pharm Sci 101:1355–77.
- Ojo AT, Lee PI. A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions. J Pharm Sci. 2021;110(4):1495-1512. doi:10.1016/j.xphs.2020.08.006.
- Xie T, Taylor LS. Improved Release of Celecoxib from High Drug Loading Amorphous Solid Dispersions Formulated with Polyacrylic Acid and Cellulose Derivatives. Mol Pharm. 2016;13(3):873-884.
- Zhang et al, “Investigation of itraconazole ternary amorphous solid dispersions based on Povidone and Carbopol” European Journal of Pharmaceutical Sciences 106 (2017) 413-421.
- Guy Van den Mooter et al, Salt formation in solid dispersions consisting of polyacrylic acid as a carrier and three basic model compounds resulting in very high TG temperatures and constant dissolution properties upon storage” European Journal of Pharmaceutical Sciences 25 (2005) 387-393.
- Raj Suryanarayanan et al, “Role of the strength of drug-polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions” Molecular Pharmaceutics 12 (2015) 3339-3350.
Dr. Liliana Miinea is a Technology Manager with Lubrizol Life Science Health. Her work focuses on developing new technologies for pharmaceutical applications mainly in the area of controlled release, drug solubility enhancement, and enhanced mucosal delivery. She has more than 20 years of experience in developing and characterizing ingredients, including nanomaterials, polymer/nanomaterials composites, and novel excipients. Prior to Lubrizol she worked at Avantor Inc., NJ, and conducted post-doctoral research at Washington University in St. Louis, and Center for Nanomaterials Research at Dartmouth College, US. She earned her PhD in Chemistry from the University of Houston, TX.
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