FUNCTIONAL EXCIPIENTS - Improving the Water Solubility of Oral Drugs With Amorphous Solid Dispersions (ASDs)

INTRODUCTION

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.

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.

REFERENCES

1. GLOBAL REPORT – 2020 Global Drug De­livery & Formulation Report
2. 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.
3. T Loftsson, ME. Brewster. Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Phar­macol, 62 (2010), pp. 1607-1621.
4. Kanaujia, et al. 2015. Amorphous formula­tions for dissolution and bioavailability en­hancement of poorly soluble APIs. Powder Technology, Pharmaceutical Particle Tech­nology 285, 2-15.
5. 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.
6. 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.
7. 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.
8. 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.
9. He Y, Ho C. Amorphous Solid Dispersions: Utilization and Challenges in Drug Discov­ery and Development. J Pharm Sci. 2015;104(10):3237-3258.
10. Newman A, Knipp G, Zografi G. (2012). Assessing the performance of amorphous solid dispersions. J Pharm Sci 101:1355–77.
11. 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.
12. 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.
13. Zhang et al, “Investigation of itraconazole ternary amorphous solid dispersions based on Povidone and Carbopol” Euro­pean Journal of Pharmaceutical Sciences 106 (2017) 413-421.
14. 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.
15. 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.