Oral delivery is the preferred route of drug product administration since it maximizes patient compliance and minimizes cost. However, successful oral drug delivery is challenging for drugs with low solubility in gastrointestinal (GI) fluids, which comprise a large percentage of new chemical entities (>70%).¹ Amorphous solid dispersions (ASDs) are an effective formulation strategy for addressing this challenge, since they increase drug solubility, thereby promoting dissolution in GI fluids and maximizing the amount of drug that reaches the bloodstream.² This enhancement in oral bioavailability can improve patient outcomes by reducing variability in plasma exposure, decreasing dose and removing drug-drug and food-drug interactions.³

ASDs enhance drug solubility and bioavailability by converting crystalline drugs to the amorphous form using processes such as spray drying (SD) or hot melt extrusion (HME).⁴ Amorphous drugs can have ~5-100-fold higher solubility than crystalline drugs due to their higher free energy.^5,6 While these properties offer a “solubility advantage,” they come with the cost of potential conversion of the amorphous form back to the crystalline form in GI fluids orduring storage.⁷

Techniques to Prevent ASD Recrystallization

To prevent recrystallization, ASDs are typically formulated with a polymer that stabilizes the high energy state of the drug. The type and amount of polymer required for stabilization depends upon drug physicochemical properties and drug product packaging and storage requirements.7 The ratio of the drug melt temperature to the glass transition temperature (Tm/Tg) is an important drug property indicating its propensity to recrystallize, with a higher Tm/Tg (> ~1.3 (K/K)) suggesting a higher risk of recrystallization.⁸ High Tm/Tg drugs often require a high percentage of polymer in the ASD (e.g. >75%) to maintain the amorphous form throughout the drug product shelf-life.⁹

To be effective, the ASD polymer needs to interact effectively with both the active pharmaceutical ingredient (API) and GI fluids to prevent recrystallization.10 For example, hydroxypropyl methylcellulose acetate succinate (HPMCAS) is an effective ASD polymer for many drugs since its hydrophobic acetyl groups can interact with hydrophobic drugs, and its carboxylate groups can interact with the aqueous phase at the drug-water interface to inhibit crystal nucleation and growth in intestinal fluids.⁸

To prevent recrystallization during storage, high Tg, non-hygroscopic polymers are particularly effective. A high polymer Tg stabilizes the drug by limiting molecular mobility and kinetically trapping the drug in the amorphous state.⁷

The non-hygroscopic nature of the polymer ensures the high Tg of the ASD is maintained upon exposure to increased humidity by decreasing water uptake and preventing plasticization of the polymer by water.¹¹ HPMCAS is an example of a high Tg (120°C) polymer with low hygroscopicity.8 Due to its effectiveness at inhibiting crystallization in GI fluids and during storage, HPMCAS is included in 11 of the 32 commercial ASD drug products.^4,12

How to Reduce Pill Burden for ASD Drug Products

Recent advances in ASD formulation architecture have the potential to maximize the effectiveness of and optimize selection of ASD stabilizing polymers, thereby improving ASD drug products. For example, Lonza recently developed a high loaded dosage forms (HLDF) formulation architecture to reduce dosage form burden of ASD drug products.^13,14 This architecture is particularly suited to drugs with a high crystallization tendency (Tm/ Tg) and low Tg that typically need a high percentage of stabilizing polymer in the ASD to prevent recrystallization. This requirement often results in low drug loading in the dosage form, resulting in a large dosage form size, and/or a high number of dosage form units, particularly for drugs with a high (>~100 mg) dose.

Rather than relying on a single polymer in the ASD (e.g., HPMCAS) to stabilize the drug in both GI fluids and during storage, the HLDF platform “divides the work” between two different polymers. A high-Tg polymer (such as poly[methacrylic acid-co-methyl methacrylate], trade name Eudragit L,100, Tg= 190°C) is used in the ASD to ensure drug stabilization during storage at a high drug loading, and effective stabilizing polymer (such HPMCAS) is used external to the ASD (i.e., in the dosage form) to ensure stabilization in GI fluids. This approach decreases dosage form size by ~40% while maintaining performance, stability, and manufacturability of the dosage form.^13,14

How to Reduce Development Timelines for ASD Drug Products

Newly developed in vitro techniques and formulation development approaches can de-risk ASD performance and reduce development timelines by optimizing and speeding up selection of the most effective polymer(s) for stabilizing amorphous drugs. For example, a high-throughput, material-sparing in vitro solvent-shift UV test can be used to identify the most effective stabilizing polymers for a particular drug, reducing the number of ASD formulations that must be manufactured using SD or HME.^5,15 The manufactured ASDs can then be screened using a high-throughput, small-scale dissolution apparatus with fiber optic UV probes to select the lead ASD(s) before incorporating the ASD into a dosage form, thereby reducing tablet manufacturing and testing burden.¹⁶ These approaches can also be combined with biorelevant dissolution testing and in silico absorption modeling to predict ASD performance in vivo, maximizing the chance of success in the clinic.^15,17,18

Conclusion

ASDs are effective at enabling and improving oral medicines of poorly soluble drugs. Stabilization of the amorphous drug is crucial for meeting drug product in vivo performance and storage stability requirements. While numerous ASD drug products exist on the market, new advances in ASD formulation development and analytical techniques will continue to support launch of new ASD products at greater speeds with enhanced drug
product attributes. 

References
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Deanna Mudie, PhD, is a principal scientist in research and development at Lonza’s site in Bend, OR. Since she joined Lonza in 2016, her focus has been on enabling bioavailability-enhancing amorphous solid dispersions by developing dosage form platforms and in vitro dissolution methodologies to predict bioperformance. Mudie earned her BSE degree in chemical engineering and her Ph.D. in pharmaceutical sciences from the University of Michigan. She has seven years of predoctoral experience at Pfizer and Merck developing and manufacturing oral dosage forms from preclinical to commercial scale.