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Polymeric amorphous solid dispersions are the most commonly used technology, but amorphous APIs remain inherently unstable.
A large percentage of small-molecule APIs in development today suffer from poor solubility and bioavailability. Stabilizing these APIs in their amorphous forms can help overcome these issues because a supersaturated state is achieved upon dissolution and delivery. Such a state can result in enhanced absorption across gastrointestinal membranes and improved bioavailability, according to Lindsay Johnson, global technical marketing manager for BASF’s Pharma Solutions business.
“The high thermodynamic energy of an amorphous, supersaturated state is inherently unstable, however, and such systems are driven towards crystallization, liquid-liquid phase separation, or non-descript precipitation,” Johnson says. Tendencies to recrystallize, absorb moisture, and participate in side
reactions that generate impurities must also be overcome.
Depending on the chemical nature of API candidates, there are a variety of mechanisms that can be used to overcome solubility challenges. Amorphization of the API is one mechanism that can be pursued, observes Johnson, and commonly amorphous APIs are stabilized in amorphous solid dispersions (ASDs) formed via solvent evaporation processes such as spray drying (SD) or fluid-bed coating or melt processes such as hot-melt extrusion (HME).
These methods for stabilizing amorphous formulations are polymer-based, notes Daniel Joseph Price, strategic marketing manager, excipients for solid dosage at MilliporeSigma. “Although different processing methods are used and formulations vary, the end result is the same: a polymeric matrix, with hopefully a homogenous distribution of API throughout the polymer,” he adds. The distribution of the API in the polymer essentially immobilizes the API in the amorphous form, preventing re-crystallization.
Currently, there are 17 commercially available spray-dried dispersion amorphous drug products and 13 approved HME products (1,2). “Both of these technologies are established in the industry, easily scaled-up, and continuous,” comments Molly Adam, an R&D engineer at Lonza.
Both methods have advantages and disadvantages, too. Spray drying does not expose the API to high temperatures, but requires the use of large quantities of organic solvents and nitrogen gas and can have low throughputs, all of which make the process costly, Adam says. While extrusion has a lower footprint and a higher throughput, the process involves high temperatures and shear stresses that can degrade some APIs.
Generally speaking, the selection of amorphous formulation technologies should be guided by the glass-forming ability of the API, according to Price. “The glass-forming ability essentially describes how likely it is for a molecule to re-crystallize,” he explains. “Poor glass formers are molecules that have very poor stability in the amorphous form, and so have an inherent re-crystallization risk. It is therefore recommended to only use polymeric amorphous solid dispersions when working with good or moderate glass formers,” he continues.
The choice of spray drying or HME depends on several factors, including processing space, scale-up needs, performance drivers, and the properties of the API, says Gereint Sis, an R&D scientist with Lonza. Important physicochemical properties that drive API stabilization are the melt and glass-transition temperatures (Tm and Tg, respectively). APIs with significantly high melting points are not typically amenable to HME due to degradation, while APIs with poor solvent solubility are challenging for spray drying.
Ultimately, the amorphous system (API-polymer interactions, weight percent of API, temperature, humidity, and the region of the phase diagram the formulation occupies) will drive the extent of stabilization (3).
“The optimum selection strategy involves cooperatively conducting high-throughput, small-scale manufacturing, iterative in silico modeling, bench-top testing, polymer screening, and discriminating in vitro testing,” Sis states.The resulting optimum stabilization method should ensure performance, manufacturability, physical and chemical stability, and enable patient compliance, he adds.
One challenge, Sis observes, is the difficulty of striking a balance between these metrics while alleviating complexity and lowering costs. “Strategic and agile technology selection methodologies can help manage these issues,” he says. In addition, adding robust data sets coupled with machine learning to current selection strategies will likely ensure shorter timelines and alleviate cost burdens to drug-product-development lifecycles (4).
Common excipients include polyvinylpyrrolidones (PVPs), their copolymers, and their cross-linked derivatives, polyvinyl acetates (PVAs), and some functionalized cellulosic materials such as hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS).
Typically, a binary API-polymer system that affords favorable API-polymer interactions to provide the stabilization is used in an ASD (3). These excipients are usually required to have specific material properties, including a relatively high Tg (usually 70 °C or higher), according to Johnson. Polymers with high Tg values are great at stabilizing amorphous APIs because they increase the Tg of the dispersion and decrease mobility, Adam remarks.
In addition to the Tg, other excipient properties to consider include the degradation temperature, solubility in organic solvents, water uptake, and typical sustainment performance during dissolution, according to Adam. She says that polymers with a wide processing temperature range are great for HME because they have a lower chance of degradation.
Poloxamers or polyethylene glycol (PEG) are also common in HME to improve processability by plasticizing the system, which decreases its melt temperature and melt viscosity. For SD, polymers with good organic solubility and low solution viscosity when dissolved are crucial to enable sufficient solubility for both the API and polymer.
Depending on the stabilizing mechanism, Johnson also notes that excipients for ASDs may contain functional groups that can participate in specific polymer-drug intermolecular interactions or have a rough solubility parameter that matches the hydrophilic/hydrophobic balance of the API in order to offer non-specific interactions that can be stabilizing.
Furthermore, polymers can aid in stabilizing the drug in gastrointestinal fluids in vivo and in the solid state during storage, according to Adam. Neutral polymers like PVP grades and HPMC can maximize dissolution rates throughout the whole range of pH of the GI tract. Enteric polymers such as HPMCAS and Evonik’s Eudragit L functional delayed release polymer can enable acid-sensitive APIs to be released in the intestine rather than the stomach if they degrade at low pH or have low solubility in the stomach.
For poor glass-forming APIs with inherent mobility, Price points out that mesoporous silica has emerged in recent years as an excellent excipient for stabilization. “The steric confinement of the API in nanosized pores after loading substantially reduces the mobility of the API in the formulation,” he explains.
Even though amorphous APIs are stabilized in ASDs, instability can remain an issue during storage and once the formulation has been administered to the patient. “The one downside to polymeric ASDs is the inherent mobility of both the polymer and the API in the formulations, which can lead to re-crystallization of poor glass-forming APIs,” Price states.
The mechanisms by which amorphous forms destabilize are phase separation and crystallization, according to Sis. “When an amorphous solid dispersion phase separates, distinct polymer-rich and API-rich amorphous phases form, which can make the amorphous API more prone to crystallization. Phase separation may or may not be a precursor to crystallization, with the rate-limiting step for crystallization being either diffusion or crystal nucleation,” he explains. Nucleation occurs when small seed crystals of the API form that then grow until a thermodynamically stable polymorph is obtained, according to Price.
Internal factors affecting the extent of stabilization of ASDs include the API loading, the polymer properties, and the drug-polymer interactions within the ASD, Sis outlines. For instance, hydroscopic excipients that absorb moisture will have negative consequences, as will formulations that contain plasticizers that increase polymer and API mobility, according to Johnson.
Environmental factors such as humidity and temperature can thus also affect the chemical and physical stability of the amorphous API within the formulation by increasing the kinetics of unwanted reaction pathways, such as degradation in the presence of water. Increased API mobility leads to a shift in the phase diagram, phase separation, and API recrystallization (3). “Smart formulation decisions and storage strategies are necessary to mitigate these risks,” Sis contends.
The behavior of the amorphous form upon dissolution in the body must also be considered, says Price. “When an amorphous API is dissolved, supersaturation generally occurs, and the API is in solution at concentrations higher than its thermodynamic solubility. Supersaturation is not a stable condition and is thermodynamically unfavorable. The API may precipitate out of solution and undergo nucleation and crystal growth, or API-rich liquid domains may separate out of solution,” he says.
Upon dissolution, observes Johnson, the stability of amorphous APIs is often segmented by their relative molecular and physiochemical properties, which will dictate which formulation approach is likely to be successful at stabilization. “In order to be amorphous and solubilized, any drug molecule needs to dissociate from its crystal lattice, and the dissolving media needs to solvate the drug molecule at the molecular level. Both of these processes require energy to either overcome drug-drug intermolecular forces or solvate the compound, respectively,” she explains.
Depending on which step is more solubility-limiting for a particular API, Johnson continues, the molecule can be referred to as a “brick dust” molecule or a “grease ball”. “Grease ball” and “brick-dust” APIs are associated with low and high melting points, respectively, and thus Tm and lipophilicity (log P) are often predictors of this categorization. In fact, Tm and log P can be used in combination with an API’s amorphous solubility to steer the selection of formulation type, according to Johnson.
“The supersaturation concentration achieved relative to that amorphous solubility is what dictates the destabilization process—whether direct crystallization that occurs below the amorphous solubility threshold or liquid-liquid phase separation that occurs above the amorphous solubility threshold,” Johnson concludes.
It is therefore important, stresses Price, to ensure not only the stability of the amorphous form in the solid state, but also stabilization of the supersaturated state upon dissolution.
Recent literature has expanded the interest in the field in co-amorphous systems, specifically ones that are not cocrystal forming. These co-amorphous systems include the API and a low-molecular-weight molecule that may be another pharmacologically relevant API or an excipient, Johnson observes.She adds that such formulations are commonly produced via mechanical milling, melt quenching, or solvent evaporation.
As an example, Price points to the spray drying of a mixture of an API with an amino acid, with the latter stabilizing the API in the amorphous form. “The two main benefits of this approach are processing and quality. For small-molecule coformers, it is easier to identify cosolvents for spray drying, and from a quality perspective, a small-molecule coformer is more well-defined and easier to control than a polymer,” he states.
Co-amorphous forms may also benefit from higher intermolecular interactions that prevent crystallization, higher conformational flexibility to prevent phase separation, and the anti-plasticizing effect of small molecules (5). They have also been shown to have increased solubility, dissolution rates, and physical stability compared to polymer ASDs with weak intermolecular interactions, Adam comments.
There are challenges to the formation of co-amorphous systems, however. Their typically higher molecular mobility, for instance, can lead to a greater tendency to crystallize during processing and storage, according to Johnson. She notes that significant performance variability can result, so co-amorphous formulations must be extensively studied in order to mitigate these impacts.
Recent advances in ASD technology are helping to overcome some of the limitations posed by the nature of poorly soluble APIs. High-shear mixing as an alternative to HME has the benefit of fast processing times combined with reduced exposure to high temperatures, according to Adam. “This technology has the potential to greatly impact the use of amorphous APIs by opening up the processing space where both SD and HME fall short, because it can be used for APIs with low organic solubility and high melt temperatures without degrading them,” she comments.
For APIs with poor solubility in common SD solvents, Adam points to temperature-shift spray drying as another important manufacturing advance. In this process, a slurry of the API is rapidly heated using an inline heat exchanger before atomization to increase solubility and throughput around 10-fold (6).
Another development noted by Adam involves increasing the drug loading for ASDs while improving stability and maintaining performance. High loaded dosage form (HLDF) architecture takes advantage of a high Tg polymethacrylate-based copolymer to significantly improve the stability of the ASD and HPMCAS to help sustain supersaturation upon dissolution. “This technology is applicable in formulations where the API tends to crystallize in gastrointestinal fluids and a polymethacrylate copolymer alone cannot effectively stabilize the amorphous API under these conditions,” she explains. “HLDF not only allows for higher ASD drug loadings, but also decreases tablet size and tablet burden,” she adds.
With traditional ASDs, the API is already in the amorphous state before it is processed into tablet form. Induced amorphization is the process of amorphizing crystalline API within a dosage form, thus converting from crystalline to amorphous phase during tableting.Deliberately utilizing this technique on a final dosage form can be described as in situ amorphization (ISA) and can be achieved using microwave radiation and other methods (7,8).
Price points to several examples in which APIs have been combined with small-molecule coformers such as amino acids, compressed into a tablet, and irradiated with microwaves to trigger ISA. One of the benefits of this approach is the ability to avoid using large weight fractions of polymer excipients, which dilute the concentration of API in the product, according to Sis. Physical stabilization of ASD formulations typically involves employing large weight fractions of polymers or other excipients in the final dosage form, which in some cases causes increased tablet burden, possibly lowering patient compliance (8). “Decreasing the need for long-term amorphous API stabilization results in final dosage forms containing only crystalline API and having dramatically reduced excipient fractions,” Sis explains.
In addition, eliminating the need to manufacture SD or HME formulations could avoid flowability issues associated with ASDs and drive down manufacturing costs (7). “Other important advantages to this approach relate to the stability and shelf-life of the product,” Price comments. “If the API is converted to the amorphous form directly at the point of care (pharmacy or hospital), the shelf-life relating to the stability of the amorphous form is less important,” he posits.
There are significant hurdles that must be overcome before such a dosage form is realized, however, particularly with respect to regulatory and quality concerns, Price temporizes. The technology is currently in its infancy, however, Sis notes.
In at least one example, some seed crystals were still present following microwaving of a tablet formulation (8). For some drug products, that may not affect the dissolution rate, but for others it could have a negative impact.
Overall, Sis believes ISA technology appears promising and warrants further development and investigation, with efforts focused on complete crystalline to amorphous conversion. He observes that considerations should also be taken to develop and understand the landscape in which FDA approval could occur. “ISA process technology must first be proven safe, effective, and scalable,” he concludes.
Rapidly evolving characteristics for candidate drug substances are driving the need for continued advances in technologies for the stabilization of amorphous APIs. Already formulators are challenged by the poor solubility of Biopharmaceutics Classification System II and IV APIs in the development pipeline.
“The ideal scenario for each of these drug substances would be to achieve a kinetic (beyond physio-relevant timelines) or thermodynamic increase in solubilization that allows for effective bioavailability,” contends Johnson. To achieve that goal, she believes continued investment in novel excipients that balance the need for increasing solubility while not hindering absorption due to competing thermodynamic or partitioning mechanisms will be necessary.
Adam points to the increasing number of “brick dust” candidates in the pipeline that are poorly soluble in both water and typically used organic solvents. That makes SD infeasible due to poor throughput or high emissions of harsh solvents. Because they often have higher Tm values, HME is also often challenging or not possible. “Strategies that can overcome the manufacturing complications with brick dust compounds will drive future formulation opportunities for needed therapeutics,” she concludes.
Drug loading also remains an issue for amorphous API dosage forms because they sometimes require high amounts of polymers to help with stabilization. In addition to HLDF architecture, Adam remarks that further improvements in stabilization technologies that enable decreased polymer amounts are needed to address this issue.
For Price, growing numbers of proteolysis targeting chimeras (PROTACs) and beyond rule-of-five (bRo5) compounds with molecular weights greater than 500 Daltons making their way through the clinic will be an important driver of innovation in amorphous technologies. “These larger molecules have the potential to totally transform the treatment of disease, in much the same way that mRNA is currently doing. The big difference is that PROTACs and bRo5 molecules have a high likelihood of being orally bioavailable and thus can be delivered orally. Development efforts must therefore be directed at identifying amorphous technologies for the formulation and stabilization of these novel and exciting modalities to ensure acceptable absorption from the GI tract,” he says.
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2. S.V. Bhujbal, et al., Acta Pharmaceutica Sinica B 11, 2505-2536 (2021).
3. D. T. Friesen, et al.,Mol. Pharm., 5, 1003-1019 (2008).
4. Y. Kapoor, et al., Molecular Pharmaceutics, 18, 2455-2469 (2021).
5. R. B. Chavan, et al., International Journal of Pharmaceutics, 515, 403-415 (2016).
6. D. T. Friesen, et al., Spray-drying process. Patent US2017333861A1, 2017.
7. W. Qiang, et al., Pharmaceutics, 12, 655 (2020).
8. M. Doreth, et al., International Journal of Pharmaceutics, 519, 343-351 (2017).
Volume 45, Number 12
When referring to this article, please cite it as C. Challener, “Stabilization of Amorphous APIs,” Pharmaceutical Technology 45 (12) 2021.