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The key is to ensure that excipients only interact with APIs via desired mechanisms.
Excipients are essential components of drug formulations. While physiologically inert, they have functionalities that achieve many formulation goals, such as API stabilization, taste masking, and extended release. “Functional excipients play an integral role in achieving the desired biological performance of many drug formulations,” asserts Robert Lee, president of the CDMO division of Lubrizol Life Science Health. Many excipients, however-depending on the API structure, dosage form, packaging configuration, and storage, handling, and use conditions-may also interact via mechanisms that negatively impact efficacy and safety. The challenge is to identify the right excipients for each formulation.
Interactions between excipients and APIs can occur via both chemical and physical mechanisms. “Many small-molecule APIs are inherently complex and have diverse functional groups that can undergo multiple reactions either simultaneously or in sequence,” says Anil Kane, executive director and global head of technical and scientific affairs with Thermo Fisher Scientific. Thus, the degradation of pharmaceuticals is an area that is complex.
The major mechanisms for chemical decomposition of pharmaceuticals with other excipients include hydrolysis, dehydration, oxidation, isomerization/epimerization, decarboxylation, dimerization, polymerization, and photolysis, according to Kane. Complexation with excipients to form salts is also possible.
In some cases, the excipient itself doesn’t initially interact in a negative manner with the API. For that to occur, it must first undergo a chemical reaction to generate a new species that can affect the API. For instance, Lee notes that some unsaturated polymers can in the presence of oxygen form peroxides that will degrade oxidatively labile APIs.
“While many pathways of degradation are obvious from basic organic chemistry principles, it is not uncommon to find surprising degradation chemistry leading to unexpected degradation products and pathways,” Kane observes.
Physical interactions include hydrophobic and hydrophilic media interaction and interactions that affect particle size and shape. For instance, in nanoparticulate suspensions, excipients physically adsorb to the surfaces of the API nanoparticles via steric or charge-charge interactions.
In fact, the dosage form plays a role in determining the potential interactions that can occur. Molecular mobility in solids is far less than in the liquid state, hence chemical reactivity in the solid state generally occurs under severe conditions of temperature and/or humidity or in presence of a catalyst, according to Kane. Considerations for chemical degradation are more critical for non-sterile oral liquids and sterile parenteral products because the excipients and APIs are more mobile and there are more opportunities for chemical reactions. For lyophilized products, interactions can occur in the initial buffered solution as well as in the lyophilized cake.
Interactions between excipients can be either beneficial or harmful. Hydrophilic and hydrophobic media interactions are generally beneficial, according to Richard Shook, director of drug product technical services and business integration at Cambrex. “Through these mechanisms, polymers can delay the release of the drug substance to better target the site of absorption and protect the API from degradation in the gastrointestinal tract. Polymers can also be used to enable prolonged duration of API release, increasing the time of drug absorption and decreasing patient dosing frequency, thereby assisting treatment compliance,” he explains.
For example, lower-molecular-weight polymers assist in “bridging” of particles during wet granulation processing and can be used to coat API particles to increase their interface with surrounding media during dissolution. Higher-molecular-weight polymers, meanwhile, can form hydrogels that restrict the release of API, enabling extended release. Preferential polymer bridging between smaller and larger particles during wet granulation, meanwhile, can affect particle size and shape selection, leading to desirable granule formation. Saturated fat-based lubricants such as magnesium stearate and stearic acid can create a hydrophobic barrier within the dosage form to ensure proper delivery.
For nanoparticulate suspensions, which offer increased dissolution rates and potential higher bioavailability due to the high surface area of the particles, the high-energy milling process used to create the nanoparticles generates crystals with high surface energies. Use of excipients to lower the surface energy and stabilize the nanoparticles is therefore necessary, according to Lee. Polymeric stabilizers such as polyvinyl pyrrolidone provide steric stabilization, while charged excipients such as sodium lauryl sulfate participate in electrostatic interactions.
APIs containing aromatic groups can, in some cases, benefit from interactions with polymeric excipients that also possess aromatic functionality, according to Lee. In this case, there is the potential for the aromatic rings to stack together (π-π stacking), which may lead to stabilization of the API.
Some chemical reactions are also desirable. For instance, Shook points to the use of pH-enhancing excipients such as citric acid, sodium hydroxide, etc., which can stabilize pH-sensitive APIs by creating microenvironments within dosage forms. Alternatively, certain excipients can be added to participate in competitive reactions as a means of protecting the API. One example is butylated hydroxytoluene, which in some formulations is preferentially oxidized over the API.
When interactions of the API with functional excipients lead to degradation and the formation of known or unknown impurities, however, the results are generally not beneficial. In these cases, the interactions can have a number of consequences, such as physical changes including discoloration, agglomeration, plug formation, precipitation, cloudiness in liquids, etc., according to Kane.
One of the most important undesirable reactions is the Maillard reaction between amines and alcohol functionalities, the latter of which are common in sugar excipients such as lactose. The result is formation of high-molecular-weight brown polymeric material with a strong aroma, leading to formulations that are discolored and have an unpleasant odor, according to Shook. Another common issue is the degradation of pH-sensitive APIs due to exposure to acidic or basic environments. In some cases, encapsulation can protect APIs that are hydrolytically or enzymatically labile, Lee notes.
“The main impact of the interactions of APIs and excipients, however, is not only loss of potency and the intended therapeutic efficacy, but also formation of degradation products that may or may not be toxic,” he observes. “Degradation of the API will result in a drug product not meeting specifications for its assay (or potency) and content uniformity. The dissolution performance of the active drug substance may also decrease. Thus, the drug product will not meet its expected critical quality attributes,” he continues.
With efforts to reduce time and cost to market, the potential for stability issues increases dramatically, according to Kane. The ability to rapidly predict and assess the potential for stability and safety concerns is, therefore, an important part of speeding the development of innovative drug therapies. “Degradation prediction enables understanding of labile functionalities critical in designing less reactive, more stable analogs, and degradation studies conducted by a chemistry-guided, predictive, stability approach enable analysts to deliver stability-indicating methodology more efficiently,” he asserts.
The first step is to examine the possible mechanisms of chemical decomposition for the API in the context of the common functional groups that are present in the molecule. APIs containing functional groups, such as ionizable moieties, amines, and carboxylic acids, present the greatest risk for interacting with excipients, according to Lee. Excipients that can enhance these mechanisms should be avoided.
In addition, it is important, according to Kane, to consider the excipient impurity profile, which is generally lot specific. Impurities of concern include water, solvents, metals, acidic/basic compounds, and reactive molecules (e.g., peroxides, aldehydes, organic acids). The amorphous content is an additional factor, as is the equilibrium moisture content and hygroscopicity profile, effective pH in water, and the thermal and thermal/humidity solid-state stability (chemical and physical).
It is worth noting, adds Lee, that in some cases, excipient suppliers offer special, extremely high-purity versions of certain products. When an API is identified as being susceptible to oxidation, for instance, “cleaner” excipients with very low limits of oxidizing substances would be preferred as a means for reducing the risk of undesirable interactions.
The choice of excipients is usually based on forced degradation data for the API. “Forced degradation data provide information about the potential degradation pathways for the API and for the formation of impurities in acidic and basic environments, when exposed to light or oxidative conditions, and under high temperature and high humidity conditions,” he says.
Proper characterization of excipient/drug substance interactions using physical and chemical testing is paramount, Shook agrees. “No stone should be left unturned when identifying critical material attributes of a target drug substance. For example, various excipient compatibility studies, such as binary blends, formulated prototypes, compressed versus loose powder, etc., can be designed to align with the available API and timeline,” he observes. The studies, he adds, are best employed in a phase-appropriate manner.
Prior to initiation of any compatibility studies, a thorough review of relevant drug substance information available at the time of the compatibility studies is extremely important, according to Kane. This evaluation should include a review of the structural understanding of the molecular scaffold and the sites of known reactivity, a detailed review of the synthetic route, a review of the API solution state stability data (pH, thermal, and photostability challenges), any and all forced degradation data, and metabolite formation information and output from predictive models of degradation.
“A risk-assessment approach should be used that involves combining the knowledge of reactive impurities in excipients along with an understanding of the potential degradation pathways for the API. Other factors such as the drug-to-excipient ratio, crystal form of the API, environmental conditions, surface acidity, and microenvironmental pH must also be considered during the assessment and mitigation of risk. Finally, mitigation strategies should include ‘designing out’ the incompatibilities through formulation design, packaging configurations, or through establishment of a control strategy,” Kane comments.
There are a number of strategies that can be employed to minimize undesirable excipient-API interactions ranging from avoidance of problematic excipients to the use of excipients that stabilize or protect APIs, devices that physically separate formulation ingredients until the time of administration, and packaging that incorporates chemical agents that inhibit certain chemical reactions.
For oral solid-dosage forms, there are several different options for protecting APIs that are sensitive to moisture or oxidative degradation. In the former case, Kane notes that excipients with low moisture content should be used to reduce the probability of chemical interaction due to hydrolysis and silica should be added to adsorb any moisture picked up in the formulation. Moisture-barrier film coatings can also be employed, according to Shook. Inclusion of desiccant packs in the drug product bottle pack and/or flushing an inert gas such as nitrogen or dry air during packaging are also recommended.
For APIs that can react with oxygen, excipients that contain or can generate peroxides should be avoided, while antioxidants should be added to the formulation in the optimal quantity, according to Kane. Selection of the right packaging components and reducing the headspace of the pack may help prevent exposure of the product to an oxidative environment. Inclusion of oxygen scavengers in the bottle pack and blistering and/or bottling the drug product under inert atmosphere (dry air or nitrogen) is also recommended to improve the stability of a packaged product.
For fat-based lubricants such as magnesium stearate and stearic acid, proper characterization of material blending is important, according to Shook. “Blending times must be optimized to balance proper introduction of the lubricant with minimal coating of the drug substance particles,” he says.
For non-sterile oral liquids and liquid injectables, the addition of acidic or basic excipients or buffering agents as appropriate can help maintain the desired pH and prevent degradation of the API, according to Kane. If an excipient is necessary to achieve proper delivery but cannot be in contact with the API for extended periods of time, the use of dual-chamber syringes or packaging in separate vials are options for keeping the ingredients physically separate until the time of administration, according to Lee. “The key for these solutions is to have a good understanding of the length of time during which the combined ingredients will be stable in order to ensure that patients are being administered the correct formulation,” he comments.
Whichever solutions are chosen, they are selected based on extensive pre-formulation and analytical work and intended to provide design control that will lead to acceptable products, according to Lee.
Most importantly, Lee stresses that it is essential to make certain that each excipient used in a formulation has a well-defined function. “It is critical to question every excipient that is added to a formulation. Formulators must be able to justify the use of each and every excipient in their formulations and ensure that they are using the minimal quantity for each that will afford the target product profile,” he asserts.
To achieve that goal requires experience and expertise in formulation development and the potential physical and chemical mechanisms of interaction between excipients and APIs with a wide range of functionalities.
“The best strategy to prevent future drug substance and excipient interaction headaches is to partner with an experienced, proactive formulation team,” says Shook. “Strong collaboration between a formulation team and an analytical team conducting forced degradation on the drug substance can also prove highly beneficial,” he concludes.
Vol. 43, No. 12
When referring to this article, please cite it as C. Challener, “Managing Excipient Interactions," Pharmaceutical Technology 43 (12) 2019.