Highly potent drugs exhibit a combination of high toxicity and therapeutic efficacy at low doses. They also often suffer from poor aqueous bioavailability, have specific release requirements to minimize potential toxicological effects, and bitter taste. As such, they present formulation challenges, including selection of necessary and appropriate excipients such as solubility and permeation enhancers to improve bioavailability, polymeric excipients to modify release profiles and flavor compounds to mask taste, according to Marcus Jenkins, Technical Consultant with SGS.
Analysis of high-potency formulations can also be difficult. The main analytical in-vitro release tests required for pharmaceutical drug products are confirmation of identity and quantification of the drug substance and impurities, as well as performance tests, such as determination of dissolution behavior for solid-dose products. In addition to the use of numerous and varying excipients, dose-form design and solubility pose specific challenges for analytical method development and implementation for highly potent drug formulations.
Real examples of highly potent analytical challenges
SGS has worked with many different highly potent drug formulations, and each has presented its own set of challenges. Two examples include a thyroid hormone product and a highly potent drug candidate dosed in the microgram range.
For the thyroid hormone product, solid-phase extraction (SPE) technology was used to reduce excipient interference. Initially, reproducible recovery of the drug was challenging when using low rinse volumes to maintain the required concentrations for analysis, according to Marcus Jenkins, Technical Consultant with SGS, as the loss of even small amounts of drug substance during sample preparation resulted in a large percentage decrease in its assay result. “Fortunately,” he says, “SPE technology has advanced and today more reliably prepared cartridges with a wide range of stationary phases are now available that allow analysis of drug substances with different physicochemical properties.”
The drug candidate dosed in the microgram range severely limited sample dilution. In fact, a higher concentration was required for impurity analysis to maintain the necessary level of sensitivity and ensure that low-level impurities could be effectively quantified. In addition, the use of dedicated glassware was necessary to avoid contamination and ensure no additional compounds (drugs or excipients) from other ongoing projects could interfere with the analysis. Dilution was then performed prior to analysis of the drug substance assay.
Numerous issues must be resolved
There are a few main analytical challenges that developers of highly potent drug formulations face. First, the high potency and low concentration of the drug substances in these formulations make it necessary to limit sample dilution in order to achieve suitable nominal concentrations for testing. “While the limitations will depend on the physicochemical properties of each drug substance, low sample dilution typically results in high excipient contributions to samples when they are tested,” Jenkins comments.
Low sample dilution may also enable greater external interference of samples via contamination from glassware, processes, or equipment. Such an issue is generally not observed for higher-dose products because the low levels of contaminants present are often diluted out of testing concentration ranges, according to Jenkins.
A second issue is the level of sensitivity needed for effective impurity analysis. “Due to the low doses for highly potent drugs, analytical testing concentrations will often be low and thus provide a challenge to the sensitivity of any method or equipment used,” Jenkins states. The use of higher sample loading to improve the response and sensitivity for low-dose products creates the third challenge, which is that larger injection volumes increase the quantities of injected excipients.
This approach can not only result in reduced equipment lifetimes, but also require the addition of extra cleaning steps, contributing to increased equipment downtime and reduced throughput and capacity in testing laboratories, Jenkins adds. Furthermore, to minimize or eliminate excipient interference requires additional preparation steps, which lengthen the process and increase complexity, potentially leading to greater variability.
Last but not least, to ensure the safety of operators and the environment, handing of highly potent drug samples must be pursued with the proper controls in place, which can include containment such as hoods or isolators. Jenkins notes that this additional complexity can also introduce variability to testing processes.
Excipients cause concern during uniformity determination
For highly potent, low-dose drugs, ensuring the uniform distribution of the drug substance throughout the matrix is essential and often challenging. “Accurate and reliable analytical data [are] needed to enable effective and efficient product-development decisions. Should there be any doubt about the the accuracy of the analytical data regarding drug substance uniformity, development time, effort, and associated cost may be wasted trying to resolve potential formulation issues that are not real,” Jenkins observes.
The biggest issue often relates to detection difficulties due to the presence of excipients that absorb in UV wavelength regions similar to those for drug substances. One way to avoid this issue is to consider the analytical impacts of excipients during early screening and selection efforts before too much time and effort have been invested in prototype generation, according to Jenkins. Another approach is to choose alternative detection wavelengths that minimize excipient contribution, but the ability to do so depends on the absorption properties of the drug substance.
Polymeric excipients used to modify the in-vivo release of drugs can impact accurate extraction during sample preparation. “For some high-potency drug formulations it may be necessary to complete additional preparation steps to ensure full recovery of the drug substance as required to meet industry in-process checks or finished-product specifications,” Jenkins says.
Polymeric excipients may also present challenges to lab equipment such as chromatographic columns, as they can be difficult to remove and may create the need for additional cleaning/regeneration steps to return columns to optimal performance or irreversibly reduce column lifetimes, according to Jenkins. “Column deterioration during analysis can, in fact, increase the risk of an analysis failing to meet typical system suitability criteria, leading to the need to repeat analyses, thus reducing testing efficiency and cost-effectiveness,” he states.
Careful solvent selection essential
To achieve effective analysis, all ingredients of interest in a drug formulation must be soluble in a solvent suitable for the intended method of analysis. That can be an issue for highly potent drug substances with poor water solubility, as organic solvents are typically required. “For a particular formulation, the solvent should effectively dissolve the drug substance or other ingredient of interest (e.g., preservative or anti-oxidant) but not the other formulation excipients in order to minimize excipient contributions; however, drug substances and excipients often exhibit similar properties and tend to be soluble in the same solvents,” Jenkins explains.
Careful column stationary- and mobile-phase selection can be used to separate unwanted excipient interference from peaks of interest ensuring acceptable specificity. These choices can be guided somewhat by consideration of the chemical structures of the compounds involved, according to Jenkins. “Polar functionalities in the drug substance will interact with imbedded polar groups on columns, while delocalized electron systems will interact with similar systems in certain stationary phases such as pentafluorophenyl, and alkyl chains will interact with C8 or C18 stationary phases, etc. Modern analytical columns now have combinations of these groups to allow for a wider range of stationary phases for evaluation during analytical development,” he observes.
Another approach is to use secondary or tertiary wavelength maxima to minimize interference from excipients in a highly potent drug formulation. “It is necessary, however, to consider the analysis of degradation products, as they can have different UV absorbances compared to their parent moieties,” Jenkins states. He adds that while longer wavelengths will reduce excipient contribution to the analysis, they do not prevent physical interactions of excipients with the stationary phase and the need for additional cleaning steps.
Sustained-release formulations require increased sensitivity and non-routine analyses
Highly potent drug formulations that are engineered to enable sustained release of the drug substance with targeted delivery to minimize potential toxicological effects often rely on alternative or novel excipients. These systems, according to Jenkins, reduce the initial onset and prolong the therapeutic effect window.
In-vitro release testing for such formulations requires detection of low levels of drug substances (particularly at early time points) released at slow rates. For instance, a sustained-release formulation may release 5–0% of the drug substance after 5–10 minutes, while an immediate-release formulation will typically release >45%, observes Jenkins. “Increased sensitivity achieved through use of higher-sensitivity detectors or modifications such as higher path-length flow cells or application of non-routine/non-pharmacopeial equipment, such as micro-dissolution and/or sample concentrators, is therefore often necessary. Justification of the suitability, control, and use of such equipment is, however, usually required during regulatory review,” he says.
Other dissolution testing hurdles
It is not just sustained-release formulations that can cause challenges to effective dissolution analysis. For oral-dosage-form drugs formulated as capsules, during dissolution analysis certain combinations of excipients, dissolution media, and the polymers used to form the capsule shells can react to form pellicles that retard drug-substance release, according to Jenkins. “This issue is addressed either through the development of specific dissolution media to prevent crosslinking or the inclusion of the enzyme pepsin to degrade any formed pellicles,” he says. He does note, however, that these approaches are not generally applied from the outset, as often this problem does not appear until several months into
stability testing of a product.
Need for instrument innovation combined with analytical expertise
As more knowledge is gained about disease mechanisms and new drug targets are identified, the nature of highly potent drug substances continues to evolve. They are becoming steadily more potent while their solubility/permeability continues to decline. At the same time, demands for safer, easier-to-use drugs that are not only developed with patients in mind but also cost-effective are growing.
Formulation of highly potent drugs that meet those demands can be challenging, particularly given the complexity of drug formulation and analysis for these products. “The largest contribution to the cost of new, novel medicines is the time taken for development (circa 8–12 years). Improving the efficiency of development should therefore result in a reduction in the cost-per-unit and earlier availability of drugs to patients. One way to reduce development times is through introduction of more advanced analytical instruments and methods with greater sensitivity that support quick resolution of analytical challenges,” Jenkins contends.
Combining innovative systems with experienced analytical and formulation scientists using a collaborative approach would, Jenkins adds, further ensure sound scientific rationale resulting in effective development decisions. He points to, for example, consideration of the downstream impacts of formulation development decisions on required analytical methodologies. The overall result, Jenkins believes, would ultimately be expedited development timeframes for novel medicines that address unmet patient needs.
About the author
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Article details
Pharmaceutical Technology
Vol. 47, No. 7
July 2023
Pages: 20-23
Citation
When referring to this article, please cite it as Challener, C.A. Overcoming Analytical Challenges in High Potency Formulation. Pharmaceutical Technology 2023 47(7).
