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Within the broader context of the pharmaceutical industry’s drug development trajectory, the drug’s stability goes beyond being a quality measure; it influences safety, effective marketing, and compliance with governmental regulations. Pharmaceutical companies undergo strict quality control measures, and any lapse in a drug product’s stability profile during development, storage, or shipment would render any and all work done to them futile. Stability is a moving attribute, progressive and in most cases, influenced by the interplay of a number of dynamics. The purpose of this article is to examine five such elements to aid drug formulators adjust to risks proactively by ensuring appropriate decisions and preserving the product’s integrity.
One of the enduring and longest-standing challenges in drug formulation is the poorly soluble Active Pharmaceutical Ingredients (APIs) especially in BCS Class II and IV drugs. Even with the appropriate pharmacological profiles, such drugs tend to have low solubility and low permeability, posing challenges to absorption. This dual challenge not only increases these compounds’ bioavailability challenges but also has the potential to derail the development timelines.
The formulation challenges such poorly soluble APIs create does not only increase the costs, but also change the timelines. APIs that do not dissolve encounter issues with absorption, leading to sub-therapeutic concentration and pharmacokinetic issues. This, in turn, increases the likelihood of failure in preclinical and clinical stages, only raising the costs of development.
To proactively tackle these issues, scientists and researchers are implementing advanced formulation strategies such as solid dispersion and amorphous transformation. Active polymorph screening is also aimed to enhance the dissolution rates of poorly soluble compounds.In the early stages of drug development, predictive solubility modeling is also helping researchers get a better understanding of how a molecule behaves under specific conditions, leading to formulation decisions in the early stages.
The environment can materially affect the quality and stability of drug products throughout their life cycle. With regards to APIs and excipients, moisture, heat, and oxygen can pose great risks. Storage and processing of many compounds can result in chemical degradation, like hydrolysis, due to moisture absorption from the environment. Additionally, polymorphic transitions can occur during processing. Predicting shelf life becomes very difficult without thorough modeling of stability in advance.
Set formulation strategies aside, environmental destabilization is the main formulation failure. Deformulation or structural alteration during a drug’s shelf life can affect the product’s safety, potency, and regulatory compliance which in turn can lead to expensive recalls, reformulation, or delayed marketing, or litigation.
To mitigate the above risks, stability profiling is integrated into every stage of formulation development. Controlled studies at varying levels of temperature and humidity reveal how a given material responds to real-world extremes. This approach also determines the moisture protective package and the excipients and their processing conditions that need to be used for maximum stability. With strong modeling and proactive design, robust predictive shelf-life estimates can be achieved.
Interacting with active pharmaceutical ingredients or APIs, excipients are often considered “inactive” ingredients, but their interactions with APIs are anything but trivial. Not well understood drug–excipient interactions can undermine a drug’s stability, modify its release profile, or therapeutic effectiveness. Striking a balance between choosing an excipient that enhances solubility and one that triggers no degradation is painstaking, and often delusional in early development stages due to shallow development screening tools.
Inappropriate excipients can destroy even the best formulations. Formulators do not have accurate predictive models and understanding of material interactions, they fall into a costly trial and error routine. This not only elongates the timeline and budget but also increases chances of formulation failure in late stages.
To sharpen accuracy and effectiveness, formulation scientists are improving compatibility studies as well as using accelerated screening techniques.
By looking into material moisture affinity, particle surfaces, and even reactivity, formulating scientists can now detect troublesome interactions way earlier. This allows for flexible excipient selection to ensure drug stabilized performance in designs.
It’s not often that the success of a formulation achieved at the lab scale translates directly to full scale manufacturing. With the increase in production volume emerges the nasty challenge of poorly performing drug due to inconsistencies in process parameters such as granulation, drying temperature, and mixing strength. Symptoms such as subpar flow of powder, poor compressibility, and batch-to-batch inhomogeneity highlight scale-up inadequacies.
Unresolved reproducibility issues during scaling up could lead to nearly indistinguishable lots of drugs produced, but result in expensive production halts, corrupted test batches and prolonged regulatory clearance.
Regulations demand uniform and consistent quality and accuracy in every batch, so consistent and reproducible processes during development are imposed to meet the requirements.
Modern formulation experts are anticipating the scaling up challenge early in the development process. With the assistance of advanced material science software, developers are able to measure critical aspects such as particle size, distribution, morphology, surface energy, and even moisture during moist formulation stages. Anticipating formulative behaviors allows precise mid-stream adjustments instead of requiring scrambling in a desperate attempt to finalize a formulation. By anticipating changes early and designing iteratively with scale in mind, last minute changes are avoided in turn accelerating the timeline to market.
Advanced Sorption Analyzers for Solid-state Materials
The impact of moisture on pharmaceutical formulations is far from subtle. A wide variety of APIs and excipients have some degree of sensitivity to moisture, which can lead to water absorption that crystallizes, amorphizes, or chemically degrades certain compounds. Developers require precise models of sorption behavior to accurately predict how these changes will impact a drug’s stability, performance, and shelf life.
Uncontrolled moisture absorption and sorption can lead to unanticipated failures and reduced product life. Inadequate understanding of how moisture behaves can affect choices of drug packaging, sometimes resulting in over-engineered solutions, or, worse, under-engineered ones that fail to perform in the real world and provide protection to the drug.
In a bid to counter these risks, scientists are now applying humidity-controlled environments to derive precise sorption profiles of APIs and excipients. Relative mapping of material interaction with moisture aids in understanding in moisture level interactions APIs, packaging selection, the storage conditions, and even in the stability modeling.
These Strategies help to enhance formulation design, making them more efficient and cost-effective.
Key international bodies—the FDA, EMA, and NMPA—as well as major Pharmacopeias—USP, Ph. Eur., and ChP—collectively articulate the stability testing blueprint that governs the pharmaceutical industry. Their published directives outline the entire stability examination process, addressing protocols for design, temperature and humidity profiles, projected kinetic modeling, and primary packaging.
Compliance with these harmonised recommendations not only supports the validity of stability data but also secures regulatory acceptance, facilitating the accelerated approval and expedient launch of products on a worldwide basis.
With rising poorly soluble APIs, amorphous systems, and targeted delivery technologies, pharmaceutical formulations have become more complex and research has to predict and control complex phenomena in material science and engineering much sooner.
Advanced solid-state characterization is one of the new approaches to these problems, and includes:
All of these are allowing for more predictive formulation approaches and strategies, faster troubleshooting, and more regulatory confidence from preformulation to formulation and finally even to stability testing.
For more information on advanced materials analysis techniques for drug formulation research, click here https://www.particlelaboratories.com/r/kh4
