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Tablets & Capsules March 2020 25 has a primary amine group. Similarly, you should avoid using povidone with APIs that degrade in the presence of peroxides because chemical manufacturers use hydrogen peroxide as an initiator for povidone manufacturing, and povidone always contains traces of peroxide. Often, due to budgetary constraints or to accommo- date aggressive timelines, pharmaceutical manufacturers overlook ECSs and choose to rely solely on finished-prod- uct stability data. This can be costly, and incompatibilities detected during those studies can severely delay the drug development process as well as regulatory submission. Stability An SDD is a metastable amorphous molecular disper- sion of an API in a polymer matrix. Under certain condi- tions, an SDD may revert from the free amorphous state to the more stable, but less soluble, crystalline state. This affects solubility, bioavailability, and ultimately, drug efficacy. Throughout downstream processing and storage, you must be cognizant of conditions that help maintain an SDD's amorphous state. Deviations in temperature, humidity, or light can cause reversions. Also, if you don't properly understand the drug-degradation pathway, you may select a process that could degrade the API (such as heat, oxygen, or chemical or mechanical stress) or intro- duce harmful degradants. The typical drug load of an SDD is about 30 to 50 percent, which limits the excipient amounts a formula- tion can contain to keep the tablet size acceptable for oral administration. For higher doses, you can achieve a smaller tablet size by densifying the SDD using a roller compaction process if the API is amenable. The SDD's particle size distribution must be suitable for downstream processing to avoid segregation in a direct blend process. For a cohesive and poorly flowing SDD, you can improve flow by adding glidants. You must establish critical process parameters (CPPs) for the manufacturing process as well as critical quality attributes (CQAs) for the product early in the develop- ment process. If you don't give these and other potential While you may think you've analyzed an API's chem- istry, manufacturing, and controls (CMC), the guidelines for new technologies such as spray-dried dispersions (SDDs) are still poorly defined, and you must ensure that your analysis holds up. A robust regulatory strategy and timeline can help prioritize CMC activities. This article discusses the factors you should consider when develop- ing a drug product with a complex API. Preformulation studies Finite resources combined with a rush to market can tempt developers to eliminate or delay key preformu- lation studies, but knowing your API candidate's phys- icochemical properties from the start can help fore- stall problems. The studies can help you select the best development approach, minimizing the need to repeat experiments or alter a formulation during later clini- cal-development phases and helping to avoid process and manufacturing challenges. Also, clinical teams may not appreciate your wish to circle back and perform a phys- icochemical characterization or modify a process and/or formulation late in development. Comprehensive preformulation studies can help you identify a more stable API than you otherwise would to achieve your desired drug product attributes. For example, API physical characterization might uncover hydrates, solvates, or polymorphs with variable proper- ties, including those related to solubility and stability. A thorough evaluation of different API forms, pH sol- ubility, pKa, and animal pharmacokinetic data can help you determine if a particular dosage form, such as modi- fied-release, could provide an appropriate dosing strategy and eliminate last-minute surprises during development. When you have identified the intended dosage form, excipient compatibility studies (ECSs) can ensure that the selected excipients are compatible with the API and won't affect the product's potency or produce harmful degradants. Recognizing patterns of incompatibility during early development phases can save you time. For example, to avoid a Maillard reaction, you might want to eliminate reducing sugars from a formulation if the API Photo 1: Preformulation studies can help you select the best formulation approach, minimizing the need to repeat experiments or alter a formulation during later clinical-development phases and helping to avoid process and manufacturing challenges. Photo 2: Establishing critical process parameters for the manufacturing process early in development will help prevent downstream problems during scale-up.