Flexibility in Drug Product Development: A Perspective.

The process of bringing a drug to market involves innumerable decisions to refine a concept into a final product. The final product goes through extensive research and development to meet the target product profile and to obtain a product that is manufacturable at scale. Historically, this process often feels inflexible and linear, as ideas and development paths are eliminated early on to allow focus on the workstream with the highest probability of success. Carrying multiple options early in development is both time-consuming and resource-intensive. Similarly, changing development pathways after significant investment carries a high "penalty of change" (PoC), which makes pivoting to a new concept late in development inhibitory. Can drug product (DP) development be made more flexible? The authors believe that combining a nonlinear DP development approach, leveraging state-of-the art data sciences, and using emerging process and measurement technologies will offer enhanced flexibility and should become the new normal. Through the use of iterative DP evaluation, "smart" clinical studies, artificial intelligence, novel characterization techniques, automation, and data collection/modeling/interpretation, it should be possible to significantly reduce the PoC during development. In this Perspective, a review of ideas/techniques along with supporting technologies that can be applied at each stage of DP development is shared. It is further discussed how these contribute to an improved and flexible DP development through the acceleration of the iterative build-measure-learn cycle in laboratories and clinical trials.

Quantifying Pharmaceutical Formulations from Proton Detected Solid-State NMR under Ultrafast Magic Angle Spinning.

Probing form conversions of active pharmaceutical ingredients in solid dosages is critical for understanding the physicochemical stability of drug substances in formulations. The multicomponent and low drug loading nature of drug products often results in challenges to quantify the phase stability, at a low detection limit and with the chemical resolution that differentiate drug molecules and excipients, for routine laboratory techniques. Recent advancement of ultrafast magic angle spinning (UF-MAS) enables proton-detected solid-state nuclear magnetic resonance (ssNMR) techniques to characterize pharmaceutical materials with enhanced resolution and sensitivity. This study demonstrates one of the first documented cases implementing 60 kHz UF-MAS techniques to quantify the minor content of pioglitazone free base (PIO-FB) in a binary system with its hydrochloride salt (PIO-HCl) and a multicomponent formulation with typical excipients. One-dimensional 1H methods can unambiguously differentiate the two forms and exhibit a limit of detection at 1.77% (w/w). Moreover, we extended it to a two-dimensional 1H-1H correlation for minimizing peak overlap and successfully quantifying approximately 2.0% (w/w) PIO-FB in a multicomponent formulation. These results have demonstrated that 1H ssNMR as a novel method to quantify solid dosages at a higher resolution and faster acquisition than conventional 13C techniques.

Modeling the Air Pressure Increase Within a Powder Bed During Compression-A Step Toward Understanding Tablet Defects.

The cause of tablet defects, such as cracking, bubbling, and capping, during compression is currently not fully understood. Prior experimental work suggests that an increase in internal air pressure on powder compression can directly contribute to the formation of cracks within a tablet. The present study examines the air pressure increase on compression in a fully two-dimensional axisymmetric tablet geometry while being coupled to a plasticity model describing the evolution of tablet relative density on consolidation. It is shown numerically that increasing compression speed results in a large air pressure increase on the order of 1-1.5 MPa which approaches the diametrical tensile strength of tablets. In addition, it is shown experimentally through X-ray microcomputed tomography scans of tablets made at various dwell times that increasing dwell times equivalent to that on a tablet press has no effect on the degree of cracking within the tablet. Only when dwell times reach a time scale of 10 to 100 s does the air pressure diminish to a point at which cracking is eliminated. The reduction in air pressure during these extended dwells is captured by the current model. The experimental and numerical work presented here couples for the first time an air pressure model and plasticity model on compression. In addition, it provides a foundation for understanding how realistic tableting aspects such as precompression and tablet size impact the air pressure increase on consolidation.

Temperature and cholesterol composition-dependent behavior of 1-myristoyl-2-[12-[(5-dimethylamino-1-naphthalenesulfonyl)amino]dodecanoyl]-sn-glycero-3-phosphocholine in 1,2-dimyristoyl-sn-glycero-3-phosphocholine membranes.

We present a steady-state and time-resolved fluorescence emission spectra analysis of the membrane probe 1-myristoyl-2-[12-[(5-dimethylamino-1-naphthalenesulfonyl)amino]dodecanoyl]-sn-glycero-3-phosphocholine (DANSYL) in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol multi-lamellar vesicles (MLV) prepared by modified rapid solvent exchange. We report that the dose-dependent cholesterol-induced blue shifts in the steady-state fluorescence emission spectra observed in DMPC MLV are due to complex solvent effects that include time-dependent dipolar relaxation and the formation of internal charge transfer (ICT) states. A key finding of this investigation is identification of two distinguishable DANSYL populations existing at both shallow and deep locations in the membrane; these two DANSYL populations are evidence of laterally phase-separated domains at cholesterol compositions between X(chol) = 0.30 and 0.60 at 30 degrees C in DMPC MLV.