Identifying Conformational Isomers of Organic Molecules in Solution via Unsupervised Clustering.

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterized by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the Fast Search and Find of Density Peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase, and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that while Sildenafil can adopt more than 100 metastable conformational configurations, only 12 are significantly populated across all of the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

Recent Advances in Co-processed APIs and Proposals for Enabling Commercialization of These Transformative Technologies.

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

FDA/M-CERSI Co-Processed API Workshop Proceedings.

These proceedings contain presentation summaries and discussion highlights from the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) Workshop on Co-processed API, held on July 13 and 14, 2022. This workshop examined recent advances in the use of co-processed active pharmaceutical ingredients as a technology to improve drug substance physicochemical properties and drug product manufacturing process robustness, and explored proposals for enabling commercialization of these transformative technologies. Regulatory considerations were discussed with a focus on the classification, CMC strategies, and CMC documentation supporting the use of this class of materials from clinical studies through commercialization. The workshop format was split between presentations from industry, academia and the FDA, followed by breakout sessions structured to facilitate discussion. Given co-processed API is a relatively new concept, the authors felt it prudent to compile these proceedings to gain further visibility to topics discussed and perspectives raised during the workshop, particularly during breakout discussions. Disclaimer: This paper reflects discussions that occurred among stakeholder groups, including FDA, on various topics. The topics covered in the paper, including recommendations, therefore, are intended to capture key discussion points. The paper should not be interpreted to reflect alignment on the different topics by the participants, and the recommendations provided should not be used in lieu of FDA published guidance or direct conversations with the Agency about a specific development program. This paper should not be construed to represent FDA's views or policies.

Investigating the Role of Solvent in the Formation of Vacancies on Ibuprofen Crystal Facets.

Surface defects play a crucial role in the process of crystal growth, as incorporation of growth units generally takes place on undercoordinated sites on the growing crystal facet. In this work, we use molecular simulations to obtain information on the role of the solvent in the roughening of three morphologically relevant crystal faces of form I of racemic ibuprofen. To this aim, we devise a computational strategy to evaluate the energetic cost associated with the formation of a surface vacancy for a set of ten solvents, covering a range of polarities and hydrogen bonding propensities. We find that the mechanism as well as the work of defect formation are markedly solvent and facet dependent. Based on Mean Force Integration and Well Tempered Metadynamics, the methodology developed in this work has been designed with the aim of capturing solvent effects at the atomistic scale while maintaining the computational efficiency necessary for implementation in high-throughput in-silico screenings of crystallization solvents.

A Structured Approach To Cope with Impurities during Industrial Crystallization Development.

The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.

Dynamics and Thermodynamics of Ibuprofen Conformational Isomerism at the Crystal/Solution Interface.

Conformational flexibility of molecules involved in crystal growth and dissolution is rarely investigated in detail and usually considered to be negligible in the formulation of mesoscopic models of crystal growth. In this work, we set out to investigate the conformational isomerism of ibuprofen as it approaches and is incorporated in the morphologically dominant {100} crystal face, in a range of different solvents: water, 1-butanol, toluene, cyclohexanone, cyclohexane, acetonitrile, and trichloromethane. To this end, we combine extensive molecular dynamics and well-tempered metadynamics simulations to estimate the equilibrium distribution of conformers, compute conformer-conformer transition rates, and extract the characteristic relaxation time of the conformer population in solution, adsorbed at the solid/liquid interface, incorporated in the crystal in contact with the mother solution, and in the crystal bulk. We find that, while the conformational equilibrium distribution is weakly dependent on the solvent, relaxation times are instead significantly affected by it. Furthermore, differences in the relaxation dynamics are enhanced on the crystal surface, where conformational transitions become slower and specific conformational transition pathways are hindered. This leads us to observe that the dominant mechanisms of conformational transition can also change significantly moving from the bulk solution to the crystal interface, even for a small molecule with limited conformational flexibility such as ibuprofen. Our findings suggest that understanding conformational flexibility is key to provide an accurate description of the solid/liquid interface during crystal dissolution and growth, and therefore, its relevance should be systematically assessed in the formulation of mesoscopic growth models.

Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design.

This review seeks to offer a broad perspective that encompasses an understanding of the drug product attributes affected by active pharmaceutical ingredient (API) physical properties, their link to solid form selection and the role of particle engineering. While the crucial role of active pharmaceutical ingredient (API) solid form selection is universally acknowledged in the pharmaceutical industry, the value of increasing effort to understanding the link between solid form, API physical properties and drug product formulation and manufacture is now also being recognised. A truly holistic strategy for drug product development should focus on connecting solid form selection, particle engineering and formulation design to both exploit opportunities to access simpler manufacturing operations and prevent failures. Modelling and predictive tools that assist in establishing these links early in product development are discussed. In addition, the potential for differences between the ingoing API physical properties and those in the final product caused by drug product processing is considered. The focus of this review is on oral solid dosage forms and dry powder inhaler products for lung delivery.