Lipid nanoparticles (LNPs) are increasingly finding applications in targeted drug delivery, including for subcutaneous, intravenous, inhalation, and vaccine administration. While a variety of microscopy techniques are widely used for LNP characterization, their resolution does not allow for characterization of the spatial organization of different components, such as the excipients, targeting agents, or even the active ingredient. Herein, an approach is presented to probe the spatial organization of individual constituent groups of LNPs used for siRNA-based drug delivery, currently in clinical trials, by multinuclear solid-state magic-angle-spinning nuclear magnetic resonance (MAS NMR) spectroscopy. Dynamic nuclear polarization is exploited (DNP) for sensitivity enhancement, together with judicious 2H labeing, to detect functionally important LNP constituents, the siRNA and the targeting agent (<1-2 w/v%), respectively, and achieve a structural model of the LNP locating the siRNA in the core, the targeting agent below the surface, and the sugars above the lipid bilayer at the surface. The integrated approach presented here is applicable for structural analysis of LNPs and can be extended more generally to other multi-component biological formulations.

Understanding the behavior of tablet disintegrants is valuable in the development of pharmaceutical solid dosage formulations. In this study, high-resolution magnetic resonance imaging has been used to understand the hydration behavior of a series of commercial sodium starch glycolate (SSG) samples, providing robust estimates of tablet disintegration rate that could be correlated with physicochemical properties of the SSGs, such as the extent of phosphorus (P) cross-linking as obtained from infra-red spectroscopy. Furthermore, elemental analysis together with powder X-ray diffraction has been used to quantify the presence of carboxymethyl groups and salt impurities, which also contribute to the disintegration behavior. The utility of Fast Low Angle SHot magnetic resonance imaging has been demonstrated as an approach to rapidly acquire approximations of the volume of a disintegrating tablet and, together with a robust voxel analysis routine, extract tablet disintegration rates. In this manner, a complete characterization of a series of SSG grades from different sources has been performed, showing the variability in their physicochemical properties and demonstrating a correlation between their disintegration rates and intrinsic characteristics. The insights obtained will be a valuable aid in the choice of disintegrant source as well as in managing SSG variability to ensure robustness of drug products containing SSG.

Results of high-energy X-ray diffraction experiments coupled to atomic pair distribution function analysis of disordered low-Z materials are presented. Several scientifically and technologically important classes of disordered low-Z materials such as small and large organic molecules, graphitic powders, polymers and liquids are intentionally explored to certify the technique's performance. Results clearly show that disordered low-Z materials can be well characterized in terms of material's phase identity, relative abundance in mixtures and atomic-scale structure. The demonstrated efficiency of the technique provides the scientific community with much needed confidence to apply it more often than now.

The influence of two structurally different anionic surfactants on the anhydrous-to-dihydrate transformation of carbamazepine (CBZ) was investigated. The surfactants studied were sodium lauryl sulfate (SLS), a surfactant commonly used in compendial dissolution methods, and sodium taurocholate (STC), an important surfactant in the solubilization and absorption of drugs and lipids in the gastrointestinal tract. Results show that both surfactants promoted the crystallization of CBZ dihydrate [CBZ(D)] during dissolution of the anhydrous monoclinic polymorph [CBZ(A)]). Examination of crystal surfaces showed that SLS facilitated the surface-mediated nucleation of CBZ(D) on CBZ(A) crystals at surfactant concentrations below the critical micelle concentration (cmc). Solubilization of a dye and related color changes provided visual evidence for adsorbed SLS assemblies on CBZ(A) crystal faces below the cmc. Above the cmc, both surfactants promoted the transformation by increasing the bulk nucleation of CBZ(D). STC changed the crystal morphology of CBZ(D) from acicular to prismatic, depending on STC concentration. Such morphology changes originate from interactions between STC and molecular structures of CBZ(D) crystal faces that interfere with the formation of a hydrogen-bonded chain of water molecules and carboxamide dimers.

This paper describes the kinetics of the solution-mediated phase transformation of the anhydrous monoclinic polymorph of carbamazepine (CBZ(A)) to the dihydrate crystal form (CBZ(D)). Monitoring both solution concentration and solid phase composition identified the steps and mechanisms that control the kinetic processes, and regulate the concentration of drug achieved during dissolution of the metastable solid phase, CBZ(A). The results show that the kinetics and the rate-controlling step for the transformation depend on grinding and storage conditions of CBZ(A). Grinding CBZ(A) shortened the transformation times and changed the rate-controlling step from crystallization of CBZ(D) to dissolution of CBZ(A). Grinding may cause various degrees of disorder in the form of lattice defects and/or amorphous regions. These disordered regions promote the anhydrous to dihydrate transformation by facilitating the surface nucleation of CBZ(D) on freshly ground CBZ(A) and on amorphous CBZ. The concentration-time profiles revealed aging effects on the solution-mediated transformation of ground CBZ(A) that were undetectable by diffraction and thermal analysis. These results have significant consequences on the concentration-time profiles of active pharmaceutical ingredients during dissolution of metastable solid phases, crystalline or amorphous.

Metastable thermodynamic states are frequently encountered in pharmaceutical systems, in the intentional or unintentional creation of supersaturation, in the crystallization of desired solid-state modifications, and in the control of solid-phase conversions during isolation, manufacturing, storage, and dissolution.1-4 Some examples in which metastable states are encountered include solid solutions, freeze-concentrated solutions, solutions of weak acids or bases exposed to a pH change, solutions prepared by dissolving a solid-state modification with a higher solubility (higher free energy), and residual solutions during filtration, granulation, and drying. Because crystallization provides a way of reducing the free energy of metastable thermodynamic states, the extent to which metastable states can be maintained is determined by the crystallization mechanisms and kinetics.5-16 What is surprising, however, is that despite the important role that crystallization has in process control and in determining solid-phase outcomes, crystallization phenomena are often neglected in the pharmaceutical industry until a problem is encountered. While emphasis is often given to the knowledge of equilibrium phase diagrams with the purpose of identifying the concentration and temperature regions of thermodynamic stability of solid phases, information on crystallization processes can only be obtained by combining studies of thermodynamic properties with kinetic measurements. Cases of unwanted or previously unknown nucleation events abound. Dunitz and Bernstein17 documented cases of “disappearing or elusive polymorphs” that provide evidence for the consequences of poor process control in crystallization of polymorphic systems. The recent shortage in the supply of capsules of the HIV protease inhibitor Norvir (indinavir), due to the sudden formation of a crystalline structure different from the one harvested for months,18 illustrates the decisive role that nucleation mechanisms and kinetics have on crystallization. Nichols and Frampton19 have reported considerable efforts that failed to crystallize the metastable polymorph of paracetamol as described in the initial publication of the crystal structure.20 The critical role of crystallization kinetics in determining the appearance of crystalline modifications is also recognized by the FDA and described in the guidelines for the manufacture of drug substances:21 “Appropriate manufacturing and control procedures (including in-process testing when needed) should be established for the production of the desired solid-state form(s). It should be emphasized that the manufacturing process (or storage condition) is responsible for producing particular polymorphs or solvates; the control methods merely determine the outcome.” Even when the parameters that regulate crystallization phenomena are neglected, the illusion of process control is motivated by a crystallization process that yields the desired productssolid phase modification, shape, or size distributionsand by the robust analytical methods used for solid state characterization. This situation is greatly complicated by the recent emphasis on an exclusively * Corresponding author. Tel: 734-763-0101. Fax: 734-763-2022. e-mail: nrh@umich.edu. † University of Michigan. ‡ Dupont Pharmaceuticals. July 1999