Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available amorphous solid dispersions (ASDs), due to its ability to aid dissolution of poorly soluble drugs while impeding drug recrystallization. Nuclear magnetic resonance (NMR) spectroscopy is a well-suited approach to provide structural information on amorphous solids and access intermolecular interactions in multicomponent materials such as ASDs. The 13C spectral assignments for HPMC-AS differ in the literature, largely due to the significant structural complexity of this polymer, but are critical to identify drug-polymer interactions in ASDs containing HPMC-AS. A dynamic nuclear polarization (DNP) enhanced 2D 13C-13C refocused incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum is obtained to identify the one-bond 13C-13C connectivity in the polymer, which confirms the most recent 13C spectral assignments of HPMC-AS. Moreover, the spatial distribution of substituents in cellulose-based polymers is known to affect their physical properties and hence the dissolution or absorption of a formulated drug. Here, we use the definitive 13C spectral assignments of HPMC-AS and exploit the relayed-DNP of enhanced 1D cross-polarization (CP) spectra to determine that the HPMC-AS substituents are homogeneously distributed in three commercial grades of the polymer. Now, NMR experiments performed on ASDs containing HPMC-AS can more accurately correlate observed drug-polymer interactions to specific sites of the polymer. Therefore, a greater understanding into the mechanisms by which HPMC-AS stabilizes amorphous drugs.

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.

Excipients are added to biopharmaceutical formulations to enhance protein stability and enable the development of robust formulations with acceptable physicochemical properties, but the mechanism by which they confer stability is not fully understood. Here, we aimed to elucidate the mechanism through direct experimental evidence of the binding affinity of an excipient to a monoclonal antibody (mAb), using saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopic method. We ranked a series of excipients with respect to their dissociation constant (KD) and nonspecific binding constants (Ns). In parallel, molecular dynamic and site identification by ligand competitive saturation (SILCS)-Monte Carlo simulations were done to rank the excipient proximity to the proteins, thereby corroborating the ranking by STD NMR. Finally, the excipient ranking by NMR was correlated with mAb conformational and colloidal stability. Our approach can aid excipient selection in biologic formulations by providing insights into mAb-excipient affinities before conventional and time-consuming excipient screening studies are conducted.

Pharmaceutical amorphous solid dispersions (ASDs) represent a widely used technology to increase the bioavailability of active pharmaceutical ingredients (APIs). ASDs are based on an amorphous API dispersed in a polymer, and their stability is driven by the presence of strong intermolecular interactions between these two species (e.g., hydrogen bond, electrostatic interactions, etc.). The understanding of these interactions at the atomic level is therefore crucial, and solid-state nuclear magnetic resonance (NMR) has demonstrated itself as a very powerful technique for probing API-polymer interactions. Other reviews have also reported exciting approaches to study the structures and dynamic properties of ASDs and largely focused on the study of API-polymer miscibility and on the identification of API-polymer interactions. Considering the increased use of NMR in the field, the aim of this Review is to specifically highlight recent experimental strategies used to identify API-polymer interactions and report promising recent examples using one-dimensional (1D) and two-dimensional (2D) experiments by exploiting the following emerging approaches of very-high magnetic field and ultrafast magic angle spinning (MAS). A range of different ASDs spanning APIs and polymers with varied structural motifs is targeted to illustrate new ways to understand the mechanism of stability of ASDs to enable the design of new dispersions.

The decomposition of primary sodium alkoxide salts under ambient storage conditions and the effects of this phenomenon on commonly employed transition-metal-catalyzed cross-coupling reactions are described. By utilizing NMR, IR, and Raman spectroscopy, along with a modified Karl Fischer analysis, the main inorganic degradants were characterized, and CO2 in the air was found to be a critical reactant within the decomposition process. The effects of storage conditions on decomposition were evaluated, and the preliminary experiments to understand the kinetics of this process were performed.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug–polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that 1H–13C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14N–1H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

1H Time-Domain Nuclear Magnetic Resonance (TD-NMR) is used to characterize solutions of antibodies that simulate biologic pharmaceutical formulations. The results from these measurements are compared with those from solutions in which the concentration or identity of the antibody has been altered. TD-NMR is shown to be very sensitive to differences in the amount of antibody in solution, with the ability to detect variations in as low as 2 mg/mL. It is therefore capable, by comparison with data from known formulations, of determining whether a particular sample is likely to be of an authentic biologic formulation. This method expands on the previous use of HPLC, UV/VIS, Near-IR and High-Resolution NMR to detect adulterated pharmaceutical materials. While the sensitivity of the method is high, it is a fingerprinting methodology, illustrating differences but not elucidating their origin. The extracted relaxation times reflect the combined effect of all solutes (antibody, buffer components, etc.) on the solvent (water).

The objective of this study was to understand the impact of coating excipients on the chemical stability of active pan coated peliglitazar, which was prone to acid as well as base-catalyzed degradation. Four different coating formulations containing either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC) as a coating polymer and triacetin (glycerol triacetate) or polyethylene glycol (PEG) as a plasticizer/detackifier were used for coating of peliglitazar in a perforated pan coater. Tablets of one-milligram strength were manufactured by suspending the drug in the coating suspension and spray coating onto inert core tablets. The active coated tablets were placed on stability (40 degrees C/75% RH) in high-density polyethylene (HDPE) bottles in closed condition with desiccants or in open condition. Tablet samples were withdrawn and analyzed for degradants using a stability-indicating HPLC method. The overall stability for the film-forming polymer-plasticizer/detackifier combination showed the rank order: HPMC-triacetin > PVA-triacetin > HPMC-PEG > PVA-PEG. Higher stability of triacetin systems over PEG systems was attributed to lower solubility of peliglitazar in triacetin coating systems. For the same plasticizer/detackifier, higher stability of HPMC over PVA-based formulations was attributed to lower solubility and mobility of peliglitazar in HPMC compared with the PVA-based coating.

Solar energy is a promising sustainable power source asset. If the solar panels have an opposite profile to the beams of the sun it will create more vitality. The objective of the work is to track the sun, so that the rays of sun will always be in perpendicular with panel. As the cost of manufacturing the solar tracking setup is high, there are alternative less expensive choices that have been proposed. This works aims to design and develop a model of solar tracking system. ATMega328P micro controller is utilized for the manufacture of control circuit. Light Dependent Resistors (LDR) is utilized to recognize daylight which impels the servo motor to turn the solar panel. The solar panel is kept in a region of most extreme exposure to daylight. Greatest torque and speed are achieved by a servo motor. Servo motor is most efficient with the scope of 80-90%. Servo motors are free from vibration issues. Execution and attributes of solar panel are examined tentatively. solar cells made of Silicon produced an maximum efficiency of 20%. Most of the solar panels still operate at level less than 40%. Because of their reduced performance. The initial cost increases due to the purchase of large sized panels, else the number of panels has to be increased. The efficiency and cost of the panel is inversely proportional to each other solar tracking finds a better way of improving the performance without increasing the rate of the panel. The area of exposure to sunlight is increased. Classification is based on the number of trackers single axis trackers are less efficient than Dual trackers A single tracking system is used. It is cheaper, less complex to install and still achieves the required efficiency. The increase in the initial setup cost is negligible when compared to the increase of power output. Maintenance costs are not high.

Magnetic Resonance in ChemistryVolume 58, Issue 11 p. 987-987 SPECIAL ISSUE EDITORIAL Advances of solid-state NMR spectroscopy in material sciences Anuji Abraham, Corresponding Author Anuji Abraham [email protected] orcid.org/0000-0003-3811-7071 Materials Science and Engineering, Drug Product Development, Bristol Myers Squibb, New Brunswick, NJ, USA Correspondence Anuji Abraham, Materials Science and Engineering, Drug Product Development, Bristol Myers Squibb, 1 Squibb Dr, New Brunswick, NJ 08903, USA. Email: [email protected]Search for more papers by this authorElodie Salager, Elodie Salager orcid.org/0000-0002-5443-9698 CNRS, CEMHTI UPR3079, University Orléans, Orléans, FranceSearch for more papers by this authorDamodaran Krishnan, Damodaran Krishnan orcid.org/0000-0001-8170-9000 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USASearch for more papers by this authorYongchao Su, Yongchao Su orcid.org/0000-0001-5063-3218 Pharmaceutical Sciences, Preclinical Development, Merck & Co, Inc., Rahway, NJ, USASearch for more papers by this author Anuji Abraham, Corresponding Author Anuji Abraham [email protected] orcid.org/0000-0003-3811-7071 Materials Science and Engineering, Drug Product Development, Bristol Myers Squibb, New Brunswick, NJ, USA Correspondence Anuji Abraham, Materials Science and Engineering, Drug Product Development, Bristol Myers Squibb, 1 Squibb Dr, New Brunswick, NJ 08903, USA. Email: [email protected]Search for more papers by this authorElodie Salager, Elodie Salager orcid.org/0000-0002-5443-9698 CNRS, CEMHTI UPR3079, University Orléans, Orléans, FranceSearch for more papers by this authorDamodaran Krishnan, Damodaran Krishnan orcid.org/0000-0001-8170-9000 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USASearch for more papers by this authorYongchao Su, Yongchao Su orcid.org/0000-0001-5063-3218 Pharmaceutical Sciences, Preclinical Development, Merck & Co, Inc., Rahway, NJ, USASearch for more papers by this author First published: 01 October 2020 https://doi.org/10.1002/mrc.5086Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume58, Issue11Special Issue: Solid‐State NMRNovember 2020Pages 987-987 RelatedInformation

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the C-13 NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

Characterization of lipid based (SPC/GDO/H2O) liquid crystal (LC) drug delivery system is non-trivial and highly complex, especially when multiple and intermediate phases are present. The phase behavior of such mixtures during hydration or delivery is still poorly understood and therefore, characterizing these systems is crucially important towards controlling their function and enhancing the understanding of their drug release behavior. Current work has established an easy way to identify liquid crystal phases and phase mixtures using deuterium (2H) solid-state nuclear magnetic (NMR) spectroscopy under static conditions without disrupting the three dimensional structure and phases, as magic-angle spinning (MAS) could lead to disruption of the phases. Small angle X-ray scattering (SAXS) technique and optical microscopy were also employed to corroborate the study.

Determining the moisture content in lyophilized solids is a fundamental step towards predicting the quality and stability of lyophilized products, but conventional methods are time-consuming, invasive, and destructive. High levels of residual moisture in a lyophilized product can lead to cake collapse, product degradation, and reduced shelf life. The aim of this study was to develop a fast, noninvasive, nondestructive, and inexpensive method for determining the moisture content in a lyophilized monoclonal antibody (mAb) formulation using benchtop low-field time-domain nuclear magnetic resonance spectroscopy.

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.

A combination of solid-state NMR techniques, including13C/1H correlation,2H magic-angle spinning NMR and first principles calculation are employed to characterise the role of water in different hydration states of sildenafil citrate.

A simple and robust method for obtaining fluorine-carbon proximities was established using a (19)F-(13)C heteronuclear correlation (HETCOR) two-dimensional (2D) solid-state nuclear magnetic resonance (ssNMR) experiment under magic-angle spinning (MAS). The method was applied to study a crystalline active pharmaceutical ingredient (API), avagacestat, containing two types of fluorine atoms and its API-polymer composite drug product. These results provide insight into the molecular structure, aid with assigning the carbon resonances, and probe API-polymer proximities in amorphous spray dried dispersions (SDD). This method has an advantage over the commonly used (1)H-(13)C HETCOR because of the large chemical shift dispersion in the fluorine dimension. In the present study, fluorine-carbon distances up to 8 Å were probed, giving insight into the API structure, crystal packing, and assignments. Most importantly, the study demonstrates a method for probing an intimate molecular level contact between an amorphous API and a polymer in an SDD, giving insights into molecular association and understanding of the role of the polymer in API stability (such as recrystallization, degradation, etc.) in such novel composite drug products.

Simulations of l-cysteine molecules attaching on Au nanoparticles provide insight on how larger biomolecules (such as proteins and peptides) can interact with Au nanoparticles. The attaching mode is still in debate and of strong impact on the fundamental research in biosensors and biomedicine. We used a density functional theory (DFT) approach to calculate the interactions between l-cysteine molecules and the quantum sized Au nanoparticle Au55. Our results support the attaching mode recognized in solid-state NMR studies, which indicate that a double layer of l-cysteine molecules is the likely configuration. A strong electronic interaction between gold and sulfur atoms establishes a strong-bonding inner layer, while a hydrogen-bond network between zwitterion-structured cysteine molecules stabilizes the existence of a second layer with thiol (−SH) groups oriented outward. Such a structure has high potential for further biofunctionalization.

(1)H MAS NMR experiments were performed on gold nanoparticles coated with l-cysteine. The experiments show that l-cysteine molecules are zwitterions and support a structural model of cysteine forming two layers. The inner layer is composed of cysteine molecules chemisorbed to the gold surface via the sulfur atom. The outer layer interacts with the chemisorbed layer. The (1)H NMR suggests that the cysteine in the outer layer exhibits large amplitude motion about specific carbon-carbon bonds.

The dehydration/desolvation of two hydrate solvates of the pharmaceutically important compound finasteride (namely, bisfinasteride monohydrate monotetrahydrofuran and bisfinasteride monohydrate mono-1,4-dioxane) has been studied by solid-state nuclear magnetic resonance, powder X-ray diffraction, thermogravimetric analysis (including coupling with mass spectrometry) and dynamic vapour sorption. The structure is unusual in that water holds the host finasteride molecules together by hydrogen bonding to form channels in which the solvent is sited. Whilst the solvent guest molecules are not strongly bound to the host, their presence is essential for structural stability. Desolvation is not found to occur at a well-defined temperature or even to consistently produce the same anhydrous form (form I vs. form II), but is instead highly dependent on the physical environment and, therefore, on the technique used. This behaviour complicates investigations, but the combination of complementary methods does allow the desolvation to be understood. Water and solvent are shown to be lost simultaneously, with no evidence of an intermediate form or increased mobility of the hydrogen-bonded water molecules. The results are consistent with a model in which structural collapse and rearrangement follows the loss of a small fraction of the solvent molecules from the channel structure, with the final form produced being very sensitive to the presence of water vapour during desolvation.

The NMR spectra of polymorphs I, II, and III of the pharmaceutical drug compound phenobarbital are discussed in relation to the crystal structures. Whilst some features can be explained by inspection of the structures, others require more detailed work. In this paper, shielding computations for the 13 C, 15 N, and 1 H nuclei using crystallographic repetition (with optimization of the positions of all atoms) are presented. These have enabled the majority of the signals to be assigned with some confidence and several features of NMR crystallography are illuminated. In particular, resonances have been attributed separately for the three independent molecules of form I (and also for form II). Moreover, the chemically equivalent but crystallographically distinct nuclei forming the two halves of the phenyl ring (and likewise of the heteronuclear ring) have been distinguished and a structural conformational motif attached to the 15 N chemical shifts revealed. The small differences between the spectra of forms I and II (which have very closely related crystal structures) are well-reproduced. The value of computations for establishing precise assignments of signals to crystallographic sites of atoms is emphasised. Conversely, the work provides a good test of the accuracy of computations for crystalline materials.