Effect of pH on the Surface Layer of Molecular Crystals at the Solid-Liquid Interface.

Dissolution of solid matter into aqueous solution is one of the most challenging physicochemical aspects related to drug development. While influenced by several parameters, the effect of pH remains the most important one to be fully understood. The dissolution process is essentially controlled by activity at the surface of the molecular crystals, which is difficult to characterize experimentally. To address this, a combination of in situ atomic force microscopy (AFM) with molecular dynamics (MD) simulation is reported. AFM allows for direct visualization of the crystal surface of basic and acidic model compounds (carvedilol and ibuprofen) in contact with an aqueous medium with varying pH. A dramatic increase in surface mobility in the solid-liquid interface could be observed experimentally as a function of pH. The in situ AFM approach opens up for a more detailed understanding of the behavior of particulate matter in solution with importance at different levels, ranging from engineering aspects related to crystallization, and biological considerations related to bioavailability of the final drug product.

PhAI: A deep-learning approach to solve the crystallographic phase problem.

X-ray crystallography provides a distinctive view on the three-dimensional structure of crystals. To reconstruct the electron density map, the complex structure factors [Formula: see text] of a sufficiently large number of diffracted reflections must be known. In a conventional experiment, only the amplitudes [Formula: see text] are obtained, and the phases ϕ are lost. This is the crystallographic phase problem. In this work, we show that a neural network, trained on millions of artificial structure data, can solve the phase problem at a resolution of only 2 angstroms, using only 10 to 20% of the data needed for direct methods. The network works in common space groups and for modest unit-cell dimensions and suggests that neural networks could be used to solve the phase problem in the general case for weakly scattering crystals.

Unveiling polyamorphism and polyamorphic interconversions in pharmaceuticals: the peculiar case of hydrochlorothiazide.

Polyamorphism has been a controversial and highly debated solid-state phenomenon in both material and pharmaceutical communities. Although some evidence of this fascinating phenomenon has been reported for several inorganic systems, and more recently also for a few organic compounds, the occurrence of polyamorphism is poorly understood and the molecular-level organization of polyamorphic forms is still unknown. Here we have investigated the occurrence of polyamorphism and polyamorphic interconversions in hydrochlorothiazide (HCT), using both experimental and computational methods. Three distinct HCT polyamorphs, presenting distinct physical and thermal stabilities as well as distinct relaxation properties, were systematically prepared using spray-drying (SD), quench-cooling (QC) and ball milling (BM) methods. HCT polyamorph II (obtained by QC) was found to be more physically stable than polyamorphs I and III (obtained by SD and BM, respectively). Furthermore, polyamorphs I and III could be converted into polyamorph II after QC, while polyamorph II did not convert to any other polyamorph after SD or BM. Molecular dynamics simulations show that HCT dihedral angle distributions are significantly different for polyamorphs I and II, which is postulated as a possible explanation for their different physicochemical properties.

Computational Dehydration of Crystalline Hydrates Using Molecular Dynamics Simulations.

Molecular dynamics (MD) simulations have evolved to an increasingly reliable and accessible technique and are today implemented in many areas of biomedical sciences. We present a generally applicable method to study dehydration of hydrates based on MD simulations and apply this approach to the dehydration of ampicillin trihydrate. The crystallographic unit cell of the trihydrate is used to construct the simulation cell containing 216 ampicillin and 648 water molecules. This system is dehydrated by removing water molecules during a 2200 ps simulation, and depending on the computational dehydration rate, different dehydrated structures were observed. Removing all water molecules immediately and removing water relatively fast (10 water molecules/10 ps) resulted in an amorphous system, whereas relatively slow computational dehydration (3 water molecules/10 ps) resulted in a crystalline anhydrate. The structural changes could be followed in real time, and in addition, an intermediate amorphous phase was identified. The computationally identified dehydrated structure (anhydrate) was slightly different from the experimentally known anhydrate structure suggesting that the simulated computational structure could represent a kinetically trapped dehydration intermediate.

Endoscopic surgery of inverted papillomas under image guidance--a prospective study of 42 consecutive cases at a Danish university clinic.

BACKGROUND: To evaluate the feasibility of endoscopic surgery with image guidance in the treatment of inverted papillomas. STUDY DESIGN AND SETTING: This prospective cohort study comprised 42 consecutive patients with biopsy-confirmed inverted papillomas that were diagnosed between 1998 and 2003. All patients were treated by the first author (C.B.). Image guidance based on preacquired CT scans of the patients was used to assist the surgeon aiming at endoscopic resection of inverted papilloma. The success of the surgery was judged primarily by the recurrence rate and the treatment morbidity. RESULTS: The study group consisted of 30 males and 12 females with a median age of 61 years. The follow-up period ranged from 9 months to 69 months (median, 37 months). The only additional procedure performed was the Caldwell-Luc procedure (8 cases). Recurrence was diagnosed in 10 cases (24%), all in the original tumor site. Eight of these had undergone previous surgery for inverted papilloma. The recurrences were predominantly located in the maxillary or in the frontal sinus (8 cases). In 2 cases, the recurrence was simply removed endoscopically while performing the biopsy procedure. All recurrences were identified within the first 9 months. Associated malignancy was not shown. No severe complications occurred. CONCLUSIONS: A treatment based on endoscopic resection with image guidance appears to offer a safe treatment modality of inverted papilloma with insignificant morbidity. Predominantly cases with nonmedial involvement of the maxillary sinus still require a supplement with the Caldwell Luc procedure. Although all the recurrences were found within 9 months postoperatively, later recurrences cannot be excluded. Long-term follow-up is recommended.

ProCS15: a DFT-based chemical shift predictor for backbone and Cß atoms in proteins.

We present ProCS15: a program that computes the isotropic chemical shielding values of backbone and Cß atoms given a protein structure in less than a second. ProCS15 is based on around 2.35 million OPBE/6-31G(d,p)//PM6 calculations on tripeptides and small structural models of hydrogen-bonding. The ProCS15-predicted chemical shielding values are compared to experimentally measured chemical shifts for Ubiquitin and the third IgG-binding domain of Protein G through linear regression and yield RMSD values of up to 2.2, 0.7, and 4.8 ppm for carbon, hydrogen, and nitrogen atoms. These RMSD values are very similar to corresponding RMSD values computed using OPBE/6-31G(d,p) for the entire structure for each proteins. These maximum RMSD values can be reduced by using NMR-derived structural ensembles of Ubiquitin. For example, for the largest ensemble the largest RMSD values are 1.7, 0.5, and 3.5 ppm for carbon, hydrogen, and nitrogen. The corresponding RMSD values predicted by several empirical chemical shift predictors range between 0.7-1.1, 0.2-0.4, and 1.8-2.8 ppm for carbon, hydrogen, and nitrogen atoms, respectively.