Reticular synthesis of porous molecular 1D nanotubes and 3D networks.

Synthetic control over pore size and pore connectivity is the crowning achievement for porous metal-organic frameworks (MOFs). The same level of control has not been achieved for molecular crystals, which are not defined by strong, directional intermolecular coordination bonds. Hence, molecular crystallization is inherently less controllable than framework crystallization, and there are fewer examples of 'reticular synthesis', in which multiple building blocks can be assembled according to a common assembly motif. Here we apply a chiral recognition strategy to a new family of tubular covalent cages to create both 1D porous nanotubes and 3D diamondoid pillared porous networks. The diamondoid networks are analogous to MOFs prepared from tetrahedral metal nodes and linear ditopic organic linkers. The crystal structures can be rationalized by computational lattice-energy searches, which provide an in silico screening method to evaluate candidate molecular building blocks. These results are a blueprint for applying the 'node and strut' principles of reticular synthesis to molecular crystals.

Modelling of crystal structure of cis-1,2,3,6 and 3,4,5,6-tetrahydrophthalic anhydrides using lattice energy calculations.

Lattice energy calculations using a model potential were performed to model the crystal structures of cis-1,2,3,6- and 3,4,5,6-tetrahydrophthalic (THP) anhydrides. The optimized molecular models using the DFT method at the B3LYP/6-31G** level were found consistent with the available experimental evidence and allowed all differences observed in crystal packing between cis-1,2,3,6- and 3,4,5,6-THP anhydrides to be reproduced. Calculations provide evidence for the presence of dipole-dipole C=O⋯C=O intermolecular interactions and support the idea that the molecules distort from their ideal geometries, improving packing in both crystals. The search for minima in the lattice energy of both crystals amongst the more common space groups with Z' = 1, using a simulated annealing crystal structure prediction procedure followed by lattice energy minimization showed that the observed structure of 3,4,5,6-THP anhydride (Z' = 2) is the thermodynamically most stable, and allowed us to justify why 3,4,5,6-THP anhydride crystallizes in such a complex structure with 16 molecules in the unit cell. The computational model was successful in predicting the second observed form at 173 K for cis-1,2,3,6-THP anhydride as a polymorph, and could predict several hypothetical structures with Z' = 1 that appear competitive with the observed structures. The results of phonon estimates of zero point intermolecular vibrational energy and entropy suggest that crystal structures of cis-1,2,3,6-THP anhydride cannot be predicted solely on the basis of lattice energy; factors other than thermodynamics favor the observed structures.

A strategy for predicting the crystal structures of flexible molecules: the polymorphism of phenobarbital.

A computational exploration of the low energy crystal structures of the pharmaceutical molecule phenobarbital is presented as a test of an approach for the crystal structure prediction of flexible molecules. Traditional transferable force field methods of modelling flexible molecules are unreliable for the level of accuracy required in crystal structure prediction and we outline a strategy for improving the evaluation of relative energies of large sets of crystal structures. The approach involves treating the molecule as a set of linked rigid units, whose conformational energy is expressed as a function of the relative orientations of the rigid groups. The conformational energy is calculated by electronic structure methods and the intermolecular interactions using an atomic multipole description of electrostatics. A key consideration in our approach is the scalability to more typical pharmaceutical molecules of higher molecular weight with many more atoms and degrees of flexibility. Based on our calculations, crystal structures are proposed for the as-yet uncharacterised forms IV and V, as well as further polymorphs of phenobarbital.

Understanding the influence of polymorphism on phonon spectra: lattice dynamics calculations and terahertz spectroscopy of carbamazepine.

Rigid molecule atomistic lattice dynamics calculations have been performed to predict the phonon spectra of the four polymorphs of carbamazepine, and these calculations predict that there should be differences in the spectra of all four forms. Terahertz spectra have been measured for forms I and III, and there are clearly different features between polymorphs' spectra, that are accentuated at low temperature. While carbamazepine adopts the same hydrogen bonded dimers in all of its known polymorphs, the calculations show that differences in packing arrangements of the dimers lead to changes in the frequency ranges for each type of hydrogen bond vibration, giving a physical explanation to the observed differences between the spectra. Although the agreement between calculated and observed spectra does not allow a definitive characterization of the spectra, it is possible to make tentative assignments of many of the observed features in the terahertz region for the simpler form III; we can only make some tentative assignments of specific modes in the more complex spectrum of form I. While harmonic rigid molecule lattice dynamics shows promise for understanding the differences in spectra between polymorphs of organic molecules, discrepancies between observed and calculated spectra suggest areas of improvement in the computational methods for more accurate modeling of the dynamics in molecular organic crystals.

A third blind test of crystal structure prediction.

Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

The prediction, morphology, and mechanical properties of the polymorphs of paracetamol.

The analgesic drug paracetamol (acetaminophen) has two reported metastable polymorphs, one with better tableting properties than the stable form, and another which remains uncharacterized. We have therefore performed a systematic crystal structure prediction search for minima in the lattice energy of crystalline paracetamol. The stable monoclinic form is found as the global lattice-energy minimum, but there are at least a dozen energetically feasible structures found, including the well-characterized metastable orthorhombic phase. Hence, we require additional criteria to reduce the number of hypothetical crystal structures that can be considered as potential polymorphs. For this purpose the elastic properties and vapor growth morphology of the known and predicted structures have been estimated using second-derivative analysis and the attachment-energy model. These inexpensive calculations give reasonable agreement with the available experimental data for the known polymorphs. Some of the hypothetical structures are predicted to have a low growth rate and plate-like morphology, and so are unlikely to be observed. Another is only marginally mechanically stable. Thus, this first consideration of such properties in a crystal-structure prediction study appears to reduce the number of predicted polymorphs while leaving a few candidates for the uncharacterized form.

Circadian differences in pharmacological blockade of meal-stimulated gastric acid secretion.

The effects of identical morning (08.05 hours) and evening (20.05 hours) meals on intragastric pH were compared in 12 healthy volunteers receiving gastric antisecretory medication. Dosing included continuous intravenous infusion ranitidine (50 mg bolus followed by 12.5 mg/h) or a matching placebo which were randomly administered prior to and following 7 days of treatment with oral omeprazole (40 mg mane). Intragastric pH was monitored continuously using a tethered indwelling pH probe. Subjects were divided into groups, one of which began the pH monitoring session in the morning, the other in the evening. The median 24-h intragastric pH was significantly increased by all active dosing regimens (P less than 0.05). Combined omeprazole and ranitidine produced the highest median pH, 5.92. However, a breakthrough drop in intragastric pH occurred during the evening after all active dosing. Intragastric pH fell prior to and after consumption of the evening meal with median pH values less than 4 during all sessions. The evening meal led to significantly lower intragastric pH compared to the morning meal for omeprazole and the combined omeprazole and ranitidine dosing periods (P less than 0.05). There was no difference between morning and evening pH during the placebo or ranitidine periods. Ranitidine and omeprazole, either alone or in combination, were unable to prevent the meal-stimulated decline in intragastric pH during the evening time period.

The activity of neutral ribonucleases in nuclei of rat sympathetic ganglia and effects of nerve injury.

Nuclei were isolated from homogenates of rat superior cervical ganglion by a conventional differential centrifugation technique with approximately 60% recovery. Ribonuclease activity at pH 7.1 (neutral ribonuclease) was associated with the "nuclei fraction" and represented 19% of the overall activity in normal ganglia. Ribonuclease in the "nuclei fraction" was stimulated variably by the sulfhydryl blocker N-ethylmaleimide indicating that a proportion was bound to the endogenous ribonuclease inhibitor present in these ganglia. The total activity of nuclear ribonuclease was increased 2-6 days after postganglionic nerve injury, such that the inhibitor-bound form of the enzyme increased maximally by 600% at day 4. The percentage of the total ganglionic activity in the "nuclei fraction" decreased in injured ganglia as a result of a rise in the activity of non-nuclear components. The changes in nuclear ribonuclease activity were distinct from those in the 850 g supernatant indicating that specific nuclear enzymes are being affected during regeneration.

Electrolyte abnormalities in very low birthweight infants.

In 30 very low birth weight (VLBW) infants, fed a commercial formula at 200 ml/kg/24 hr to provide 160 cal/kg/24 hr, hyponatremia (plasma Na+ less than 130 mEq/liter) occurred in 23 patients (14 appropriate for gestational age (AGA), 9 small for gestational age (SGA)) between the ages of 2 and 6 weeks. In five infants the hyponatremia recurred even after adequate correction of the deficit. Calcium supplementation given to 14 of the infants did not affect the incidence or severity of hyponatremia. In AGA infants, the hyponatremia was more severe than in SGA babies. Hyperkalemia (plasma K+ greater than 5.5 mEq/liter) was more common in AGA than in SGA infants (16/17 AGA, 7/13 SGA). Decrease in mean plasma chloride concentrations was proportionate to the decrease in mean Na+. Urinary Na+ averaged 1.0 mEq/kg/24 hr and was equal between groups during the first balance at a mean age of 18 days. In subsequent balances it appeared to decrease more rapidly in noncalcium-supplemented than in calcium-supplemented infants, but the difference was not significant (P less than 0.1). Fecal excretion of Na+ did not differ between groups. Symptoms were unrelated to the degree of hyponatremia or hyperkalemia and were nonspecific. Hyponatremia in AGA infants occurred in 50% of instances when growth was less than or equal to 0.75 cm/week, whereas it occurred in only 13.5% of infants when growth exceeded 1 cm/week (P less than 0.01). A similar trend in SGA infants was not statistically significant (P less than 0.2).

Growth and mineral metabolism in very low birth weight infants. I. Comparison of the effects of two modes of NaHCO3 treatment of late metabolic acidosis.

Twenty-six infants weighing less than 1,300 g at birth were divided into pairs according to birth weight (900-1,100 and 1,101-1,300 g) and gestational age ("appropriate" (AGA) = mean 31 weeks; and "small" (SGA) = mean 34 weeks). One member of the pairs was then allocated randomly to one of two treatment regimens with oral sodium bicarbonate. Group A was treated whenever base excess was greater than -8mEq/liter as detected on twice weekly testing and/or when suspected to be acidotic from failure to gain weight. In group B, base excess was maintained within 1 SD of normal (-3.2 +/- 1.7 mEq/liter). The infants received Enfalac 200 ml/kg/24 hr, at 67 cal/100 ml, with vitamin D 400 IU/24 hr added from age 2 weeks. The following measurements were made: daily weight, weekly length, skinfold thickness, head circumference, twice weekly blood pH, PaCO2, base excess, and weekly plasma total calcium, ionic calcium, total magnesium, inorganic phosphorus, and total protein. There were six pairs of each of AGA and SGA infants and two unpaired group A infants. Weekly weight gains did not differ between group A and group B or between AGA and SGA. Length increment was greater in AGA than in SGA babies (0.94 +/- 0.02 vs 0.85 +/- 0.04 cm/week) but not significantly so (P less than 0.1), and in group B babies compared to group A babies (0.973 +/- 0.029 vs 0.83 +/- 0.037 cm/week) (P less than 0.01). Plasma pH was lower in group A (7.23 +/- 0.02) than in group B (7.30 +/- 0.02) and calcium ion activity higher (group A 2.72 +/- 0.04; group B 2.51 +/- 0.06 mEq/liter) between ages 20 and 29 days. Plasma magnesium was higher in group A (1.77 +/- 0.04 mEq/liter) than in group B (1.56 +/- 0.06 mEq/liter) from age 20 to 39 days. Inorganic phosphorus concentrations were consistently higher in group A than in group B, but the differences did not reach significance. Mean total protein concentrations did not rise above 4.5 g/100 ml and tended to be higher in babies of group A than of group B. Bone age was retarded in all babies. Radiographs available for 7 of 13 SGA infants were normal, whereas 6 of 11 radiographs of AGA babies showed some osteoporotic changes.

Growth and mineral metabolism in very low birth weight infants. II. Effects of calcium supplementation on growth and divalent cations.

Infants of two groups, one of 16, one of 14 infants, who weighed less than 1.3 kg at birth (mean 1.01 +/- 0.05 kg), were studied from age 14 days until they reached 1.8 kg body weight. Infants were pair-matched for gestational age and birth weight and one member was randomly allocated to two treatment groups. Infants in group A received no calcium supplement and those in group B received calcium lactate, 800 mg/kg/24 hr hr, in divided doses with each feed. All were fed "Improved" SMA, 200 ml/kg/24 hr, 160 cal/kg/24 hr, and were given a multivitamin preparation containing 500 IU vitamin D2/dose. The infants' weekly length gain did not differ between groups (1.08 +/- 0.04 cm/week vs 1.11 +/- 0.04 cm/week; mean +/- SEM). Mean weight and head cercumference increments also were similar (group A, 163 +/- 6 g/week; 1.12 +/- 0.03 cm/week; group B, 170 +/- 6 g/week and 1.18 +/- 0.03 cm/week). An increase in blood pH from 7.33 +/- 0.01 to 7.41 +/- 0.01 (P less than 0.01) in group A babies was associated with a decrease in PCO2 from 44.2 +/- 1.0 to 38.9 +/- 1.4 mm Hg. Values remained unchanged with age in group B babies...