Large-scale green chemical synthesis of adjacent quaternary chiral centers by continuous flow photodecarbonylation of aqueous suspensions of nanocrystalline ketones.

To demonstrate the ease of scale-up and synthetic potential of some organic solid state reactions, we report the synthesis, crystallization, and solid state photochemistry of acyclic, homochiral, hexasubstituted (+)-(2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-pentanone 1. We demonstrate that solid state photodecarbonylation of (+)-(2R,4S)-1 affords (+)-(2R,3R)-2-carbomethoxy-3-cyano-2,3-diphenyl-butane 2 with two adjacent stereogenic, all-carbon substituted quaternary centers, in quantitative chemical yield and 100% diastereoselectivity and enantiomeric excess. The efficient multigram photodecarbonylation of (+)-(2R,4S)-1 as a nanocrystalline suspension in water using a continuous flow photoreactor shows that the large-scale synthesis of synthetically challenging compounds using photochemical synthesis in the solid state can be executed in a remarkably simple manner.

Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid.

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.

Enantiospecific synthesis of vicinal stereogenic tertiary and quaternary centers by combination of configurationally-trapped radical pairs in crystalline solids.

[reaction: see text] Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions. Experiments with optically pure and racemic crystals showed that the intermediate radical pairs undergo a highly diastereo- and enantiospecific radical-radical combination that leads to the formation of two adjacent stereogenic centers in good chemical yield and with high chemical control. Reactions with chiral crystals occurred with quantitative enantiomeric yields and >95% diastereomeric yields.

Sources of information and factual knowledge in Europeans with inflammatory bowel diseases: a cross-cultural comparison between German and Irish patients.

BACKGROUND: Disease related knowledge may be associated with quality of life, coping skills and medication adherence. However, little is known of cross-cultural variations regarding inflammatory bowel disease knowledge or sources of information and no study has assessed knowledge in diverse European IBD populations. AIM: To assess sources of information and patient knowledge in Irish and German inflammatory bowel disease patients. METHODS: Three hundred and three disease, gender, age and education matched German and Irish patients completed a previously validated knowledge questionnaire. Additional data were collected on age, gender, education, disease type and duration, family history, smoking habits, medication use, previous surgery and quality of life. RESULTS: German patients obtained knowledge from a wider range of sources than Irish patients (p<0.001), most notably from the internet (p<0.001), newspapers and magazines (p=0.002). Both cohorts answered a similar number of questions correctly (Irish, mean 4.4 questions (Standard deviation (S.D.) 2.4); German, mean 4.3 (S.D. 2.2); p=0.67). In addition, both nationalities answered "don't know" to a similar number of questions (Irish, mean 3.3 (S.D. 3.1); German, mean 2.7 (S.D. 2.8); p=0.12) while Irish patients answered slightly fewer questions wrongly (Irish, mean 2.4 (S.D. 1.8); German, mean 3.1 (S.D. 1.9); p=0.002). A multivariate analysis included only Crohn's disease, female gender, young age and higher educational status as being significantly and independently associated with knowledge. CONCLUSIONS: Our data suggest few differences between German and Irish IBD patients, despite cultural and linguistic differences, with regard to disease related knowledge of IBD.

Effective gelation of water by an amphiphilic drug.

We report the formation of aqueous gels at low concentrations (less than 1 wt%) of an amphiphilic drug, a derivative of a chromane-2-carboxylic acid, at pH values 6.2-6.4. Formation of gels in the vicinity of the apparent pK(a) of the drug suggests that on the molecular level, the gels are composed of the aggregates of the ionized and protonated forms of the drug, which are stabilized by hydrogen bonding and hydrophobic interactions. In contrast, its identical analog, which differs by one methylene group, did not form gels or viscous solutions. We believe that additional steric hindrance, brought by the presence of the bulkier ethyl group (as compared to methyl group), prevents efficient interaction between the carboxylic acid groups thus hindering the gelation process.

Discovery of a stable molecular complex of an API with HCl: a long journey to a conventional salt.

We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 140 degrees C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development.

Supramolecular behavior of the amphiphilic drug (2R)-2-ethylchromane-2-carboxylic acid arginine salt (a novel PPARalpha/gamma dual agonist).

PURPOSE: This study was conducted to evaluate the aggregation properties of an amphiphilic drug. METHODS: Aggregation of the drug was studied by various methods including phase-contrast and polarized microscopy, spectrophotometry, surface tensiometry, atomic force microscopy, and dynamic light scattering. Lymph-cannulated rats were used to assess fractions of drug that were absorbed into lymphatics. RESULTS: During the pharmaceutical development of an alpha/gamma dual PPAR agonist, a derivative of a chromane-2-carboxylic acid (compound 1), it was discovered that the compound was able to form various aggregates in aqueous media from pH 6.5 to 7.1, whereas aggregating predominantly into micelles at higher pH values. Critical micelle concentrations seemed to be quite low, about 0.25 mM (0.17 mg/mL) in deionized water as determined by spectrophotometric (dye) and surface tensiometry (du Nuoy) methods. Aggregation of compound 1 into large supramolecular aggregates was visualized via phase-contrast microscopy and atomic force microscopy. The observed aggregates ranged from 250 nm to greater than 10 microm in size. Formation of liquid crystalline phases was observed by polarized microscopy as the material was gradually hydrated with water. Lymph studies in rats indicated that up to 6.9% of the orally administered dose of compound 1 in pH 6.5 buffer appeared in lymph, suggesting that supramolecular aggregation may also occur in vivo leading to partitioning between the portal and the lymph routes. CONCLUSIONS: The aforementioned supramolecular aggregation was found to have a profound effect on the pharmaceutical development of the drug and potentially on in vivo absorption of the drug.