Comparison of quantitative methods for analysis of polyphasic pharmaceuticals

Adequate very sensitive quantification methods are needed for the development and are also now required for the monitoring of undesirable solid form(s) as routine tests. The pre-requisite for quantitation are selectivity, sensitivity and most important the purity of standards and their proper storage, what is a challenge for metastable forms. Several analytical techniques are available such as X-ray diffraction, spectroscopy, thermal analysis and microcalorimetry. The different steps of the validation of the analytical methods and problems to be solved are discussed. Examples illustrate the different techniques and compare their possible advantages and limits. The relative standard deviation of measurements should allow for checking the homogenization procedure of mixtures for calibration. The validation should be carried out following ICH guidelines for validation of analytical methods. Comparison of different techniques in adequate concentration range add confidence in the analytical results.     

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance. This revised version was published online in July 2006 with corrections to the Cover Date.     

Cure of epoxy resins with cyanoacetamides

Cyanoacetamides are a novel class of curing agents for epoxy resins. Since reaction products of epoxy compounds with cyanoacetamides have not yet been described, we investigated the reaction of phenyl-glycidylether (PGE) and N-isobutylcyanoacetamide (NICA) under the conditions of the epoxy cure (120–150°C). Twenty-two fractions of the reaction product have been separated by preparative TLC and characterized by FD and MS mass spectroscopy. The structures of 10 reaction product have been elucidated by MS, NMR, and IR techniques. They belong to the classes of cyclic urethanes, spiro-dilactones, cyclo-oxa-1-hepten-4-one-2, pyrimidones, aminocrotononitrile, and tertiary amine. This complex model reaction mixture does not enable us to propose a curing mechanism. However practical cure of Bisphenol A diglycidylether (BADGE) yields clear and tough solids with a glass transition temperature up to 200°C, good mechanical strength, and high adhesion to metal surface. Cyanoacetamides are latent hardeners requiring a curing initiator. Since N-4-chlorophenyl-N′-dimethylurea is a latent initiator, liquid, homogeneous, storage stable “one shot” systems can be formulated which harden quickly above 120°C. Heat aging properties of cured specimens are reported. A series of novel liquid, resinous, and crystalline cyanoacetamides and their potential as curing agent are described.     

A Note on Intramolecular Photochemical Cycloaddition of N-substituted Dimethacrylimides

The intramolecular photochemical [2+ 2]-cycloaddition of N-substituted dimethacrylimides 1a and 1c , respectively, proceeds under conditions of direct irradiation (λ = 254 nm) as well as triplet photosensitization highly regioselectively yielding predominantly the «cross» bonding (head-to-tail) cycloadducts 3a and 3c , respectively, with a 3-azabicyclo [3.1.1]heptane ring system.     

Synthesen von 3-Hydroxy-4-methyl-3-cyclobuten-1,2-dion (Methylmoniliformin)

Syntheses of 3-Hydroxy-4-methyl-3-cyclobutene-1,2-dione (Methylmoniliformin) New routes to 3-hydroxy-4-methyl-3-cyclobutene-1,2-dione (9) , the lowest homologue of the mycotoxine moniliformin are described. A common feature of all pathways is the synthesis of methylcyclobutanes having the oxidation level 6. Precursors, which are easily transformed to 9 by acid catalyzed hydrolysis, include [2+2]-cycloadducts of in situ generated methyl ketene to tetraethoxyethylene and [2+2]-photocycloadducts of dichlorovinylenecarbonate with 1,1-dichloro-1-propene. The acid hydrolysis of [2+2]-cycloadducts of chlorotrifluoroethylene to N, N-diethyl-1-propynylamine yields the diethylamide of 9 (=22) in 50% overall yield. In addition, a convenient one-pot-two-steps synthesis of a new electronrich ethylene, 1,1,2-triethoxy-2-trimethylsilyloxy-ethylene (11) , is described.     

Cure of epoxy resins with esters of cyanoacetic acid

Esters of cyanoacetic acid are a novel class of epoxy curing agents. The model reaction between ethyl cyanoacetate (ECA) and phenyl glycidylether (PGE) yielded a cyano-spiro-dilactone under conditions similar to the resin cure. The structure of the spiro compound resulting from 2 ECA and 2 PGE was elucidated by MS, IR, ¹H-, and ¹³C-NMR techniques. Ammonia is split off from 1 ECA and acts in statu nascendi as a satellite hardener. An overall model reaction equation for the cyanoacetyl cure is proposed. The cure of bisphenol A–diglycidylether (BADGE) with ECA and with neopentylglycol-biscyanoacetate (NPGCA) is described over a wide range of the molar ratio. Clear and tough solids are obtained with a glass transition temperature up to 130°C. Cyanoacetates are latent hardeners requiring a curing initiator. Since N-4-chlorophenyl N′-dimethylurea is a latent initiator, liquid “one-shot” systems can be formulated that are stable at room temperature and harden quickly above 120°C. Heat aging properties of cured specimens are reported. A series of novel liquid, resinous, and crystalline cyanoacetates and their potential as curing agents are described.