A quality control method enhancement concept-Continual improvement of regulatory approved QC methods.

Quality Control methods (QC-methods) play an important role in the overall control strategy for drug manufacturing. However, efficient life-cycle management and continual improvement are hindered due to a variety of post-approval variation legislations across territories and a lack of harmonization of the requirements. As a result, many QC-methods fall behind the technical development. Developing the QC-method in accordance with the Quality by Design guidelines gives the possibility to do continual improvements inside the original Method Operable Design Region (MODR). However, often it is necessary to do changes outside the MODR, e.g. to incorporate new technology that was not available at the time the original method was development. Here, we present a method enhancement concept which allows minor adjustments, within the same measuring principle, outside the original MODR without interaction with regulatory agencies. The feasibility of the concept is illustrated by a case study of a QC-method based on HPLC, assumed to be developed before the introduction of UHPLC, where the switch from HPLC to UHPLC is necessary as a continual improvement strategy. The concept relies on the assumption that the System Suitability Test (SST) and failure modes are relevant for other conditions outside the MODR as well when the same measuring principle is used. It follows that it should be possible to move outside the MODR as long as the SST has passed. All minor modifications of the original, approved QC-method must be re-validated according to a template given in the original submission and a statistical equivalence should be shown between the original and modified QC-methods. To summarize, revalidation is handled within the pharmaceutical quality control system according to internal change control procedures, but without interaction with regulating agencies.

Absolute asymmetric synthesis of a tetrahedral silver complex.

Even though the isolation of tetrahedral stereoisomers usually presents a synthetic challenge, a highly enantioenriched tetrahedral silver complex could be easily accessed by either crystallization or Viedma ripening. The overall preparation may be regarded as an example of absolute asymmetric synthesis. Experimental results indicate that both crystallization and Viedma ripening follow a similar cluster-controlled mechanism.

Absolute asymmetric synthesis: protected substrate oxidation.

Three new conglomerates incorporating bidentate sulfide ligands coordinated by Ru(II) centers have been prepared. Total spontaneous resolution by slow crystallization gives highly enantioenriched crystal batches, which are used in enantioselective oxidation of the sulfide ligands to give chiral sulfoxide complexes with >98 % ee. All relevant stereoisomers have been characterized by single-crystal X-ray diffraction, CD spectroscopy, and chiral HPLC. If the ligand range can be extended to monodentate sulfides, a large-scale and recyclable process for enantioselective oxidation of sulfides can be designed.

Absolute asymmetric synthesis of enantiopure organozinc reagents, followed by highly enantioselective chlorination.

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1-chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp = 2,6-dichlorophenoxy and tmeda = N,N,N',N'-tetramethylethylenediamine) (3) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6-dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N-chlorosuccinimide in the presence of benzoquinone in 2-propanol to give 1-chloroindene in >98 % enantiomeric excess. It was found that (R)-3 gave (R)-1-chloroindene upon reaction, indicating an SE 2'-mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.

A different approach to enantioselective organic synthesis: absolute asymmetric synthesis of organometallic reagents.

Voilà, optical activity: Both enantiomers of 1-chloroindene have been synthesized in high selectivity from solely achiral starting materials, and without using optically active catalysts (see scheme). These symmetry-breaking syntheses provide a proof-of-concept for a new approach to asymmetric synthesis. NCS=N-chlorosuccinimide.

catena-Poly[[[aqua-(propane-1,3-diamine-κN,N')copper(II)]-µ-fumarato-κO:O'] monohydrate].

The asymmetric unit of the title compound, {[Cu(C(4)H(2)O(4))(C(3)H(10)N(2))(H(2)O)]·H(2)O}(n), consists of two Cu(II) atoms, half each of two propane-1,3-diamine ligands and two coordinated water mol-ecules, all lying on crystallographic mirror planes, also one fumarate dianion and one uncoordinated water mol-ecule in a general position. The Cu(C(3)H(10)N(2))(H(2)O) units are linked via fumarate dianions into a zigzag chain running along the a axis. A longer Cu-O distance [2.873 (3) Å] is to a water mol-ecule bridging equivalent Cu(II) atoms in adjacent chains, forming a three-dimensional framework. One of the Cu(II) atoms is in a distorted square-pyramidal environment and the other is in a pseudo-octa-hedral geometry of the [5+1] type. O-H⋯O and N-H⋯O hydrogen bonds are observed in the crystal structure.