An Improved Impact Ratio for Identifying Critical Process Parameters in Pharmaceutical Manufacturing Processes.

The identification of critical process parameters in biologics and small molecule process development is a key element of quality by design. The objectivity and consistency of procedures to identify critical process parameters can be improved with the use of impact ratios. Impact ratios quantify a process parameter's practical effect on a critical quality attribute relative to the critical quality attribute's acceptance limits. If the impact ratio is large, i.e., exceeds a predefined impact ratio threshold, the recommendation is to classify the process parameter as a critical process parameter. This article introduces an improved and mathematically well-defined impact ratio. Benefits of this impact ratio are a consistent interpretation for many scenarios commonly encountered in practice, high suitability to automation, and the possibility of standardizing on a single impact ratio definition for pharmaceutical manufacturing.

Stereoselective Synthesis of the IDO Inhibitor Navoximod.

A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(Ot-Bu)3. Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.7% ee and high purity.

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin.

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition.

A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(I)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.

Novel Series of Dihydropyridinone P2X7 Receptor Antagonists.

Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5″, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.

Studies of new indole alkaloid coupling methods for the synthesis of haplophytine.

[reaction: see text] The two novel bisindole alkaloid structures shown can be synthesized in a few steps from the canthiphytine derivative 9.

Impact of the C1' configuration of abasic sites on DNA duplex structure.

Naturally occurring abasic sites in DNA exist as an equilibrium mixture of the aldehyde, the hydrated aldehyde, and the hemiacetal forms (dominant). The influence of the configuration of the C1' hydroxyl group of the hemiacetal form on duplex structure and abasic site repair has been examined using novel carbocyclic analogues. Both the alpha- and beta-forms of this novel abasic site were introduced into oligomeric DNA using the standard DMT-phosphoramidite approach in an automated solid-phase synthesizer. Solution structures of the d(CGTACXCATGC).d(GCATGAGTACG) duplex (where X is the alpha- or beta-anomer of the carbocyclic abasic site analogue) were determined by NMR spectroscopy and restrained molecular dynamics simulations. The structures were only minimally perturbed by the presence of either anomer of the abasic site. All residues adopted an anti conformation, and Watson-Crick alignments were observed on all base pairs of the duplexes. At the lesion site, the abasic residues and their partner adenines showed increased dynamic behavior but adopted intrahelical positions in the final refined structures. Incision of duplexes having the alpha- or beta-anomer of the carbocyclic abasic site by human AP endonuclease showed that the enzyme recognizes both configurations of the lesion and nicks the DNA backbone with similar efficiency. Our results challenge the suggestion that Ape1 is stereoselective and imply a plasticity at the active site of the enzyme for accommodating either anomer of the lesion.

Simple, catalytic enantioselective syntheses of estrone and desogestrel.

Highly enantioselective and very short syntheses of the bioactive forms of estrone (3) and desogestrel (4) are described using a chiral oxazaborolidinium catalyst (2) in the key initial step. Enantiomerically pure estrone was synthesized in eight steps from the readily available starting materials diene 5 and alpha,beta-enal 6 via intermediates 8 and 9. Desogestrel was synthesized using a similar strategy from diene 5 and alpha,beta-enal 11 via intermediates 12-17. The efficient syntheses of the chiral catalyst 2 and its enantiomer are also presented.

Application of vicarious nucleophilic substitution to the total synthesis of dl-physostigmine.

A concise, highly efficient formal total synthesis of dl-physostigmine is described, using a relatively simple method that should be adaptable to the synthesis of homologous members of this type of alkaloid. The key step in the synthesis is a new vicarious nucleophilic substitution reaction between p-nitroanisole and a C-silylated derivative of N-methylpyrrolidinone. Subsequent conversion of the initial adduct to the tricyclic framework of physostigmine follows a well-established protocol and provides the key intermediate 8 in high yield. The vicarious nucleophilic substitution reaction has also been extended to six-membered lactams, with encouraging results.

Spray-dried chitinosans. Part I: preparation and characterization.

PURPOSE: Physicochemical and micromeritic characterization of chitinosans. METHODS: Chitinosans subjected to N-deacetylation and depolymerization were characterized for degree of N-deacetylation (DD), molecular weight (MW), pK(a), particle size determination and morphology, tap/bulk density measurements, surface area determinations, and determination of flow properties. RESULTS: The chitinosan DDs and MWs were dependent on the processing conditions and ranged from 66 to 89% and 2-522 kDa, respectively. Chitinosan particle sizes and shapes were dependent on drying conditions (range 8-465 microm). Spray-dried chitinosans were spherical and had smaller particle sizes than the non-spray-dried materials which were irregularly shaped particles. Higher density values were obtained for processed materials than those for the raw material. Lower specific surface areas were observed for non-spray-dried chitinosans (0.28-1.59 m(2)/g) than for spray-dried chitinosans (0.74-3.01 m(2)/g). Weight variation of chitinosan tablets indicated that spray-dried chitinosans possessed improved flow characteristics as compared with tray-dried chitinosans. CONCLUSIONS: The effect of drying method employed in chitinosan manufacture, i.e. spray versus tray drying, on the physicochemical and micromeritic properties of the resultant chitinosans were evaluated. Although the drying methods did not significantly influence the physicochemical properties, they affected the micromeritic properties of the resultant chitinosans.

Spray-dried chitinosans. Part II: in vitro drug release from tablets made from spray-dried chitinosans.

PURPOSE: Application of spray-dried chitinosans as excipients for use in drug delivery systems was explored. METHODS: Spray- and tray-dried chitinosans previously N-deacetylated and depolymerized were used. Directly compressed tablets (200mg) containing tetracycline, chitinosan, and magnesium stearate were prepared. The tablets were characterized for dimensions, weight, friability, crushing strengths, disintegration, and dissolution. RESULTS: The tablet weights, thickness, and diameters were not affected by the chitinosan selected (P>0.05). Friability of tablets containing tray-dried chitinosans was generally higher (and crushing strengths were lower) than tablets containing spray-dried chitinosans. Chitinosan molecular weight, degree of N-deacetylation, and drying method used, significantly affected crushing strengths (P<0.0001). Disintegration times were affected only by the type of chitinosan (P<0.0001) but not by the drying method used (P>0.9). Dissolution from tablets was significantly affected by the chitinosan type (P<0.025), but not affected by the drying method (P>0.5). CONCLUSIONS: Spray drying improved binding functionality of chitinosans, thereby enhancing the tablet crushing strength; however, friability, disintegration, and dissolution profiles were not significantly affected. The data obtained from this study support the usefulness of spray-dried chitinosans as excipients for use in drug delivery systems.

Chitinosan-drug complexes: effect of electrolyte on naproxen release in vitro.

The purpose of this study was to examine the potential use of electrolytes to control naproxen sodium (I) release from chitinosan (II) tablets. An ANOVA was employed to evaluate the effects of molecular weight (MW) of II, electrolyte valence (EV), and pH of the dissolution medium on I's release. The intrinsic dissolution rates and saturation solubilities of I were determined at each of the pHs used. Directly compressed tablets were prepared from admixtures containing: I, NaCl, CaCl(2), or AlCl(3), Mg stearate, and II. The tablets were characterized for their dimensions, crushing strengths, friability, disintegration times, and in vitro dissolution profiles. The slopes of the log-log cumulative percent released-time curves (t=0-5 h) were compared using ANOVA. Based on the ANOVA, each of the variables-chitinosans, EVs, and pHs-significantly affected drug release (P<0.05). Besides the poor aqueous solubility of I, the factors possibly affecting drug release included: (a) the formation of a rate-limiting II gel barrier; (b) the interaction of I with ionized amino groups of II; (c) the effect of electrolyte on the II's gel barrier formation; and/or (d) decreased aqueous solubility of I in the presence of electrolyte.

The effect of Lewis bases on the (13)c NMR of iodoalkynes.

In Lewis-basic solvents, alkynyl carbons bonded to iodine have chemical shifts approximately 12-15 ppm higher in frequency than the corresponding shifts in CDCl3. We offer computational evidence that this solvent effect comes directly from polarization of the iodoalkyne triple bond. Hartree-Fock and Density Functional Theory calculations reproduce the change in chemical shift for a gas-phase complex between the iodoalkyne and dimethyl sulfoxide as Lewis base. The amount of spin-orbit coupling from the adjacent iodine does not change appreciably in the complex, according to the calculations.