The Alder-ene reaction of neat polyisobutylene (PIB) and maleic anhydride (MAA) to produce theindustriallyimportant lubricant additive precursor polyisobutylene succinic anhydride(PIBSA) is studied at 150–180 °C. Under anaerobicconditions with [PIB] ∼ 1.24 M (550 g mol–1 grade, >80% exo alkene) and [MAA] ∼ 1.75 M, conversion of exo-PIB and MAA follows second-order near-equal ratelaws with kobs up to 5 × 10–5 M–1 s–1 for both components.The exo-alkene-derived primary product PIBSA-I is formed at an equivalent rate. The less reactive olefinic protonsof exo-PIB also react with MAA to form isomeric PIBSA-II (kobs up to 6 × 10–5 M–1 s–1). Some exo-PIB is convertedto endo-PIB (containing trisubstitutedalkene) in a first-order process (kobs ∼ 1 × 10–5 s–1),while PIBSA-I is difunctionalized by MAA to bis-PIBSAs very slowly. The MAA- and PIB-derived activation parameter ΔG‡(150 °C) 34.3 ± 0.3 kcal mol–1 supports a concerted process, with that of PIBSA-I suggestinga late (product-like) transition state.

Generation of tosylazide 12 in acetonitrile in flowunder water-free conditions using an azide resin and its use in diazotransfer to a series of aryl acetates are described. Successful telescopingwith a rhodium acetate-catalyzed O–H insertion has been achieved,thereby transforming the aryl acetate 8 to α-hydroxyester 10, a key intermediate in the synthesis of clopidogrel 11, without requiring isolation or handling of either tosylazide 12 or α-aryl-α-diazoacetate 9, or indeed having significant amounts of either present at any point.Significantly, the solution of α-diazo ester 9 wassufficiently clean to progress directly to the rhodium acetate-catalyzedstep without any detrimental impact on the efficiency of the O–Hinsertion. In addition, the rhodium acetate-catalyzed O–H insertionprocess is cleaner in flow than under traditional batch conditions.Use of the azide resin offers clear safety advantages and, in addition,this approach complements earlier protocols for the generation oftosyl azide 12 in flow; this protocol is especially usefulwith less acidic substrates.

Washing is a keystep in pharmaceutical isolation to remove theunwanted crystallization solvent (mother liquor) from the active pharmaceuticalingredient (API) filter cake. This study looks at strategies for optimalwash solvent selection, which minimizes the dissolution of API productcrystals while preventing the precipitation of product or impurities.Selection of wash solvents to avoid both these phenomena can be challengingbut is essential to maintain the yield, purity, and particle characteristicsthroughout the isolation process. An anti-solvent screening methodologyhas been developed to quantitatively evaluate the propensity for precipitationof APIs and their impurities of synthesis during washing. This isillustrated using paracetamol (PCM) and two typical impurities ofsynthesis during the washing process. The solubility of PCM in differentbinary wash solutions was measured to provide a basis for wash solventselection. A map of wash solution composition boundaries for precipitationfor the systems investigated was developed to depict where anti-solventphenomena will take place. For some crystallization and wash solventcombinations investigated, as much as 90% of the dissolved PCM andover 10% of impurities present in the PCM saturated mother liquorwere found to precipitate out. Such levels of uncontrolled crystallizationduring washing in a pharmaceutical isolation process can have a drasticeffect on the final product purity. Precipitation of both the productand impurities from the mother liquor can be avoided by using a solventin which the API has a solubility similar to that in the mother liquor;for example, the use of acetonitrile as a wash solvent does not resultin precipitation of either the PCM API or its impurities. However,the high solubility of PCM in acetonitrile would result in noticeabledissolution of API during washing and would lead to agglomerationduring the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resultedin the highest amount of precipitation among the solvent pairs evaluated.This can be mitigated by designing a multi-stage washing strategywhere wash solutions of differing wash solvent concentrations areused to minimize step changes in solubility when the mother liquorand the wash solvent come into contact.

Anefficient, scalable, and good manufacturing practice (GMP) compatibleprocess was developed for the production of docetaxel-loaded poly(ethyleneglycol)-b-poly(N-2-benzoyloxypropylmethacrylamide) (mPEG-b-p(HPMA-Bz)) micelles. First,the synthesis of the mPEG-b-p(HPMA-Bz) block copolymerwas optimized through step-by-step investigation of the batch synthesisprocedures. This resulted in the production of 1 kg of mPEG-b-p(HPMA-Bz) block copolymer with a 5 kDa PEG block andan overall molecular weight of 22.5 kDa. Second, the reproducibilityand scalability of micelle formation was investigated for both batchand continuous flow setups by assessing critical process parameters.This resulted in the development of a new and highly efficient continuousflow process, which led to the production of 100 mL of unloaded micelleswith a size of 55 nm. Finally, the loading of the micelles with theanticancer drug docetaxel was successfully fine-tuned to obtain precisecontrol on the loaded micelle characteristics. As a result, 100 mLof docetaxel-loaded micelles (20 mg/mL polymer and 5 mg/mL docetaxelin the feed) with a size of 55 nm, an encapsulation efficiency of65%, a loading capacity of 14%, and stable for at least 2 months inwater at room temperature were produced with the newly developed continuousflow process. In conclusion, this study paves the way for efficientand robust large-scale production of docetaxel-loaded micelles withhigh encapsulation efficiencies and stability, which is crucial fortheir applicability as a clinically relevant drug delivery platform.

Nearly 10 years ago, Frank Guptonand I had a chance encounterwhere we learned that we both had interest in creating efficient routesto generic medicines. Lucky for me, Frank and I began mentoring eachother—Frank teaching me wisdom gained from 30 years in industryand I sharing what I knew about the academic world. As some who knowFrank will understand, his lessons in some cases seem devilishly obviousand should be chanted daily like a zen koan while others are subtleand complex, requiring many years of reflection. Frank was asked by OPR&D to offer these lessons in a condensed form sothat others might learn what I have. Frank and I decided that a transcriptof our many conversations condensed into one document might do thetrick.

Self-optimizationof chemical reactions enables faster optimizationof reaction conditions or discovery of molecules with required targetproperties. The technology of self-optimization has been expandedto discovery of new process recipes for manufacture of complex functionalproducts. A new machine-learning algorithm, specifically designedfor multiobjective target optimization with an explicit aim to minimizethe number of “expensive” experiments, guides the discoveryprocess. This “black-box” approach assumes no a prioriknowledge of chemical system and hence particularly suited to rapiddevelopment of processes to manufacture specialist low-volume, high-valueproducts. The approach was demonstrated in discovery of process recipesfor a semibatch emulsion copolymerization, targeting a specific particlesize and full conversion.

Characterization of crystalline polymorphs and their quantitation has become an integral part of the pre-clinical drug development process. Raman spectroscopy is a powerful technique for the rapid identification of phases of pharmaceuticals. In the present work we demonstrate the use of low wavenumber Raman vibrational spectroscopy (including phonon measurement) for discrimination among polymorphs. A total of 10 polymorphic pharmaceuticals were employed to conduct a critical assessment. Raman scattering in the low frequency region (10-400 cm-1), which includes crystal lattice vibrations, has been analyzed and the results indicate lattice phonon Raman scattering can be used for rapid discrimination of polymorphic phases with additional discriminating power compared to conventional collection strategies. Moreover structural insight and conformational changes can be detected with this approach.