Pharmaceutical separations can be divided into three categories: high throughput, high productivity, and high resolution. These categories contain specific pharmaceutical applications, each of which has distinct separation goals. Traditionally, these goals have been achieved utilizing conventional HPLC with typical column dimensions and particle sizes. The recent introduction of ultra-HPLC (UHPLC) has provided a new potential for method development and analysis. Pharmaceutical chemists must determine the impact of this emerging technology. UHPLC is achieved by using sub-2 microm particle size column packing at increased linear velocities. In order to utilize this technology, mobile phase viscosity must be minimized or the chromatography system must be redesigned to withstand an increased backpressure. Today, there are many commercially available UHPLC systems capable of exceeding conventional pressure limits of 400 bar. The advantage of UHPLC over conventional HPLC is the capability to increase the speed without sacrificing efficiency. In comparison to traditional HPLC, our research showed that UHPLC can decrease run times up to 7 x. In addition, for high resolution applications, UHPLC achieved significant efficiency advantages over traditional HPLC. This paper will evaluate the potential roles for utilizing UHPLC in the pharmaceutical industry.

A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxabicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.

The benefits of sub-2 micron particle size columns have been widely researched and published. The use of these columns on ultrahigh-pressure liquid chromatography (UHPLC) instrumentation may lead to increased efficiencies and higher throughput. However, these instruments may not be readily available to the pharmaceutical chemist. Within the past year, a practical alternative has been introduced which offers increased efficiencies, but at conventional HPLC pressure limitations. These particles are called fused-core particles and are comprised of a 1.7-micron solid core encompassed by a 0.5-micron porous silica layer (dp = 2.7 micron). The goal for this research was to test these columns for efficiency and robustness utilizing a mixture of Torcetrapib and its relative impurities. Our results indicate that excellent theoretical plates (approximately 14000) were achievable for run times less than 5 min. Compared to the Waters Acquity particles, the fused-core particles achieved approximately 80% of the efficiency but with half the observed backpressure. Our robustness results concluded that these separations were reproducible for at least 500 injections while the % RSD for retention time, theoretical plates, peak asymmetry, and resolution was found to be less than 1%.

Quantitative NMR spectrometry (qNMR) is an attractive, viable alternative to traditional chromatographic techniques. It is a fast, easy, accurate, and nondestructive technique which allows an analyst to gain quantitative information about a component mixture without the necessity of authentic reference materials, as is the case with most other analytical techniques. This is ideal for the synthesis of active pharmaceutical ingredients (API) that are in the early stages of development where authentic standards of the analytes may not be available. In this paper, the application of (19)F and (1)H qNMR for reaction monitoring and in situ potency determinations will be discussed for an early stage pharmaceutical candidate with several analytical challenges. These challenges include low UV absorption, low ionization, thermal instability, and lack of authentic reference standards. Quantitative NMR provided quick, fit-for-purpose solutions for process development where conventional separation techniques were limited.

The process development of a nicotine analog or hapten (1) for conjugation to a protein as an antigen is described. The original process in early development used an Ir-catalyzed borylation reaction to enable rapid derivatization of nicotine with the desired regiocontrol. While the process was very efficient, it required chromatography to meet purity targets. A related process was later developed that possessed crystalline intermediates to better control levels of process-related impurities and heavy metals in 1. This control strategy for 1 was essential due to the strict purity requirements for conjugation of 1 when forming an antigen. In addition, the Ir-catalyzed borylation was studied to enable robust manufacture via this methodology which led to an efficient process for the preparation of 1.