Zhihong Ge

Merck, Whitehouse Station, New Jersey, United States

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Publications (27)53.25 Total impact

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    ABSTRACT: Potential genotoxic impurities (PGI) are chemical compounds that could potentially damage DNA and lead to mutation. Controlling the occurrence of PGIs in active pharmaceutical ingredients (APIs) poses a big challenge for chemists, as levels of these compounds must be reduced well below the amounts required for other types of less toxic impurities. In situations where formation of PGIs cannot be avoided, an ideal solution would allow the complete removal of PGIs after the synthesis is complete, for example, by recrystallization, preparative chromatography or other downstream processing approaches. Some disadvantages of using these approaches are potential high yield loss, high solvent consumption, and additional time and resources required for process development. In this work, we present a simple and rapid approach to remove electrophilic PGIs from APIs. A selected nucleophilic resin can be added to the final API solution to reduce or totally remove the PGI. Esters of methanesulfonic acid (MSA), benzenesulfonic acid (BSA), and p-toluenesulfonic acid (pTSA) were used as model electrophilic PGIs. Several nucleophilic resins were screened, and the resins with the highest efficiency of PGI removal were chosen. A recommended procedure is presented for the removal of MSA, BSA, and pTSA esters. The kinetics of PGI removal, resin loading capacity, solvent effects, and API matrix effects are demonstrated.
    Organic Process Research & Development - ORG PROCESS RES DEV. 04/2010; 14(4).
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    ABSTRACT: Simultaneous enantioseparation of a basic API compound, (R)-2-Amino-N-[2-[1,2-dihydro-1-(methylsulfonyl) spiro [3H-indole-3,4'-piperidin]-1'-yl]-2-oxo-1-[(phenylmethyloxy) ethyl]-2-methylpropanamide monomethanesulfonate (compound-A) and its neutral penultimate intermediate, (R)-2-BOC-Amino-N-[2-[1,2-dihydro-1-(methylsulfonyl) spiro [3H-indole-3,4'-piperidin]-1'-yl]-2-oxo-1-[(phenylmethyloxy) ethyl]-2-methylpropanamide monomethanesulfonate (compound-B) was investigated using reversed phase (RPLC) and normal phase liquid chromatography (NPLC). After an initial screening, a Sepapak-4 column, a new type of polysaccharide chiral stationary phase (CSP), was selected for further method development based on hits on separation selectivity for both compounds under RPLC and NPLC. After comparing the pros and cons, a method utilizing the Sepapak-4 chiral column (150 mm x 4.6 mm, 3 microm particle size) in RPLC mode was finally developed. Separations were performed in gradient elution mode starting at 50% A (10 mM, NH(4)COOH at pH 6.5)/50% B (50/50 EtOH/MeCN) to 25% A (10 mM, NH(4)COOH at pH 6.5)/75% B (50/50 EtOH/MeCN). The flow rate was 1.0 mL/min; the column temperature was 50 degrees C; the UV wavelength was 220nm and the mass spectrometric detection was APCI in the positive ionization mode. The reaction mixture sample was directly diluted in ethanol. Baseline enantioseparation were achieved for both compound-A and its intermediate simultaneously with resolution greater than 2.0. The method was validated in terms of injection precision, linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, and ruggedness. The specificity of the method was further evaluated by spiking a mixture of enantiomers of compound-A and its intermediate into a reaction matrix containing all of the synthetic reagents. No matrix interference was observed across the elution windows of compound-A and its intermediate. Additionally, the peak purity of each enantiomer was evaluated by mass spectra, indicating the specificity of the method.
    Journal of pharmaceutical and biomedical analysis 09/2009; 51(1):153-7. · 2.45 Impact Factor
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    ABSTRACT: The enantioselectivity of a collection of neutral pharmaceutical compounds on six different types of polysaccharide chiral stationary phases (CSPs), Chiralpak AD (and AD-RH), Chiralcel OD (and OD-RH), Chiralpak OJ (and OJ-R), Chiralcel AS (and AS-RH), Sepapak-2 and Sepapak-4 are compared using reversed phase (RPLC) and normal phase liquid chromatography (NPLC). Screening strategies for maximizing the probability of achieving an initial chiral separation hit for neutral compounds using both RPLC and NPLC are described. Further method optimizations are demonstrated by modifying parameters such as organic modifier composition, eluent pH or CSP particle size. Several practical examples of the application of chiral methods for the study of synthetic reaction mixtures are presented. The most critical validation aspects, including limit of detection, specificity, and ruggedness, are also briefly presented.
    Journal of pharmaceutical and biomedical analysis 06/2009; 49(4):964-9. · 2.45 Impact Factor
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    ABSTRACT: Due to the high method variability (typically > or = 0.5%, based on a literature survey and internal Merck experience) encountered in the HPLC weight percent (%) assays of various active pharmaceutical ingredients (APIs), it is proposed that the routine use of the test in stability studies should be discouraged on the basis that it is frequently not sufficiently precise to yield results that are stability-indicating. The high method variability of HPLC weight % methods is not consistent with the current ICH practice of reporting impurities/degradation products down to the 0.05% level, and it can lead to erroneous out-of-specification (OOS) results that are due to experimental error and are not attributable to API degradation. For the vast majority of cases, the HPLC impurity profile provides much better (earlier and more sensitive) detection of low-level degradation products. Based on these observations, a Quality-by-Design (QbD) approach is proposed to phase out the HPLC weight % assay from routine API stability testing protocols.
    Journal of pharmaceutical and biomedical analysis 06/2009; 50(5):794-6. · 2.45 Impact Factor
  • Lili Zhou, Bing Mao, Zhihong Ge
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    ABSTRACT: The enantioselectivity of two protein chiral stationary phases, alpha1 acid glycoprotein (AGP) and ovomucoid protein (OVM) are compared. Neutral, basic and acidic pharmaceutical compounds were screened on both stationary phases. Selected parameters such as mobile phase pH, temperature, and organic modifier were varied in order to achieve chiral separations. Relations between the enantioselectivities of the two stationary phases and the properties of the compounds (acidity, basicity, structure of molecule) were also investigated. The OVM column tends to separate larger molecules better than the AGP column. Reversal of elution order for some compounds was observed on the two columns under similar experimental conditions, or with the same column as a function of pH and organic modifier. Many practical aspects were also discussed.
    Journal of Pharmaceutical and Biomedical Analysis 05/2008; 46(5):898-906. · 2.95 Impact Factor
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    ABSTRACT: Optical pure (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid, a chiral crown ether, was successfully used as a chiral selector for the stereoisomeric separation of numerous real pharmaceutical compounds. Both practical and mechanistic aspects were described. Effects of chiral selector concentration under different pH values of BGE were discussed. Chiral recognition for the enantiomeric compounds with (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was investigated through model compounds using CE and infrared spectroscopic techniques. Relations between the enantioselectivity of the chiral crown ether and the structural features of the studied compounds were also investigated. Unusual resolutions of compound-p and its enantiomer as well as compound-o and its 2b epimer were described. These compounds contained only tertiary amine, believed to be nonbinding with crown ethers in general. The possible mechanisms for the interaction between compound-o and the chiral crown ether were investigated using CE, electrospray MS (ESI-MS), and proton ((1)H) NMR spectroscopy. All experiments provided clear evidence that binding between compound-o and the chiral crown ether had occurred. ESI-MS spectra indicated that the complexes had a 1:1 stoichiometric ratio. The advantages and disadvantages of using chiral crown ether for stereoisomeric separations were compared with those using sulfated CDs.
    Electrophoresis 09/2007; 28(15):2658-66. · 3.26 Impact Factor
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    ABSTRACT: A mobile HPLC reaction monitoring tool consisting of a cart-mounted microfluidic HPLC instrument equipped with a tethered, automated sampling and dilution module is described. Several examples of the use of the instrument for carrying out reaction progress analysis are presented. Reaction aliquot size is typically only a few microliters, allowing extensive sample monitoring from small volume reactions. Reaction quenching is possible, and aliquot dilution is adjustable, with suitable precision and accuracy even at hundredfold dilution. A sampling capillary with a chemically inert stainless steel fritted terminus allows sampling from some heterogeneous reactions. The sampling interval is adjustable, from a minimum of about 4 min, upwards. Visualization of an ongoing or completed study as either stacked “waterfall” chromatograms or as graphs of integrated peak areas (or any derived function, such as percent ee or percent conversion) vs time affords the process chemist valuable information on reaction kinetics and a useful record of reaction progress over time. While online HPLC analysis has been known for some time, the compact and mobile nature of this instrument renders it especially useful for carrying out reaction progress monitoring in the laboratory environment.
    Organic Process Research & Development - ORG PROCESS RES DEV. 08/2007; 11(5).
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    ABSTRACT: Tracking the impurity profile of an active pharmaceutical ingredient (API) is a very important task for all stages of drug development. A systematic approach for tracking impurity profile of API is described. Various real pharmaceutical applications are presented through successful examples of impurity profile tracking for three different novel APIs. These include MK-0969, an M3 antagonist; MK-0677, an oral-active growth hormone secretagogue and API-A, a cathepsin K inhibitor. A general strategy including selection of a reversed phase high performance liquid chromatographic (RP-HPLC) impurity profile method based on screening various stationary phases and changing the pH of the mobile phase and elucidation of impurity structures through the utilization of LC-MS, preparative-LC and NMR is demonstrated. A series of studies were conducted on the peak purity check by using the LC-UV diode-array and LC-MS detections. The advantages and disadvantages of each technique in the evaluation of peak purity are discussed.
    Journal of Pharmaceutical and Biomedical Analysis 07/2007; 44(2):421-9. · 2.95 Impact Factor
  • 06/2007; , ISBN: 9780470027325
  • NIR news 01/2007; 18(5).
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    ABSTRACT: The crystallization of Etoricoxib, a polymorphic compound, has been optimized and controlled by seeding with the desired polymorph at a moderate supersaturation condition. To enhance the process robustness, near infrared spectroscopy (NIRS) has been evaluated as an inline measurement method for the concentration of Etoricoxib prior to seeding in the crystallization process. In this NIRS method, a spectral discriminant analysis based on principal component analysis (PCA) was established to detect the presence of solids produced by premature crystallization, or bubbles in the path of light. Once a spectrum was qualified as that of clear solution, concentration of Etoricoxib was calculated by a NIRS calibration model built with partial least squares (PLS) regression and with offline HPLC analysis as the reference method. This model was accurate with a standard error of cross validation (SECV) less than 1.2 mg/g Etoricoxib and a standard error of prediction (SEP) less than 1.7 mg/g over the concentration range from 50 to 170 mg/g, temperature range from 49 to 65 degrees C, and different sources of materials. In addition, all aspects of the offline HPLC method, especially the sampling procedure, were optimized to provide an accurate reference for NIRS calibration models. The application of this method at a pilot plant has demonstrated its capability of accurately measuring the process concentration of Etoricoxib as well as detecting the presence of solids produced by premature crystallization before seeding.
    Journal of Pharmaceutical Sciences 12/2006; 95(11):2337-47. · 3.13 Impact Factor
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    ABSTRACT: A novel approach for the potential on-line determination of the enantiomeric excess (ee) of an M3 antagonist drug substance combining attenuated total reflectance infrared (ATR-IR) spectroscopy, guest-host complexes, and chemometric data analysis is described. Chiral recognition through a formation of diastereomeric complexes was measured by ATR-IR. Small changes on the IR spectra reflect the interaction between the guest (M3) and host (chiral selector). These changes are measured as a function of M3 enantiomer excess. The standard error of prediction is 1.3 ee%. The prediction results based on the IR method were in good agreement with the gravimetric method. The robustness of the calibration model was evaluated by varying the concentration of the chiral selector, the pH of the solution, and the organic solvents. The stability of the calibration model was also demonstrated through measuring different sets of samples on different days.
    Chirality 06/2006; 18(5):306-13. · 1.72 Impact Factor
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    ABSTRACT: An application of Fourier transform infrared (FT-IR) spectroscopy equipped with an attenuated total reflectance (ATR) probe for in-line monitoring of a hydrochloride (HCl) salt formation process of 4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluorometryl)phenyl]-1H-imidazol-5-yl}-N-[(1S)-1-phenylethyl]pyridine-2-amine (freebase), an active pharmaceutical ingredient as a P38 MAP kinase inhibitor, is described. The freebase forms both mono- and bis-HCl salts due to its structural features. The mono-HCl salt is the desired product but the bis-salt is an impurity. The key to maximizing the product yield and minimizing the impurity level is to monitor the salt-forming reaction and to terminate it at the correct HCl charge amount. The process analytical technology (PAT) provided real-time data for process control and overcame the limitations that had been previously encountered by other analytical instrumentations, such as high-performance liquid chromatography and titration. Two qualitative approaches for reaction endpoint determination were employed. In the first approach, changes in the concentration of the freebase and bis-salt were monitored via the first derivative concentration profiles. The flat point in the freebase profile and the rise in the bis-salt profile were used as a detection bracket for the endpoint of HCl charging. In the second approach, principal component analysis (PCA) was used to classify the status of the process based on a spectral library consisting of spectra collected around the endpoint. Results indicated that both methods provided adequate accuracy for endpoint control in a small window between 1.0 and 1.05 HCl to freebase mole ratio. Both methods were used to support a scaled up process. Three batches of MAP mono-HCl salt formation were successfully controlled and prepared.
    Journal of Pharmaceutical and Biomedical Analysis 05/2006; 41(1):99-104. · 2.95 Impact Factor
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    ABSTRACT: Recent advances in in situ measurement technology and automation of batch crystallizers have enabled the development of batch crystallization recipes in which the desired supersaturation profile is followed by feedback control. This paper describes a new approach for following supersaturation setpoints for antisolvent crystallizations that is easy to implement for the tried crystallization. Simulations and application to a proprietary drug compound demonstrate how this combination of automation and in process measurements enables the rapid development of batch crystallization processes in the pharmaceutical industry.
    Crystal Growth & Design - CRYST GROWTH DES. 01/2006; 6(4).
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    ABSTRACT: A practical, one-pot process for the preparation of beta-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Meldrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of beta-keto amides from acyl Meldrum's acids occurs via alpha-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated alpha-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.
    Journal of the American Chemical Society 11/2004; 126(40):13002-9. · 10.68 Impact Factor
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    ABSTRACT: Anhydrate and hemihydrate phases of etoricoxib (5-chloro-6‘-methyl-3-[4-(methylsulfonyl)phenyl]-2,3‘-bipyridine) are described. The ternary phase diagram of etoricoxib, isopropyl acetate, and water at 10 °C is reported. The critical water/isopropyl acetate ratio at this temperature, below which etoricoxib will exist as anhydrate at equilibrium, is 0.21 ± 0.04 wt % water, as determined from measurements made on the ternary solution in simultaneous equilibrium with anhydrate and hemihydrate solids.
    Organic Process Research & Development - ORG PROCESS RES DEV. 07/2003; 7(6).
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    ABSTRACT: Near infrared spectroscopy (NIRS) was utilized to determine the water content during the drying of a drug substance with Karl Fisher titration as the reference measurement. NIRS calibration models were built with Partial Least Squares (PLS) regression based on spectral region of 1822-1948 nm for samples with 1-40% (w/w) water from five batches. A standard error of prediction (SEP) of 1.85% (w/w) was obtained from validation of the model with additional batches. A second NIRS calibration model using PLS was constructed in the region of 1-10% (w/w) water with samples from the same five calibration batches. This calibration model improved the accuracy of the prediction in the critical region around the end point of drying and provided a standard error of prediction 0.42% (w/w). In addition, direct spectral analyses with Principal Component Analysis (PCA) and peak ratios were applied to distinguish between surface (unbound) water and bound water incorporated into the crystal lattice of the drug substance. Direct spectral analysis indicated the existence of significant numerical and graphical differences between samples containing both surface and bound water, and those containing bound water only. Applying this method to monitor an actual drying process with the graphical assistance of spectral analysis, the drying process can be controlled, and the end point of drying clearly determined to ensure the desired hydrate form of the product. This study has demonstrated the in-line monitoring capability of NIRS to differentiate the surface and bound water simultaneously in addition to the determination of the water level.
    Journal of Pharmaceutical Sciences 06/2003; 92(5):1058-65. · 3.13 Impact Factor
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    ABSTRACT: A simple and safe prototype apparatus was designed and adapted for the in situ determination of the moisture content of a cytotoxic compound (9-fluorenylmethyl-protected doxorubicin-peptide conjugate, or Fm-DPC) by near-infrared absorbance spectroscopy during optimization of the chemical isolation procedure. The cytotoxic nature of the compound restricts one's ability to safely sample such drying processes for more traditional means of moisture determination for fear of hazardous solids dusting, hence in situ sampling approaches are of great importance. These concerns also exist for the process development laboratory, where despite the smaller scale of operations, the volume of experiments (hence cytotoxic samples) required to define a chemical process is often more significant. In this application, partial least squares regression was used with Karl Fischer volumetric titration analysis to generate a calibration model. Although pronounced differences in cake density were observed as a function of the buffer selected for the isolation process, the model still achieved a standard error of calibration of 0.63% w/w and a standard error of prediction of 0.99% (w/w). These results demonstrated the versatility of the prototype apparatus/data processing approach to model Fm-DPC drying under extremely variable conditions, as inherently expected during the investigational laboratory development of a chemical process.
    Journal of Pharmaceutical Sciences 04/2003; 92(3):529-35. · 3.13 Impact Factor
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    ABSTRACT: Etoricoxib (5‐chloro‐6′‐methyl‐3[4‐(methanesulfonyl)phenyl]‐2,3′‐bipyridine) is a highly active and selective cyclo‐oxygenase II inhibitor. A single, stability‐indicating HPLC method has been developed and validated for both the impurity and quantitative analysis of etoricoxib. Method development incorporated the optimization of stationary phase, pH, temperature, and mobile phase composition for the resolution of thirteen process impurities and three major degradation products. Further optimization of pH and mobile phase composition was aided by the use of DryLab, a computer‐based simulation program. The stability‐indicating capability of the method was proven through the identification of photolytic and oxidative decomposition products. Method validation produced excellent results for linearity, precision, limit of quantitation and limit of detection, specificity, accuracy, recovery, and robustness. The identities of etoricoxib decomposition products were confirmed by UV, LC/MS, and NMR spectra.
    Journal of Liquid Chromatography & Related Technologies - J LIQ CHROMATOGR RELAT TECHNO. 01/2003; 26(15):2551-2566.
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    ABSTRACT: In the activation of lactol by trifluoroacetic anhydride (TFAA), an accurate charge of TFAA is critical because of the potential formation of a lactol dimer impurity caused by a TFAA undercharge, or the extra consumption of reagents by excess TFAA in the subsequent reaction step. Monitoring the charge by chromatographic methods is difficult since TFAA is reactive and activated lactol is unstable during off-line sample preparation and subsequent analysis. By using in situ Fourier transform infrared (FTIR) spectroscopy, we overcame the difficulties in analyzing TFAA and the activated lactol with chromatographic methods. The FTIR method was based on real-time monitoring of TFAA at 1875cm−1 and activated lactol at 1679cm−1 during the activation reaction. A detection limit of less than 2% equivalent (or 5mg/ml) for TFAA was achieved and was within the process specification. Thus, the reaction end-point can be determined based on the amount of TFAA in the reaction mixture. The formation of the lactol dimer impurity, based on the results of HPLC analysis, is temperature dependent. Significant amounts of lactol dimers were formed at high temperature, while little dimer was produced when the reactions were carried out under low temperature. In addition, two operation routes, i.e. adding lactol to TFAA or feeding TFAA to lactol, generated comparable but low levels of dimer impurities as long as the addition rate of the second reactant was controlled to maintain the reaction temperature below 0°C. In situ FTIR has made it possible to control the activation of lactol by TFAA promptly and effectively.
    Analytica Chimica Acta 01/2003; 497(1):155-164. · 4.39 Impact Factor