Biomedical subjects

Zhihong Ge

Publications and source records attributed to Zhihong Ge.

11 recordsLinked to original sources

PubMed2006

Impurity profile tracking for active pharmaceutical ingredients: case reports.

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.

Cathepsin K↗

PubMed2006

Determination of the enantiomeric excess of an M3 antagonist drug substance by chemometric analysis of the IR spectra of different guest-host complexes.

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.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2006

Real-time endpoint monitoring and determination for a pharmaceutical salt formation process with in-line FT-IR spectroscopy.

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.

Calibration↗

PubMed2006

In-line measurement of a drug substance via near infrared spectroscopy to ensure a robust crystallization process.

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.

Calibration↗

PubMed2004

Mechanistic evidence for an alpha-oxoketene pathway in the formation of beta-ketoamides/esters via Meldrum's acid adducts.

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 Article↗

PubMed2003

In situ moisture determination of a cytotoxic compound during process optimization.

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.

Doxorubicin↗

PubMed2003

Determination and differentiation of surface and bound water in drug substances by near infrared spectroscopy.

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.

Chemical Phenomena↗

PubMed2003

[The study on the effects of the oil from Hippophae rhamnoides in hematopoiesis].

OBJECTIVE: To investigate the possibility of the oil from Hippophae rhamnoides (OHR) in supporting the hematopoitic reconstitution after high dose chemotherapy. METHOD: The mice were fed with OHR and variation of blood cell counts of the mice was recorded. Animal models of myelosuppression were built by 5-Fu intra-peritoneal infusion. The effects of OHR in the hematopoietic reconstitution were observed. RESULTS: The counts of erythrocytes of OHR group were significantly elevated. The blood cell counts in myelosuppression mice fed with OHR exceeded those in control group, and the mortality was decreased. CONCLUSION: OHR can improve the hematopoiesis of erythroid linage. Like G-CSF, OHR can stimulate the recovery of hematopoiesis after chemotherapy.

Animals↗

PubMed2002

Examination of rofecoxib solution decomposition under alkaline and photolytic stress conditions.

Rofecoxib is a highly active and selective cyclo-oxygenase II inhibitor. A stability-indicating method for the assay of rofecoxib has been developed using reverse-phase high-performance liquid chromatography (HPLC). Stress testing of rofecoxib was conducted during the method development and validation. HPLC analysis of rofecoxib solutions stressed under alkaline and photolytic conditions revealed the presence of several degradates. Two main degradates were determined to be the cyclization product formed by photo-cyclization and the dicarboxylate formed by ring opening in the presence of base and oxygen. The identities of these degradates were confirmed by comparison of UV spectra and HPLC retention time with the independently synthesized products. The mechanistic pathways for the formation of these degradates are discussed. Further improvement of the HPLC method's ruggedness has been made based on these studies.

Alkalies↗

PubMed2002

Employment of on-line FT-IR spectroscopy to monitor the deprotection of a 9-fluorenylmethyl protected carboxylic acid peptide conjugate of doxorubicin.

A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatographic means include real time determination of the end-point of a reaction that is time sensitive to by-product formation, and elimination of sampling a highly toxic reaction mixture. The FT-IR method is based on monitoring, in real time, the disappearance of the Fm ester carbonyl band for 1b at 1737 cm(-1), during deprotection by piperidine, and calibration models were established by Partial Least Squares (PLS) regression analysis with high performance liquid chromatography (HPLC) as reference. The best calibration model was built with 5 PLS factors in the spectral range of 1780-1730 and 1551-1441 cm(-1) and resulted in a standard error of cross validation (SECV) of 0.63 mM 1b and a standard error of prediction (SEP) of 0.51 mM 1b in the range of 0-25 mM. This error of prediction is approximately 0.8% of the initial concentration of 1b and is well within our specifications of <2% initial concentration.

Antineoplastic Agents↗

PubMed2002

Development of a nonchiral HPLC method with circular dichroism detection for chiral analysis of molybdenum-catalyzed enantioselective synthesis products.

The combination of a circular dichroism detector and nonchiral liquid chromatography was used for the chiral analysis of unresolved enantiomers to determine the enantioselectivity of a molybdenum-catalyzed asymmetric allylic alkylation reaction. The CD/UV peak area ratio of the unresolved enantiomers was calculated and compared with that of a reference standard to determine the enantiomeric purity. The limit of quantitation (LOQ) is 20 ng for the chiral ligand and 1 microg for the branched chiral product. The viability of the system depends on the limit of quantitation of the CD response and the linearity range of the CD and UV response.

Catalysis↗