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28 pages, 16606 KiB

Open AccessArticle

Comprehensive Insight into Chemical Stability of Important Antidiabetic Drug Vildagliptin Using Chromatography (LC-UV and UHPLC-DAD-MS) and Spectroscopy (Mid-IR and NIR with PCA)

by Anna Gumieniczek, Anna Berecka-Rycerz, Emilia Fornal, Barbara Żyżyńska-Granica and Sebastian Granica

Molecules 2021, 26(18), 5632; https://doi.org/10.3390/molecules26185632 - 16 Sep 2021

Cited by 5 | Viewed by 2994

Abstract

During forced degradation, the intrinsic stability of active pharmaceutical ingredients (APIs) could be determined and possible impurities that would occur during the shelf life of the drug substance or the drug product could be estimated. Vildagliptin belongs to relatively new oral antidiabetic drugs [...] Read more.

During forced degradation, the intrinsic stability of active pharmaceutical ingredients (APIs) could be determined and possible impurities that would occur during the shelf life of the drug substance or the drug product could be estimated. Vildagliptin belongs to relatively new oral antidiabetic drugs named gliptins, inhibiting dipeptidyl peptidase 4 (DPP-4) and prolonging the activities of the endogenous incretin hormones. At the same time, some gliptins were shown as prone to degradation under specific pH and temperature conditions, as well as in the presence of some reactive excipients. Thus, forced degradation of vildagliptin was performed at high temperature in extreme pH and oxidative conditions. Then, selective LC-UV was used for quantitative determination of non-degraded vildagliptin in the presence of its degradation products and for degradation kinetics. Finally, identification of degradation products of vildagliptin was performed using an UHPLC-DAD-MS with positive ESI. Stability of vildagliptin was also examined in the presence of pharmaceutical excipients, using mid-IR and NIR with principal component analysis (PCA). At 70 °C almost complete disintegration of vildagliptin occurred in acidic, basic, and oxidative media. What is more, high degradation of vildagliptin following the pseudo first-order kinetics was observed at room temperature with calculated k values 4.76 × 10⁻⁴ s⁻¹, 3.11 × 10⁻⁴ s⁻¹, and 1.73 × 10⁻⁴ s⁻¹ for oxidative, basic and acidic conditions, respectively. Next, new degradation products of vildagliptin were detected using UHPLC-DAD-MS and their molecular structures were proposed. Three degradants were formed under basic and acidic conditions, and were identified as [(3-hydroxytricyclo- [3.3.1.13,7]decan-1-yl)amino]acetic acid, 1-{[(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)amino]acetyl}-pyrrolidine-2-carboxylic acid and its O-methyl ester. The fourth degradant was formed in basic, acidic, and oxidative conditions, and was identified as 1-{[(3-hydroxytricyclo[3.3.1.13,7]-decan-1-yl)amino]acetyl}pyrrolidine-2-carboxamide. When stability of vildagliptin was examined in the presence of four excipients under high temperature and humidity, a visible impact of lactose, mannitol, magnesium stearate, and polyvinylpirrolidone was observed, affecting-NH- and CO groups of the drug. The obtained results (kinetic parameters, interactions with excipients) may serve pharmaceutical industry to prevent chemical changes in final pharmaceutical products containing vildagliptin. Other results (e.g., identification of new degradation products) may serve as a starting point for qualifying new degradants of vildagliptin as it is related to substances in pharmacopoeias. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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12 pages, 1376 KiB

Open AccessEditor’s ChoiceArticle

Detection of 4a,5-dihydropravastatin as Impurity in the Cholesterol Lowering Drug Pravastatin

by Wibo B. van Scheppingen, Peter P. Lankhorst, Marcus Hans and Marco A. van den Berg

Molecules 2021, 26(15), 4685; https://doi.org/10.3390/molecules26154685 - 03 Aug 2021

Viewed by 2105

Abstract

Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected dihydropravastatin in most commercial formulations of pravastatin with LC-MS, in some cases in levels requiring identification. In fermentation broth samples of [...] Read more.

Dihydro analogues are known byproducts of the fermentative production of statins and cannot be detected with existing pharmacopoeia analysis methods. We detected dihydropravastatin in most commercial formulations of pravastatin with LC-MS, in some cases in levels requiring identification. In fermentation broth samples of the single step production of pravastatin, we detected and identified for the first time 4a,5-dihydropravastatin, and confirmed that after several recrystallization steps this impurity can be fully removed from the pravastatin powder. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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13 pages, 2431 KiB

Open AccessArticle

Testing the Limits of a Portable NIR Spectrometer: Content Uniformity of Complex Powder Mixtures Followed by Calibration Transfer for In-Line Blend Monitoring

by Tibor Casian, Alexandru Gavan, Sonia Iurian, Alina Porfire, Valentin Toma, Rares Stiufiuc and Ioan Tomuta

Molecules 2021, 26(4), 1129; https://doi.org/10.3390/molecules26041129 - 20 Feb 2021

Cited by 5 | Viewed by 2276

Abstract

(1) Background: Portable NIR spectrometers gain more and more ground in the field of Process Analytical Technology due to the easy on-site flexibility and interfacing versatility. These advantages that originate from the instrument miniaturization, also come with a downside with respect to performance [...] Read more.

(1) Background: Portable NIR spectrometers gain more and more ground in the field of Process Analytical Technology due to the easy on-site flexibility and interfacing versatility. These advantages that originate from the instrument miniaturization, also come with a downside with respect to performance compared to benchtop devices. The objective of this work was to evaluate the performance of MicroNIR in a pharmaceutical powder blend application, having three active ingredients and 5 excipients. (2) Methods: Spectral data was recorded in reflectance mode using static and dynamic acquisition, on calibration set samples developed using an experimental design. (3) Results: The developed method accurately predicted the content uniformity of these complex mixtures, moreover it was validated in the entire calibration range using ±10% acceptance limits. With respect to at-line prediction, the method presented lower performance compared to a previously studied benchtop spectrometer. Regarding the in-line monitoring of the blending process, it was shown that the spectral variability-induced by dynamic acquisition could be efficiently managed using spectral pre-processing. (4) Conclusions: The in-line process monitoring resulted in accurate concentration profiles, highlighting differences in the mixing behaviour of the investigated ingredients. For the low dose component homogeneity was not reached due to an inefficient dispersive mixing. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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20 pages, 4055 KiB

Open AccessArticle

Developing an Improved UHPLC Method for Efficient Determination of European Pharmacopeia Process-Related Impurities in Ropinirole Hydrochloride Using Analytical Quality by Design Principles

by Tim Tome, Aleš Obreza and Zdenko Časar

Molecules 2020, 25(11), 2691; https://doi.org/10.3390/molecules25112691 - 10 Jun 2020

Cited by 6 | Viewed by 3167

Abstract

This article presents the development of a reversed-phase ultra-high-performance liquid chromatographic method for determining process-related impurities in ropinirole hydrochloride drug substance applying the analytical quality by design approach. The current pharmacopeial method suffers from selectivity issues due to two coelutions of two pairs [...] Read more.

This article presents the development of a reversed-phase ultra-high-performance liquid chromatographic method for determining process-related impurities in ropinirole hydrochloride drug substance applying the analytical quality by design approach. The current pharmacopeial method suffers from selectivity issues due to two coelutions of two pairs of impurities. The development of a new method began with preliminary experiments, based on which the Acquity UPLC BEH C8 was selected as the most appropriate column. The effects of six different critical method parameters (CMPs) were then investigated using a fractional factorial screening design. Column temperature, the ratio of methanol in mobile phase B, and gradient slope turned out to be highly significant CMPs in achieving critical resolutions, and they were further evaluated using a central composite face-centered response-surface design. Mathematical models were created by applying a multiple linear regression method. Based on the elution order of an unknown degradation impurity and impurity C, two design spaces were established, and for each design space an optimal combination of CMPs was determined. The method developed was validated for precision, accuracy, linearity, and sensitivity, and it was proven suitable for determining nine process-related impurities of ropinirole. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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12 pages, 1412 KiB

Open AccessArticle

Sensing Precursors of Illegal Drugs—Rapid Detection of Acetic Anhydride Vapors at Trace Levels Using Photoionization Detection and Ion Mobility Spectrometry

by Victor Bocos-Bintintan, George-Bogdan Ghira, Mircea Anton, Aurel-Vasile Martiniuc and Ileana-Andreea Ratiu

Molecules 2020, 25(8), 1852; https://doi.org/10.3390/molecules25081852 - 17 Apr 2020

Cited by 15 | Viewed by 2564

Abstract

Sensitive real-time detection of vapors produced by the precursors, reagents and solvents used in the illegal drugs manufacture represents a priority nowadays. Acetic anhydride (AA) is the key chemical used as acetylation agent in producing the illegal drugs heroin and methaqualone. This study [...] Read more.

Sensitive real-time detection of vapors produced by the precursors, reagents and solvents used in the illegal drugs manufacture represents a priority nowadays. Acetic anhydride (AA) is the key chemical used as acetylation agent in producing the illegal drugs heroin and methaqualone. This study was directed towards quick detection and quantification of AA in air, using two fast and very sensitive analytical techniques: photoionization detection (PID) and ion mobility spectrometry (IMS). Results obtained indicated that both PID and IMS can sense AA at ultra-trace levels in air, but while PID produces a non-selective response, IMS offers richer information. Ion mobility spectrometric response in the positive ion mode presented one product ion, at reduced ion mobility K₀ of 1.89 cm² V⁻¹ s⁻¹ (almost overlapped with positive reactant ion peak), while in the negative ion mode two well separated product ions, with K₀ of 1.90 and 1.71 cm² V⁻¹ s⁻¹, were noticed. Our study showed that by using a portable, commercial IMS system (model Mini IMS, I.U.T. GmbH Berlin) AA can be easily measured at concentrations of 0.05 ppm_v (0.2 mg m⁻³) in negative ion mode. Best selectivity and sensitivity of the IMS response were therefore achieved in the negative operation mode. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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15 pages, 2141 KiB

Open AccessArticle

Determination of d-Cycloserine Impurities in Pharmaceutical Dosage Forms: Comparison of the International Pharmacopoeia HPLC–UV Method and the DOSY NMR Method

by Damjan Makuc, Živa Švab, Katerina Naumoska, Janez Plavec and Zdenko Časar

Molecules 2020, 25(7), 1684; https://doi.org/10.3390/molecules25071684 - 07 Apr 2020

Cited by 2 | Viewed by 3932

Abstract

d-cycloserine is a broad-spectrum antibiotic that is currently being used as a secondary choice in the treatment of tuberculosis. In recent years, it has become more popular, due to its effect on the nervous system. In this current study, we provide evidence [...] Read more.

d-cycloserine is a broad-spectrum antibiotic that is currently being used as a secondary choice in the treatment of tuberculosis. In recent years, it has become more popular, due to its effect on the nervous system. In this current study, we provide evidence that The International Pharmacopoeia HPLC–UV method for d-cycloserine impurity profiling is not repeatable due to the variable response of cycloserine dimer, one of d-cycloserine impurities. Therefore, we introduced the DOSY (diffusion ordered spectroscopy) NMR (nuclear magnetic resonance) technique to determine the levels of d-cycloserine impurities in pharmaceutical dosage forms. The DOSY NMR technique allowed separation of d-cycloserine, its degradation products, and key process impurities in concentrations below pharmacopoeial specification limits. The proposed DOSY NMR method allowed accurate identification and quantification of the cycloserine dimer, which was not possible through the use of the pharmacopoeial HPLC method. The current method has the potential for practical use in analytical laboratories of the pharmaceutical industry. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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18 pages, 3420 KiB

Open AccessArticle

Development of a Unified Reversed-Phase HPLC Method for Efficient Determination of EP and USP Process-Related Impurities in Celecoxib Using Analytical Quality by Design Principles

by Tim Tome, Zdenko Časar and Aleš Obreza

Molecules 2020, 25(4), 809; https://doi.org/10.3390/molecules25040809 - 13 Feb 2020

Cited by 17 | Viewed by 5652

Abstract

This article presents the development of a reversed-phase (RP) high-performance liquid chromatographic (HPLC) method for determination of process-related impurities in a celecoxib drug substance following Analytical Quality by Design (AQbD) principles. The method from European Pharmacopeia (EP) for celecoxib drug substance does not [...] Read more.

This article presents the development of a reversed-phase (RP) high-performance liquid chromatographic (HPLC) method for determination of process-related impurities in a celecoxib drug substance following Analytical Quality by Design (AQbD) principles. The method from European Pharmacopeia (EP) for celecoxib drug substance does not sufficiently separate celecoxib from its EP impurity B because the system suitability criterion is not achieved (resolution NLT 1.8). The same issue was observed with the proposed method from United States Pharmacopeia (USP) for celecoxib capsules, where EP impurity A elutes under the main peak. A new HPLC method was developed that eliminates the disadvantages of the two pharmacopeial methods and is capable of efficiently separating and determining all seven impurities listed in EP and the proposed USP monographs. The development of a new HPLC method started with method scouting, in which various C18 and phenyl stationary phases were tested. Improved selectivity was obtained only with a chiral stationary phase. An immobilized Chiralpak IA-3 column used in RP mode turned out to be the most appropriate for method optimization. The ratio of acetonitrile in the mobile phase, flow rate, and column temperature were recognized as critical method parameters (CMPs) and were further investigated using a central composite face response-surface design. A multiple linear regression (MLR) method was applied to fit the mathematical models on the experimental data to determine factor–response relationships. The models created show adequate fit and good prediction abilities. The Monte Carlo simulation method was used to establish the design space. The method developed was verified in terms of precision, sensitivity, accuracy, and linearity, and the results showed that the new method is suitable for determination of seven process-related impurities of celecoxib. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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Review

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41 pages, 2736 KiB

Open AccessReview

Challenges and Opportunities of Implementing Data Fusion in Process Analytical Technology—A Review

by Tibor Casian, Brigitta Nagy, Béla Kovács, Dorián László Galata, Edit Hirsch and Attila Farkas

Molecules 2022, 27(15), 4846; https://doi.org/10.3390/molecules27154846 - 28 Jul 2022

Cited by 24 | Viewed by 3336

Abstract

The release of the FDA’s guidance on Process Analytical Technology has motivated and supported the pharmaceutical industry to deliver consistent quality medicine by acquiring a deeper understanding of the product performance and process interplay. The technical opportunities to reach this high-level control have [...] Read more.

The release of the FDA’s guidance on Process Analytical Technology has motivated and supported the pharmaceutical industry to deliver consistent quality medicine by acquiring a deeper understanding of the product performance and process interplay. The technical opportunities to reach this high-level control have considerably evolved since 2004 due to the development of advanced analytical sensors and chemometric tools. However, their transfer to the highly regulated pharmaceutical sector has been limited. To this respect, data fusion strategies have been extensively applied in different sectors, such as food or chemical, to provide a more robust performance of the analytical platforms. This survey evaluates the challenges and opportunities of implementing data fusion within the PAT concept by identifying transfer opportunities from other sectors. Special attention is given to the data types available from pharmaceutical manufacturing and their compatibility with data fusion strategies. Furthermore, the integration into Pharma 4.0 is discussed. Full article

(This article belongs to the Special Issue Drug Analysis in Pharmaceutical Development and Drug Manufacturing)

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