Stability Of Active Pharmaceutical Ingredients Research Articles

Methods Development and Validation for the Estimation of Pioglitazone HCl in Bulk and Formulations by UV Spectroscopy and FTIR

The use of spectroscopic analysis, particularly UV spectrophotometer, is a simple and essential technique for bulk drug estimation, formulation studies, and compatibility assessments of drugs with various excipients. In the pharmaceutical industry, various analytical instruments, including Fourier transform infrared spectroscopy (FTIR), are employed for investigating drug-excipient interactions that can impact the stability of active pharmaceutical ingredients. This study aimed to develop a UV spectrophotometric method for the analysis of Pioglitazone hydrochloride in phosphate buffer (pH 7.4) and methanolic solution, assessing its linearity and compliance with Beer's Law. Furthermore, we aimed to use FTIR to characterize potential interactions between Pioglitazone and common pharmaceutical excipients, such as Guar Gum, Chitosan, and Sodium Alginate. Standard solutions of Pioglitazone were prepared in phosphate buffer (pH 7.4) and methanol. UV spectrophotometer was conducted to determine the maximum absorption wavelength. Calibration curves were constructed to evaluate linearity and adherence to Beer's Law. FTIR analyses were performed to investigate drug-excipient interactions by examining the functional groups. In phosphate buffer (pH 7.4), the maximum absorption wavelength for Pioglitazone hydrochloride was 268 nm. The calibration curve for Pioglitazone in phosphate buffer (pH 7.4) demonstrated linearity in the concentration range of 1–20 µg/ml, with a correlation coefficient of 0.998. In methanol, the maximum absorption wavelength for Pioglitazone hydrochloride was found to be 272 nm. The calibration curve in methanol exhibited linearity in the range of 1–20 µg/ml, with a correlation coefficient of 0.999. FTIR analysis revealed potential drug-excipient interactions, particularly in the case of Guar Gum, Chitosan, and Sodium Alginate, suggesting the formation of stable hydrogen bonds. The developed UV spectrophotometric method for Pioglitazone analysis is a reliable, cost-effective, and reproducible approach, making it a valuable tool for drug development and quality control. Additionally, the FTIR characterization confirmed interactions between Pioglitazone and common pharmaceutical excipients, enhancing our understanding of formulation compatibility.

Compatibility of Commonly Used Active Pharmaceutical Ingredients in a Ready-to-Use Oral Suspending Vehicle.

The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending vehicle. Oral suspensions of amoxicillin trihydrate (50 mg/mL), clozapine (25 mg/mL), indomethacin (5.0 mg/mL), levodopa/carbidopa (10.0/2.5 mg/mL), levothyroxine sodium (T4, 25 µg/mL), lomustine (4.0 and 10.0 mg/mL), methyldopa (25 mg/mL) and procarbazine (10.0 mg/mL) were formulated in SyrSpend® SF PH4 and the stability was monitored for up to 90 days, except for amoxicillin trihydrate, which was evaluated for 30 days only. The APIs' stability was determined by measuring percent recovery using stability-indicating high-performance liquid chromatography (HPLC or UHPLC) or titration (amoxicillin trihydrate only). The stability of amoxicillin trihydrate, clozapine, indomethacin and levodopa/carbidopa were studied at both refrigerated (2-8 °C) and room temperature (20-25 °C). Lomustine, procarbazine, and methyldopa were studied at refrigerated temperature only. Our data demonstrated promising stability for the compounded suspensions containing various APIs, investigated in SyrSpend® SF PH4, as all APIs exhibited stability throughout the study duration and met content uniformity criteria. These findings lead to the conclusion that the tested compounded oral suspensions present a viable approach for creating personalized, age-appropriate formulations. The capacity to ensure dose consistency and stability using APIs from diverse pharmacological classes renders them suitable choices for both pediatric and geriatric patients.

Investigating pH Effects on Enzymes Catalyzing Polysorbate Degradation by Activity-Based Protein Profiling

Host cell proteins (HCPs) are process-related impurities that can negatively impact the quality of biotherapeutics. Some HCPs possess enzymatic activity and can affect the active pharmaceutical ingredient (API) or excipients such as polysorbates (PS). PSs are a class of non-ionic surfactants commonly used as excipients in biotherapeutics to enhance the stability of APIs. The enzyme activity of certain HCPs can result in the degradation of PSs, leading to particle formation and decreased shelf life of biotherapeutics. Identifying and characterizing these HCPs is therefore crucial. This study employed the Activity-Based Protein Profiling (ABPP) technique to investigate the effect of pH on the activity of HCPs that have the potential to degrade polysorbates. Two probes were utilized: the commercially available fluorophosphonate (FP)-Desthiobiotin probe and a probe based on the antiobesity drug, Orlistat. Over 50 HCPs were identified, showing a strong dependence on pH-milieu regarding their enzyme activity. These findings underscore the importance of accounting for pH variations in the ABPP method and other investigations of HCP activity. Notably, the Orlistat-based probe (OBP) enabled us to investigate the enzymatic activity of a wider range of HCPs, emphasizing the advantage of using more than one probe for ABPP. Finally, this study led to the discovery of previously unreported active enzymes, including three HCPs from the carboxylesterase enzyme family.

Effect of atmosphere and relative humidity on photodegradation of clopidogrel under artificial solar and indoor light irradiation

Knowledge of the chemical stability of active pharmaceutical ingredients (APIs) is an important issue in the drug development process. This work describes a methodical approach and a comprehensive protocol for forced photodegradation studies of solid clopidogrel hydrogen sulfate (Clp) under artificial sunlight and indoor irradiation at different relative humidities (RHs) and atmospheres. The results showed that, at low RHs (up to 21%), this API was relatively resistant to simulated sunlight as well as indoor light. However, at higher RHs (between 52% and 100%), more degradation products were formed, and the degradation rate increased with rising RH. The influence of oxygen on the degradation was relatively low, and most degradation reactions proceeded even in humid argon atmosphere. The photodegradation products (DP) were analyzed with two different HPLC systems (LC-UV, LC-UV-MS) and selected impurities were separated by a semi-preparative HPLC and identified by high resolution mass spectrometry (ESI-TOF-MS) and 1H NMR techniques. Based on the obtained results, a light induced degradation pathway could be proposed for Clp in solid state.

Thermal Stability and Kinetics of Degradation of Moxonidine as Pure Ingredient vs. Pharmaceutical Formulation

The stability of active pharmaceutical ingredients (APIs) and the corresponding pharmaceutical formulations are nowadays of great importance in pharmaceutical research and technology. The quality of an API or of finished pharmaceutical products (FPPs) is time dependent under the influence of several parameters, such as light and air exposure, temperature, and humidity. Additionally, the stability profile of an API is influenced by the formulation composition, due to the presence of excipients or by the characteristic of the packaging materials. In this sense, the main objective of this study was to analyze the degradation kinetics of the antihypertensive drug moxonidine as a pure ingredient (MOX) and in two different solid mixtures, one corresponding to a pharmaceutical formulation (MOXTAB) and the other to an enriched pharmaceutical formulation in MOX (MOXMIX). As investigation techniques, FTIR (Fourier transform infrared) spectroscopy and TG/DTG/HF analysis were employed, while the thermoanalytical data were processed according to the ASTM E698 kinetic method and the isoconversional methods of Flynn–Wall–Ozawa (FWO) and Friedman (FR). The kinetic methods revealed that the excipients have a stabilizing effect on MOX (in terms of Ea values), but the decomposition mechanism of the samples is complex, according to the results suggested by the analysis of Ea vs. α values.

Algorithm for the early prediction of drug stability using bayesian inference and multiple measurements: Application for predicting the stability of silodosin tablets

The stability of active pharmaceutical ingredients (APIs) and formulations has become a major chemistry, manufacturing, and control (CMC) concern in the pharmaceutical industry because it can determine the feasibility of research and development, the development period, and the development costs of a certain formulation. To streamline the research and development of pharmaceutical products and create useful pharmaceutical products at an early stage, a technology that predicts the stability of formulations at an early stage and with a high degree of accuracy is needed. When predicting the stability of a substance, highly reliable data are required; however, the stability data are affected by analytical variations that depend on the experimenter, measurement device, and conditions used. Although these variations greatly affect the prediction accuracy, a stability prediction method that considers these variations has not yet been developed. Here, short-term stability data under accelerated conditions were obtained at three institutions using silodosin tablets as a model sample. By combining Bayesian inference with the temporal change in the amount of the main degradation products obtained and the conventional humidity-corrected Arrhenius equation, we developed a new algorithm that provides a narrow confidence interval, even when using data with variations. By using this algorithm and setting an appropriate number of conditions, we were able to obtain a valid confidence intervals in a short period of time. Here, by performing more measurements than those suggested by the minimum measurement frequency indicated in the guideline specified in the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use, we developed a method that can be used to reasonably predict the long-term stability of the drugs, even if the data measurement interval is short. Our results will help solve various problems in today's pharmaceutical product development scenario and contribute to worldwide health and welfare.

A Brief Chronological Overview of Buccal Film Formulations

The bioadhesive buccal film drug delivery technology that increases the safety, effectiveness, and stability of active pharmaceutical ingredients is the main focus of the current article. The buccal film is cutting-edge technology since it offers a better way to maximise treatment effectiveness. The medications that are used to increase bioavailability and have a high first-pass metabolism are ideal for this drug delivery strategy. Rolling, hot-melt extrusion, solid dispersion, solvent casting, or semi-solid casting can all be used to make Bioadhesive Buccal Films (BBF). The solvent casting method is the most popular of them. Organoleptic valuation, thickness, transparency, surface pH, moisture content, tensile strength, per cent elongation, folding endurance, swelling assets, drug content, and in vitro dissolution tests are a few of the mechanical assets that are assessed for the BBF. A small amount of material on earlier work on BBF has been provided in the article. This article will be useful for quick references to prior BBF attempts and guidance on how to assess them.

A combined differential scanning calorimetry and thermogravimetry approach for the effective assessment of drug substance-excipient compatibility

Differential scanning calorimetry (DSC) is a tool particularly recommended for rapid compatibility screening between active pharmaceutical ingredients (APIs) and excipients, whereas thermogravimetric analysis (TGA), a complementary technique to DSC, is primarily used to assess the thermal stability of APIs and excipients. Both DSC and TGA data can be converted using multivariate statistical methods, which are profitable tools in the detection of compatibility between ingredients. Principal component analysis (PCA) enables identification of compatibility by grouping samples into two clusters in a PCA score plot: acetazolamide and mixture with its highest content, and optionally a 1:1 mixture form one cluster, excipient and mixture with its highest quantity, and optionally a 1:1 mixture the second. Any variation from the arrangement of samples in the abovementioned clusters indicates incompatibility. By using cluster analysis, compatibility can be determined by four clusters, the first consisting of API, the second of groups mixture at the ratio of 7:3 and the third of two mixtures at ratios of 3:7 and 1:1, with the excipient in the remaining fourth cluster. Generally, the combination of DSC and TGA techniques with advanced statistical methods is favorable for the qualitative assessment of compatibility in acetazolamide mixtures with excipients such as mannitol, meglumine, lactose, magnesium stearate, β-cyclodextrin, chitosan, methylcellulose, starch 1500 and PVP K-30. In addition, PXRD revealed that acetazolamide retains its crystalline form after mixing. Accordingly, incompatibilities in acetazolamide mixtures can be attributed to chemical reactions.

New Saccharin Salt of Chlordiazepoxide: Structural and Physicochemical Examination.

Since the formation of organic salts can improve the solubility, bioavailability, and stability of active pharmaceutical ingredients, the aim of this work was to prepare an organic salt of chlordiazepoxide with saccharin. To achieve this goal, the saccharin salt of chlordiazepoxide was obtained from a physical mixture of both components by grinding them with a small volume of solvent and by crystallizing them with complete evaporation of the solvent. The resulting salt was examined by methods such as Powder X-ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Fourier Transform Infrared (FT-IR), and Raman spectroscopy. The results of the studies proved that saccharin salt of chlordiazepoxide crystallizes in the orthorhombic Pbca space group with one chlordiazepoxide cation and one saccharin anion in the asymmetric unit. In the crystal of the title compound, the chlordiazepoxide cation and the saccharin anion interact through strong N–H···O hydrogen bonds and weak C–H···O hydrogen bonds. The disappearance of the N–H band in the FT-IR spectrum of saccharin may indicate a shift of this proton towards chlordiazepoxide, while the disappearance of the aromatic bond band in the chlordiazepoxide ring in the Raman spectrum may suggest the formation of intermolecular hydrogen bonds between chlordiazepoxide molecules. The melting point of the salts differs from that of the starting compounds. Thermal decomposition of the salt begins above 200 °C and shows at least two overlapping stages of mass loss. In summary, the results of the research showed that the crystalline salt of the saccharin and chlordiazepoxide can be obtained by various methods: grinding with the addition of acetonitrile and crystallization from acetonitrile or a mixture of methanol with methylene chloride.

Ground-based selected ionizing space radiation effects on stability of APIs and their formulations

Primary goal of any space mission is to keep astronauts healthy and fit during entire mission. One of the important challenges for that is providing a safe and effective pharmacy with the capabilities to address both scheduled and unanticipated medical conditions that may arise during spaceflight. Extended exposure to space environmental conditions may trigger drug deterioration, impacting quality, effectiveness, and safety. To assess the influence of space ionizing radiations on the stability of medicines launched aboard spacecraft, a preliminary ground-based ionizing radiation drug interaction study was carried out at different doses in the present work. Four different types of radiations - proton, neutron (thermal, fast), gamma and heavy ions (56Fe) were used to irradiate selected drugs namely diclofenac, ciprofloxacin and metoprolol along with their formulations. Chemical stability of each irradiated sample was checked using high performance liquid chromatographic method. Significant degradation was observed in even solid-state during proton irradiation in both Active Pharmaceutical Ingredient (API) and tablet dosage form. Solution of active pharmaceutical ingredient and liquid dosage forms were prone to degradation in presence of gamma radiation. No physical and chemical changes observed after neutron and 56Fe irradiation. Irradiation of the same drug with different radiations demonstrated varying HPLC chromatographic profiles in terms of %degradation as well as proportion of same degradation products. This indicates possibility of different degradation pathways to generate degradation products.

Importance of LCMS in Forced Degradation Studies for new Chemical Entities

Forced degradation studies shows the chemical behaviour of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. In pharmaceutical industry, mandatory degradation tests are important to determine the mechanisms and measure the potential degradants during the analysis of drug material and to help to elucidate the composition of degradation materials. The Liquid Chromatography/ Mass Spectrum analysis (L.C.M.S) is a short term widely established liquid chromatography and a methodology utilizing a natural fluid process. L.C.M.S. is commonly employed in the laboratories for qualitative testing of drug substances, drugs and biological samples. Degradation studies, metabolic screening, metabolite identity and in vivo drug screening, impurity identification, amide mapping, glycoprotein mapping were consistently used in pharmaceutical development by LCMS. The FDA and ICH guidelines sets out the requirement for stability testing data to understand how the quality of the drug substance and drug product changes over time under the influence of various environmental factors. Knowledge of molecular stability helps to select the correct formulation and package as well as to provide proper storage conditions and shelf life, which is essential for regulatory documentation. Active pharmaceutical ingredients (APIs) may form impurities when exposed to excipients or environmental variables such as light, high temperatures, acidic or basic conditions, humidity; and the oxidative atmosphere. Considering that these impurities may have an impact on safety and efficacy, it is necessary to know how these impurities are produced from the drug product and to establish the path of their formation. In this context, forced drug degradation studies have been used to characterize the physicochemical stability of APIs. These studies are also essential in the validation of analytical methodologies, in order to demonstrate the selectivity of methodologies. The API and its impurities and to develop strategies to avoid the formation of degradation products. The objective of this review is to demonstrate how forced degradation studies have been conducted and application of LCMS tools in related studies.

A Glance at the Literature review on Buccal films

The present article concentrates on the Buccal film. It is a buccoadhesive drug delivery system that enhances the safety, efficacy, and stability of active pharmaceutical ingredients. The buccal film is a novel technology due to its better option to optimize therapeutic efficacy. This drug delivery system is suitable for drugs that pass through high first-pass metabolism and are used for enhancing bioavailability. The buccal film can be formulated as a solvent casting, semi-solid casting, hot-melt extrusion, solid dispersion, or rolling method. Among them, the solvent casting method is mostly adopted. The buccal films are evaluated for mechanical properties viz., Organoleptic assessment, thickness, dryness, tack test, tensile strength, percent elongation, folding endurance, swelling assets, surface pH, contact angle, transparency, uniformity in drug content, disintegration, and in-vitro dissolution tests. The article gave a handful of literature on past work done on buccal films. This article helps with quick references to the earlier attempts so far made on buccal films.

Kinetic Modeling of API Oxidation: (2) Imipramine Stress Testing.

Gauging the chemical stability of active pharmaceutical ingredients (APIs) is critical at various stages of pharmaceutical development to identify potential risks from drug degradation and ensure the quality and safety of the drug product. Stress testing has been the major experimental method to study API stability, but this analytical approach is time-consuming, resource-intensive, and limited by API availability, especially during the early stages of drug development. Novel computational chemistry methods may assist in screening for API chemical stability prior to synthesis and augment contemporary API stress testing studies, with the potential to significantly accelerate drug development and reduce costs. In this work, we leverage quantum chemical calculations and automated reaction mechanism generation to provide new insights into API degradation studies. In the continuation of part one in this series of studies [Grinberg Dana et al., Mol. Pharm. 2021 18 (8), 3037-3049], we have generated the first ab initio predictive chemical kinetic model of free-radical oxidative degradation for API stress testing. We focused on imipramine oxidation in an azobis(isobutyronitrile) (AIBN)/H2O/CH3OH solution and compared the model's predictions with concurrent experimental observations. We analytically determined iminodibenzyl and desimipramine as imipramine's two major degradation products under industry-standard AIBN stress testing conditions, and our ab initio kinetic model successfully identified both of them in its prediction for the top three degradation products. This work shows the potential and utility of predictive chemical kinetic modeling and quantum chemical computations to elucidate API chemical stability issues. Further, we envision an automated digital workflow that integrates first-principle models with data-driven methods that, when actively and iteratively combined with high-throughput experiments, can substantially accelerate and transform future API chemical stability studies.

On improving the hygroscopic stability of palmatine chloride with crystalline palmatine sulfosalicyate pharmaceutical salt

With the aim to improve the hygroscopic stability of palmatine chloride (PMTCl), an unreported single crystal of PMT—SSA (C21H20NO4·C7H5O6S·H2O) is prepared by the solvent evaporation method and characterized. A comprehensive analysis of the structure and Hirshfeld surface reveals that π—π stacking plays a crucial role in accumulating PMT—SSA. As expected, the hygroscopic stability of PMT—SSA is significantly improved compared with that of PMTCl. This may be due to the presence of π—π stacking in the structure of PMT—SSA which improves the hygroscopic stability. The present work inaugurates an avenue for improving the hygroscopic stability of active pharmaceutical ingredients and provides a novel crystalline product with a bright commercial prospect. Unfortunately, the maximum solubility of PMT—SSA is lower than that of PMTCl. How to improve its solubility will be explored in subsequent studies. However, it is surprising that PMT—SSA shows advantages with regard to antibacterial properties in comparison to PMTCl.

Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy

Cocrystal strategies to achieve excellent physiochemical performance under different environmental stress were highlighted here. The lattice energy and the energy barrier of degradation reactions are two pillars in a stable cocrystal construction.

Thermal Stability Kinetics and Shelf Life Estimation of the Redox-Active Therapeutic and Mimic of Superoxide Dismutase Enzyme, Mn(III) meso-Tetrakis(N-ethylpyridinium-2-yl)porphyrin Chloride (MnTE-2-PyPCl5, BMX-010).

Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl5, BMX-010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox-active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE-2-PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn-porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N-dealkylation reaction. The thermal stability kinetics of the N-dealkylation process leading to MnTE-2-PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid-state kinetic models and showed that MnTE-2-PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t90%) of MnTE-2-PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid-state stability of the compound. These results represent the first study on the solid-state decomposition kinetics of Mn(III) 2-N-alkylpyridylporphyrins, contributing to the development of this class of redox-active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.

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).

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.

Design of experiments applied to stress testing of pharmaceutical products: A case study of Albendazole

Forced degradation tests are studies used to assess the stability of active pharmaceutical ingredients (APIs) and their formulations. These tests are performed submitting the API under extreme conditions in order to know the main degradation products in a short period of time. The results of these studies are used to assess the degradation susceptibility of APIs and to validate chromatographic analytical methods. However, most of degradation studies are performed using one-factor-at-the-time (OFAT) which does not consider the interactions between degradation variables. This work proposes the use of Design of Experiment (DoE) approach in forced degradation of albendazole (ABZ). It was used a central composite design (CCD) to evaluate the forced degradation in a multivariate way. Experiments were performed taking into account the variables pH, temperature, oxidizing agent (H2O2) and UV radiation. It was verified the influence of the variables and their interactions on the ABZ degradation. The ABZ oxidation showed to be the main degradation route for ABZ, which is strongly influenced by the temperature. The hydrolysis was relevant at alkaline medium and high temperature. LC-IT-MSn was used to identify the degradation products. It was found three known degradation products (albendazole-2-amino, albendazole sulfoxide and albendazole sulfone) and a new derivate of albendazole molecule (albendazole sulfoxide with a chlorine). This last one was isolated and characterized by UPLC-QToF-MS and NMR analyses.

Identification of degradation impurity of TGR5 receptor agonist-ZY12201 by LC\u2013MS technique during force degradation study

Forced degradation study is a systemic characterization of degradation products of active pharmaceutical ingredient (API) at conditions which posses more harsh environment that accelerates degradation of API. Forced degradation and stability studies would be useful in selection of proper, packaging material and storage conditions of the API. These are also useful to demonstrate degradation pathways and degradation products of the API and further characterisation of the degradation products using mass spectrometry. TGR5 is a G protein-coupled receptor, activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The potent and orally bioavailable TGR5 agonist, ZY12201, shows activation of TGR5 which increase secretion of GLP-1 and help in lowering blood glucose level in animal models. Hence it is necessary to establish and study degradation pathway and stability of API for better handling and regulatory approval. Force degradation studies of ZY12201 have shown presence of one oxidative impurity during oxidative degradation in HPLC analysis. The oxidized product is further characterized by LC–MS to elucidate structure of impurity and characterize its degradation pathway.

Thermal Stability of Amorphous Solid Dispersions.

Amorphous solid dispersion drug delivery systems (ASD DDS) were proved to be efficient for the enhancement of solubility and bioavailability of poorly water-soluble drugs. One of the major keys for successful preparation of ASD is the selection of appropriate excipients, mostly polymers, which have a crucial role in improving drug solubility and its physical stability. Even though, excipients should be chemically inert, there is some evidence that polymers can affect the thermal stability of active pharmaceutical ingredients (API). The thermal stability of a drug is closely related to the shelf-life of pharmaceutical products and therefore it is a matter of high pharmaceutical relevance. An overview of thermal stability of amorphous solids is provided in this paper. Evaluation of thermal stability of amorphous solid dispersion is perceived from the physicochemical perspective, from a kinetic (motions) and thermodynamic (energy) point of view, focusing on activation energy and fragility, as well all other relevant parameters for ASD design, with a glance on computational kinetic analysis of solid-state decomposition.