Presence Of Pharmaceutical Excipients Research Articles

Mechanistic Insight in Permeability through Different Membranes in the Presence of Pharmaceutical Excipients: A Case of Model Hydrophobic Carbamazepine.

The present study reports the effects of two pharmaceutical excipients of differing natures-non-ionic surfactant pluronic F127 (F127) and anionic sulfobutylether-β-cyclodextrin (SBE-β-CD)-on the permeation of the model compound, carbamazepine (CBZ). The permeability coefficients of CBZ at three concentrations of the excipients were measured through two different artificial barriers: hydrophilic cellulose membrane (RC) and lipophilic polydimethylsiloxane-polycarbonate membrane (PDS). The equilibrium solubility of CBZ in F127 and SBE-β-CD solutions was determined. The micellization, complexation, and aggregation tendencies were investigated. Systemically increasing the solubility and the reduction of permeation upon the excipients' concentration growth was revealed. The quantitative evaluation of the permeability tendencies was carried out using a Pratio parameter, a quasi-equilibrium mathematical mass transport model, and a correction of permeability coefficients for the free drug concentration ("true" permeability values). The results revealed the mutual influence of the excipient properties and the membrane nature on the permeability variations.

DSC, FT-IR and NIR with Chemometric Assessment Using PCA and HCA for Estimation of the Chemical Stability of Oral Antidiabetic Drug Linagliptin in the Presence of Pharmaceutical Excipients.

Pharmaceutical excipients should not interact with active substances, however, in practice, they sometimes do it, affecting the efficacy, stability and safety of drugs. Thus, interactions between active substances and excipients are not desirable. For this reason, two component mixtures of oral antidiabetic drug linagliptin (LINA) with four excipients of different reactivity, i.e., lactose (LAC), mannitol (MAN), magnesium stearate (MGS) and polyvinylpyrrolidone (PVP), were prepared in a solid state. A high temperature and a high humidity of 60 °C and 70% RH, respectively, were applied as stressors in order to accelerate the potential interactions between LINA and excipients. Differential scanning calorimetry (DSC) as well as Fourier transform infrared (FT-IR) and near infrared (NIR) spectroscopy were used to estimate the changes due to potential interactions. In addition, chemometric computation of the data with principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to adequately interpret the findings. Of the excipients used in the present experiment, all of them were not inert in relation to LINA. Some of the interactions were shown without any stressing, whereas others were observed under high-temperature/high-humidity conditions. Thus, it could be concluded that selection of appropriate excipients for LINA is very important question to minimize its degradation, especially when new types of formulations with LINA are being developed and manufactured.

Eco-friendly stability-indicating HPTLC micro-determination of the first FDA approved SARS-CoV-2 antiviral prodrug Remdesivir: Study of degradation kinetics and structural elucidation of the degradants using HPTLC-MS

The worldwide spread coronavirus (covid-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a global health crisis. The world was forced to face a great challenge to control and overcome this health disaster through various containment measures including efficient vaccination side by side with effective medication. Remdesivir (RMD) is the first FDA approved antiviral agent for treatment of covid-19 pandemic and hence regarded as the first-in-class medication of this highly contagious respiratory disease. The current study represents the first stability indicating HPTLC method for the estimation of RMD in bulk form and pharmaceutical formulation. The method employed TLC silica gel aluminum plates 60 F254 as stationary phase and green mobile phase composed of ethyl acetate and ethanol (96: 4, v/v) with densitometric detection at 245 nm. Comprehensive validation of the adopted method was accomplished according to the ICH guidelines regarding linearity, ranges, detection and quantification limits, precision, accuracy and robustness. The developed method offered a neat separation of the drug in presence of pharmaceutical excipients as well as in presence of acidic, alkaline, neutral hydrolytic, oxidative and photolytic degradants. Additionally, structural elucidation of alkaline and hydrolytic oxidation degradation products was carried out using HPTLC-MS. Furthermore, for the first time the acidic and alkaline degradation kinetics of RMD were studied and its degradation rate constants and half-lives were calculated. Moreover, greenness appraisal of the developed method as well as comparison with previously published stability indicating HPLC methods were performed using analytical Eco-scale, GAPI and AGREE metrics.

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.

Solubility of Cyclodextrins and Drug/Cyclodextrin Complexes.

Cyclodextrins (CDs), a group of oligosaccharides formed by glucose units bound together in a ring, show a promising ability to form complexes with drug molecules and improve their physicochemical properties without molecular modifications. The stoichiometry of drug/CD complexes is most frequently 1:1. However, natural CDs have a tendency to self-assemble and form aggregates in aqueous media. CD aggregation can limit their solubility. Through derivative formation, it is possible to enhance their solubility and complexation capacity, but this depends on the type of substituent and degree of substitution. Formation of water-soluble drug/CD complexes can increase drug permeation through biological membranes. To maximize drug permeation the amount of added CD into pharmaceutical preparation has to be optimized. However, solubility of CDs, especially that of natural CDs, is affected by the complex formation. The presence of pharmaceutical excipients, such as water-soluble polymers, preservatives, and surfactants, can influence the solubilizing abilities of CDs, but this depends on the excipients’ physicochemical properties. The competitive CD complexation of drugs and excipients has to be considered during formulation studies.

Heterogeneous Crystallization of Fenofibrate onto Pharmaceutical Excipients

The crystallization of fenofibrate (FF) from methanol (MeOH) was carried out in the presence of the following dispersed excipients: α/β-lactose (α/β-Lac), d-mannitol (d-Man), microcrystalline cellulose, carboxymethyl cellulose (CMC), silica (SiO2), and polycaprolactone (PCL). More control was achieved over the nucleation and crystal growth of the FF particles in the presence of excipients relative to its conventional crystallization using FF seed. Each of the excipients was found to strongly reduce the FF induction time during its crystallization from supersaturated MeOH solutions relative to the rate observed in the absence of the excipients; there was a pronounced reduction in the induction time for FF from >22 h in the absence of excipients to ∼15 min in their presence at optimum conditions. These results are rationalised in terms of the lifetime of FF molecules attached to the excipient surface by hydrogen−bonding. Additionally, the FF particle size can be optimized by adjusting the FF loading (% w/w) and the crystallization temperature. The dissolution rate of the small FF particles generated via crystallization in the presence of excipients was comparable to the dissolution rate of the ground commercial FF (Lipantil Supra) and was faster compared to that of the FF crystallized in the presence of seed. Thus, the process parameters of heterogeneous crystallization in the presence of pharmaceutical excipients can reduce induction times and control API particle size.

Novel pharmaceutical cocrystals of triflusal: crystal engineering and physicochemical characterization

A platelet aggregation inhibitor, triflusal, is practically insoluble in water and rapidly converts to 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) in physiological systems. Six cocrystals of triflusal were discovered from a cocrystal screening with pharmaceutically acceptable coformers, namely, benzamide, isonicotinamide, picolinamide, propionamide, urea, and valpromide, in an attempt to find stable solid forms of triflusal. The choice of coformers was based on a crystal engineering strategy relying on the carboxylic acid group of the triflusal and the most prevalent supramolecular interactions that it can form with complementary functional groups. Crystal structure analysis revealed that all the cocrystals feature heterosynthons involving carboxylic acid group of triflusal and pyridine/amide group of the coformers. Except the cocrystals with propionamide and valpromide, all the cocrystals were found to be stable at accelerated storage condition (40 °C, 75% relative humidity). Under slurry conditions, cocrystals with benzamide, picolinamide, and valpromide were found stable, but the remaining cocrystals undergo dissociation and degration of triflusal to HTB. As triflusal is known to undergo degradation in the presence of pharmaceutical excipients, the stable triflusal cocrystals reported herein may serve as promising candidates for development of novel triflusal drug formulations.

Excipients‐Induced Salt‐to‐Free Base Phase Transformation

AbstractThe mechanism of the salt‐to‐free form drug transformation was explored by investigating the pH‐solubility profiles of a model drug in a salt form and the nucleation of the free base from the salt solution when its pH was increasing. The transformation of the salt to the free base during wet massing in the presence of pharmaceutical excipients with different pH was studied. The nucleation of the free base occurred when the pH of the salt solution reached a certain level pHmetastable, which was related to the free energy penalty associated with the creation of a new solid phase. The nucleation of the free base happened readily and thus, the salt‐to‐free base transformation occurred rapidly during wet massing with the excipients with a pH above the pHmetastable. These results can support robust formulation design of solid dosage forms containing salts by optimal excipient selection.

Analysis of 5-hydroxytryptophan in the presence of excipients from dietary capsules: comparison between cyclic voltammetry and UV visible spectroscopy

5-Hydroxytryptophan (5-HTP) is an important neurochemical and is available as a dietary supplement, which is used to regulate eating behaviour and potentially overcome depression. Dietary supplements have undergone a change in their regulation, where improved analytical assessment is required during manufacturing. We compared cyclic voltammetry with UV visible spectroscopy for the detection of 5-HTP in capsules, where an emphasis was placed in understanding if recordings could be conducted in the presence of pharmaceutical excipients. Both voltammetric and spectroscopic methods had linear responses over a concentration range between 50 and 150 mg per 25 ml−1 of 5-HTP and similar limits of detection. There current response was increased for 5-HTP in the presence of magnesium stearate and silica, however in the presence of all capsule excipients there was no difference on the voltammetric response and current. Following oxidation of 5-HTP, electrode fouling was observed on the carbon composite electrodes. The electrode surface following fouling was partly regenerated following soaking in ethanol and fully recovered when the electrode was polished in alumina slurry for 5 s. Voltammetric responses were capable of detecting 5-HTP content within individual capsules with or without filtration of pharmaceutical excipients. Only following filtration was spectroscopy able to provide stable response of 5-HTP content within an individual capsule. Overall, voltammetric responses provide a means of conducting measurements of 5-HTP dietary supplement capsules without the need for extensive sample preparation, thus providing a total analysis time within 8 minutes.

In vitro metabolic stability of moisture-sensitive rabeprazole in human liver microsomes and its modulation by pharmaceutical excipients

A reliable method to assess in vitro metabolic stability of rabeprazole and its modulation by Generally Recognized As Safe (GRAS)-listed pharmaceutical excipients was established in human liver microsomes. The metabolic stability of rabeprazole decreased as a function of incubation time, resulting in the formation of thioether rabeprazole via nonenzymatic degradation and enzymatic metabolism. Buffer type was also a determining factor for the degree of both nonenzymatic degradation and enzymatic metabolism. The net extent of enzymatic drug metabolism, obtained by calculating the difference in drug degradation between a microsome-present reaction system and a microsome-free solution, was about 9.20 +/- 0.67% in phosphate buffer and 2.27 +/- 1.76% in Tris buffer, respectively. Rabeprazole exhibited first-order kinetics in microsome-free solution but showed non-linear kinetics in the microsome-present reaction system. The maximal velocity, Vmax, in phosphate buffer was 5.07 microg mL(-1) h(-1) and the Michaelis-Menten constant, Km, was 10.39 microg mL(-1) by computer-fitting to the classical Michaelis-Menten equation for pattern of time-dependent change in the substrate concentration. The intact drug and its thioether form were well resolved and successfully identified by HPLC chromatography and liquid chromatography mass spectroscopy (LC/MS). The metabolic stability of rabeprazole was also modulated by the presence of pharmaceutical excipients. Among the five pharmaceutical excipients tested, poloxamer 188 and Gelucire 44/14 had potentially inhibitory effects on rabeprazole metabolism in human liver microsomes (p < 0.05). A greater understanding of metabolic stability and its modulation by pharmaceutical excipients would be useful for optimizing the bioavailability of rabeprazole at the early formulation stages.

Use of Drifts and PLS for the Determination of Polymorphs of Piroxicam Alone and in Combination with Pharmaceutical Excipients: A Technical Note

Piroxicam is a nonsteroidal anti-inflammatory drug used to treat arthritis and other inflammatory conditions (1). Crystalline piroxicam is polymorphic and exists in various crystalline forms designated as form I, form II, form III, and monohydrate form. Form I is also named β, cubic form, and form A, meanwhile form II is termed α, α1, α2, needle form, and form B (2,3). Form III is thermally unstable and can be converted to form II and form I, respectively (2). Additionally, the monohydrate form can dehydrate to form I (4). Generally, the polymorphic form of a drug can transform to a more stable form during storage and manufacturing process, such as drying, milling, and compaction (5,6). The extent of conversion is dependent on the relative stability of the polymorphs and kinetic factors. Moreover, these crystal structures can have different chemical and physical properties (6). Nevertheless, the crucial properties are dissolution, bioavailability and subsequently therapeutic effectiveness of the drugs. Typically, the metastable or thermodynamically instable forms exhibit best solubility and bioavailability (2,6). However, the most stable polymorphic form is often selected for pharmaceutical development based on the minimal potential for conversion to other polymorphic forms and on its greater chemical stability. However, in some cases, such as ranitidine HCl, more than one polymorph are used in commercial formulation (7). A number of techniques have been used to determine polymorphs including thermal analysis (DSC) (8), X-ray powder diffraction (XRD) (9), near-infrared spectroscopy (NIR) (10), Fourier transform infrared (FTIR) spectroscopy, attenuated total reflectance (ATR) FTIR (11), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) (9,12,13), and Raman spectroscopy (14), Different techniques are appropriate for analysis of polymorphs of particular drugs. DRIFTS has been commonly used to determine various polymorphs. This method has advantages over conventional FTIR in terms of easier and more rapid sample preparation and no crystal structure changes during sample preparation which can possibly occur in FTIR. Furthermore, these analytical approaches have been effectively used in combination with various chemometric methods including partial least square (PLS)(12,13) and artificial neural network(15) for quantification of polymorphs. Polymorphic conversion is a major concern of the pharmaceutical industry. Therefore, it is essential to characterize and quantify polymorphic forms of drugs. According to Ghan and Lalla (16), piroxicam form II can transform to form I by compression force. At present, piroxicam forms I and II are commercially available in various countries. However, form I, which is more stable than form II, is more extensively used to manufacture commercial capsules and tablets. The objective of this study is to investigate the use of DRIFTS and PLS to determine piroxicam forms I and II in binary mixtures of these two polymorphs alone and in the presence of pharmaceutical excipients. In addition, this is the first study that quantifies the mixture of piroxicam polymorphs.

A simultaneous TG-DTA study of the degradation in nitrogen of cellulose to carbon, alone and in the presence of other pharmaceutical excipients

The heat treatment of an α-cellulose and a microcrystalline cellulose (Avicel ®) in nitrogen gives a one-stage degradation to carbon. This degradation suffers a temperature transposition in the presence of pharmaceutical excipients, namely dibasic calcium phosphate, stearic acid, magnesium stearate, and silicon dioxide. It is possible to produce a kinetic evaluation of these thermal analysis studies in terms of a comparative method by constructing the theoretical TG trace of the binary mixture based on a presumed no-interaction between the two components. There is a variation in behavior to be noted in the different forms of cellulose, and also different values are shown for the Arrhenius parameters. Such variations are also noted in the Avicel ® degradation in the presence of other materials. These observations should be of use in the characterization of pharmaceutical excipients. The Arrhenius parameters for α-cellulose degradation using D3 (three-dimensional diffusion) mechanism at the temperature range from 580 to 630 K are 289.32 kJ mol −1 and 1.85×10 23 for E act and A, respectively. The Arrhenius parameters for Avicel ® degradation using F1 (first-order) mechanism at the temperature range from 562 to 604 K are 291.35 kJ mol −1 and 1.26×10 25 for E act and A, respectively.

Chromatographic solutions to pharmaceutical analytical problems

Chromatography plays a major role in pharmaceutical analysis since classic methods such as titrimetry or direct spectroscopic analyses do not provide sufficient selectivity and/or detectability. Of various chromatographic methods, HPLC offers good resolution and great versatility in handling compounds that are thermally unstable, polar, and non-volatile at low temperatures. Discussed in this paper is an example of a pharmaceutical compound viz. baclofen [4-amino-3-(p-chlorophenyl)butyric acid], a compound with low UV absorptivitiy, where HPLC provides the desired selectivity and detectability to allow precise determinations in the presence of pharmaceutical excipients. Discussed here also are investigations on mechanism of separations by ion-exchange and ion-pair reversed-phase chromatography.