Common Pharmaceutical Excipients Research Articles

Spectrophotometric Determination of Distigmine Bromide, Cyclopentolate HCl, Diaveridine HCl and Tetrahydrozoline HCl via Charge Transfer Complex Formation with TCNQ and TCNE Reagents.

The purpose of this investigation was directed to propose sensitive, accurate and reproducible methods of analysis that can be applied to determine distigmine bromide (DTB), cyclopentolate hydrochloride (CPHC), diaveridine hydrochloride (DVHC) and tetrahydrozoline hydrochloride (THHC) drugs in pure form and pharmaceutical preparations via charge-transfer complex formation with 7,7,8,8-tetracyanoquinodimethane (TCNQ) and tetracyanoethylene (TCNE) reagents. Spectrophotometric method involve the addition a known excess of TCNQ or TCNE reagents to DTB, CPHC, DVHC and THHC drugs in acetonitrile, followed by the measurement of the absorbance of the CT complexes at the selected wavelength. The reaction stoichiometry is found to be 1:1 [drug]: [TCNQ or TCNE]. The absorbance is found to increase linearly with concentration of the drugs under investigation which is corroborated by the correlation coefficients of 0.9954-0.9981. The system obeys Beer's law for 6-400, 20-500, 1-180 and 60-560 µg mL(-1) and 80-600, 10-300, 1-60 and 80-640 µg mL(-1) for DTB, CPHC, DVHC and THHC drugs using TCNQ and TCNE reagents, respectively. The apparent molar absorptivity, sandell sensitivity, the limits of detection and quantification are also reported for the spectrophotometric method. Intra- and inter-day precision and accuracy of the method were evaluated as per ICH guidelines. The method was successfully applied to the assay of DTB, CPHC, DVHC and THHC drugs in formulations and the results were compared with those of a reference method by applying Student's t and F-tests. No interference was observed from common pharmaceutical excipients.

Investigation of influence of process variables on mechanical strength, size and homogeneity of pharmaceutical granules produced by fluidised hot melt granulation

The overall aim of the project was to study the influence of process variables on the distribution of a model active pharmaceutical ingredient (API) during fluidised melt granulation of pharmaceutical granules with a view of optimising product characteristics. Granules were produced using common pharmaceutical excipients; lactose monohydrate using poly ethylene glycol (PEG1500) as a meltable binder. Methylene blue was used as a model API. Empirical models relating the process variables to the granules properties such as granule mean size, product homogeneity and granule strength were developed using the design of experiment approach. Fluidising air velocity and fluidising air temperature were shown to strongly influence the product properties. Optimisation studies showed that strong granules with homogeneous distribution of the active ingredient can be produced at high fluidising air velocity and at high fluidising air temperatures.

Biochemical stabilization of glucagon at alkaline pH.

For patients with type 1 diabetes mellitus, a bihormonal artificial endocrine pancreas system utilizing glucagon and insulin has been found to stabilize glycemic control. However, commercially available formulations of glucagon cannot currently be used in such systems because of physical instability characterized by aggregation and chemical degradation. Storing glucagon at pH 10 blocks protein aggregation but results in chemical degradation. Reductions in pH minimize chemical degradation, but even small reductions increase protein aggregation. We hypothesized that common pharmaceutical excipients accompanied by a new excipient would inhibit glucagon aggregation at an alkaline pH. As measured by tryptophan intrinsic fluorescence shift and optical density at 630 nm, protein aggregation was indeed minimized when glucagon was formulated with curcumin and albumin. This formulation also reduced chemical degradation, measured by liquid chromatography with mass spectrometry. Biological activity was retained after aging for 7 days in an in vitro cell-based bioassay and also in Yorkshire swine. Based on these findings, a formulation of glucagon stabilized with curcumin, polysorbate-80, l-methionine, and albumin at alkaline pH in glycine buffer may be suitable for extended use in a portable pump in the setting of a bihormonal artificial endocrine pancreas.

Development and Validation of Spectrophotometric Methods for the Quantification of Solifenacin Succinate: Application to Tablet Dosage Forms

Four sensitive, precise and accurate spectrophotometric methods for the estimation of solifenacin succinate (SFS) have been developed. Method A describes the interaction of SFS with potassium permanganate in alkaline medium to give green colored manganate ion with absorption maxima at 610 nm. Methods B and C are based on the formation of ternary complexes of SFS with, copper (II)/eosin (method B) and ammonium molybdate/ammonium thiocyanate (method C), respectively which are extracted into chloroform and have absorption maxima at 545 nm (method B) and 465 nm (method C). Method D was based on the formation of yellow colored ion-pair complex between bromocresol green and SFS in dichloromethane medium with absorption maxima at 415 nm. Regression analysis of Beer's law plot showed good correlation in the concentration range of 5-50, 2.5-50, 10-100 and 2-20 μg/mL for methods A, B, C and D, respectively. Different variables affecting the reaction were studied and optimized. The proposed methods were applied successfully for the analysis of SFS in tablets dosage forms. No interference was observed from common pharmaceutical excipients.

Development and Validation of Spectrophotometric Methods for the Quantification of Solifenacin Succinate: Application to Tablet Dosage Forms

Four sensitive, precise and accurate spectrophotometric methods for the estimation of solifenacin succinate (SFS) have been developed. Method A describes the interaction of SFS with potassium permanganate in alkaline medium to give green colored manganate ion with absorption maxima at 610 nm. Methods B and C are based on the formation of ternary complexes of SFS with, copper (II)/eosin (method B) and ammonium molybdate/ammonium thiocyanate (method C), respectively which are extracted into chloroform and have absorption maxima at 545 nm (method B) and 465 nm (method C). Method D was based on the formation of yellow colored ion-pair complex between bromocresol green and SFS in dichloromethane medium with absorption maxima at 415 nm. Regression analysis of Beer's law plot showed good correlation in the concentration range of 5-50, 2.5-50, 10-100 and 2-20 μg/mL for methods A, B, C and D, respectively. Different variables affecting the reaction were studied and optimized. The proposed methods were applied successfully for the analysis of SFS in tablets dosage forms. No interference was observed from common pharmaceutical excipients.

A novel identification system for counterfeit drugs based on portable Raman spectroscopy

Quick inspection methods for counterfeit drugs are of vital necessity. In this study, the feasibility of portable Raman spectroscopy as an analytical method together with a novel identification system for fake drugs detection is demonstrated. The rapid and convenient identification system based on modified local straight-line screening (LSLS) and principal component analysis (PCA) is developed to distinguish counterfeit from authentic. LSLS algorithm was originally designed to detect synthetic drug(s) adulterated in herbal medicines based on infrared spectroscopy. In order to adapt the LSLS method for the detection of the suspected counterfeit drugs based on portable Raman spectroscopy, modification of weighting is made in this paper to obtain the low false positive rate (FPR) and low false negative rate (FNR). The proposed identification system has been benchmarked by 7 kinds (40 batches) of hypoglycemic tablets and 12 common pharmaceutical excipients. The total sensitivity, specificity and accuracy are 96.77%, 97.48% and 96.35% respectively. The results indicate that the identification system is appropriate for the on-site preliminary screening of the suspected counterfeit drugs.

Mediation of in Vitro Cytochrome P450 Activity by Common Pharmaceutical Excipients

Polymers and surfactants are commonly used as excipients in oral formulations and are generally considered to be inert. However, relatively few studies have assessed their interaction with enzymes involved in the absorption, distribution, metabolism, and elimination of drugs. We have investigated the impact of twenty-three commonly used excipients (ten polymers and thirteen surfactants) on seven cytochrome P450 (CYP450) isoforms using baculosome-derived CYP450 enzymes across a range of concentrations. Time-course fluorescent readings were then taken to generate IC50 (inhibition) or EC50 (activation) values for excipient effects on CYP450 activity. All excipients had an observable effect activity of at least one CYP450 isoform with the majority of excipients altering substrate metabolism of at least 57% of CYP450s studied. In addition, most excipients were capable of inhibiting and increasing activity of several different CYP450 isoforms. Although the majority of these effects required concentrations outside those achievable therapeutically (>100 μM), almost 20% were seen at concentrations below 100 μM, and these results indicate that several excipients have the potential to modify the pharmacokinetics of administered drugs.

Effects of pharmaceutical excipients on membrane permeability in rat small intestine

Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water-soluble compounds. In some dosage conditions of methyl-β-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water-soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients.

Spectrophotometric determination of Salbutamol sulphate by coupling with diazotized 2,4-dinitroaniline

A quick, convenient and sensitive method has been developed for the determination of microgram amounts of salbutamol sulphate in its pure form and pharmaceutical preparations. The method is based on the coupling reaction of the drug with diazotized 2,4 - dinitroaniline reagent in an alkaline medium to produce an intense blue coloured Water soluble and stable azo dye which exhibits a maximum absorption at 558 nm. Beer's law was obeyed over the concentration range 0.2 - 6 µg/ml with a molar absorptivity of 9.33×104 L.mol-1.cm-1 and Sandell's sensitivity index of 0.0061 g/cm2. The limit of detection is 0.0089 µg/ml while the limit of quantitation is 0.029 µg/ml. The method shows high accuracy (average recovery 99.75%) and precision (relative standard division (RSD) is less than 2.2%.The suggested procedure was applied for determination of salbutamol sulphate without any interference from common pharmaceutical excipients. The proposed method is successfully compared with the official method.

EXTRACTIVE METHOD DEVELOPMENT AND VALIDATION OF TULOBUTEROL IN API AND ITS PHARMACEUTICAL DOSAGE FORMS BY SPECTROPHOTOMETRY

A simple, accurate, sensitive and reproducible visible spectrophotometric method has been developed for the determination of Tulobuterol (TLB) in bulk and also in its pharmaceutical dosage formulations. The proposed method was based on complexation of the drug with Bromo Cresol Green (BCG) extracted with chloroform showing absorbance maxima at 624 nm respectively. Beer's law is obeyed over a concentration range of 0.1-0.8g/mL. The respective linear regression equation being Y (0.0309) =1.065x +0.0396 for TLB. Results of analysis for the method established, was validated statistically and also by recovery studies. The color was stable for about 1 hour. The apparent molar absorptivity and Sandells Sensitivity values are 0.43x10 4 L mol-1 cm -1 and 0.7674gcm -2 respectively. The assay and recovery studies were found to be 101.43% and coefficient correlation(r) was found to be0.994.The different experimental parameters effecting the development and stability were studied carefully and optimized. No interference was observed in the presence of common pharmaceutical excipients. The validity of the methods was tested by analyzing the drug in its pharmaceutical preparations. Good recoveries were also obtained. The developed method employed was successful for the determination of TLB in various pharmaceutical preparations.

Effect of temperature increase during the tableting of pharmaceutical materials

Scale-up of tableting process is particularly difficult due to specific concerns related exclusively to the process itself and that cannot be determined on a smaller scale, which are the effect of compression speed and the build-up of heat due to the length of the compaction operations. In this work, it has been simulated the rise of temperature observed during the tablets manufacturing in a full production scale by means of an appropriate modification of a R&D rotary tablet machine. Four common pharmaceutical excipients, characterized by different chemical nature, consolidation behaviour and temperature sensitiveness have been analysed in terms of compaction mechanism (Heckel and energy analysis) and tabletability, in order to verify any effect of the increase of temperature. The results showed a relevance of the temperature on mechanical tablets properties only on materials characterized by low temperature thermal transitions (melting or glass transition), while, for compounds which do not exhibit thermal events at low temperature, it becomes less important for ductile materials and irrelevant for brittle materials. Heckel analysis highlighted a noticeable increase of ductility only in those materials whose tablets mechanical properties depended on the temperature. On the other hand, energy analysis showed low sensitivity failing to identify any temperature effect on compaction materials properties. This work showed how to simulate the process of temperature rise on a small scale and the influence of temperature on materials compaction properties. The use of a modified tableting machine, able to control the temperature and moisture levels and also capable of monitoring the punch movements, resulted in identifying the effect of temperature both on mechanical and compaction properties on materials. Thus, it represents a valuable tool in order to provide useful information at an early stage during the development of tablets formulations.

Micellar electrokinetic capillary chromatographic determination of a polypill combination containing, lisinopril, hydrochlorothiazide, aspirin, and atorvastatin

A simple, precise, and rapid micellar electrokinetic capillary chromatographic method with a photodiode array detector was developed and validated for the separation and simultaneous determination of a cardiovascular innovative polypill combination. The combined polypill components were: lisinopril (LIS), hydrochlorothiazide (HCT), aspirin (ASP), and atorvastatin (ATO). Separation was achieved utilizing a fused silica capillary (58 cm × 75 μm ID) and a background electrolyte solution consisting of borax buffer (20 mM, pH 9.5) containing 30 mM sodium lauryl sulphate, with paracetamol as the internal standard. The method was fully validated as per the guidelines of the International Conference on Harmonization for validation of analytical procedures. The method was linear over the range 0.1–200 μg mL−1 with detection limits of 3.10, 0.33, 0.74, and 0.84 μg mL−1 for LIS, HCT, ASP, and ATO, respectively. The proposed method was successfully applied for the simultaneous determination of the polypill components without interferences from the common pharmaceutical excipients. The percentage recoveries of the four drugs from the polypill were 100.07 ± 0.81, 100.30 ± 0.21, 99.73 ± 0.40, and 99.23 ± 0.49% for LIS, HCT, ASP, and ATO, respectively. The method is rapid as it involved a short run time; all the components were eluted within 8 min. Moreover, the method also permitted the separation of salicylic acid which is commonly present in aged aspirin formulations. The results demonstrated that the proposed method has a great practical value for routine application in quality control laboratories for the high-throughput simultaneous determination of the polypill components.

Investigation of the physical–mechanical properties of Eudragit® RS PO/RL PO and their mixtures with common pharmaceutical excipients

Ammonio methacrylate copolymers Eudragit® RS PO and Eudragit® RL PO have found widespread use as key components in various types of extended release solid dosage forms. The deformation behavior of neat polymers and binary mixes was evaluated using Heckel Analysis, strain rate sensitivity, work of compaction and elastic recovery index. Additionally, the compact forming ability of neat materials and binary mixes were evaluated by analyzing their tabletability, compressibility and compactibility profiles. The Heckel analysis of both polymers exhibited a speed-sensitive deformation behavior typical to plastic materials. The yield values of the binary mixes of the polymers with microcrystalline cellulose revealed a linear relationship with the weight fractions of individual components. The yield values of binary mixes of both the polymers with dibasic calcium phosphate exhibited slight negative deviations from linearity. Both polymers exhibited axial relaxation after ejection typical of viscoelastic materials, as measured by the elastic recovery index values. The work of compaction and the elastic recovery index values of the binary mixtures were found to be linearly related to the weight fractions of the individual components thus, confirming ideal mixing behavior based on the composition. Addition of microcrystalline cellulose to both polymers significantly improved their tabletability and compactibility. The tensile strengths of the compacts prepared with neat materials and binary mixes with microcrystalline cellulose, dibasic calcium phosphate and lactose were the function of their solid fraction and independent of the tableting speeds tested; thus, validating compactibility as a reliable parameter in predicting acceptable tablet properties.

Detection of Botulinum Neurotoxin Serotype A, B, and F Proteolytic Activity in Complex Matrices with Picomolar to Femtomolar Sensitivity

Rapid, high-throughput assays that detect and quantify botulinum neurotoxin (BoNT) activity in diverse matrices are required for environmental, clinical, pharmaceutical, and food testing. The current standard, the mouse bioassay, is sensitive but is low in throughput and precision. In this study, we present three biochemical assays for the detection and quantification of BoNT serotype A, B, and F proteolytic activities in complex matrices that offer picomolar to femtomolar sensitivity with small assay volumes and total assay times of less than 24 h. These assays consist of magnetic beads conjugated with BoNT serotype-specific antibodies that are used to purify BoNT from complex matrices before the quantification of bound BoNT proteolytic activity using the previously described BoTest reporter substrates. The matrices tested include human serum, whole milk, carrot juice, and baby food, as well as buffers containing common pharmaceutical excipients. The limits of detection were below 1 pM for BoNT/A and BoNT/F and below 10 pM for BoNT/B in most tested matrices using 200-μl samples and as low as 10 fM for BoNT/A with an increased sample volume. Together, these data describe rapid, robust, and high-throughput assays for BoNT detection that are compatible with a wide range of matrices.

Selective imaging of active pharmaceutical ingredients in powdered blends with common excipients utilizing two-photon excited ultraviolet-fluorescence and ultraviolet-second order nonlinear optical imaging of chiral crystals.

Second order nonlinear optical imaging of chiral crystals (SONICC) and two-photon excited fluorescence measurements [both autofluorescence and two-photon excited UV-fluorescence (TPE-UVF)] were assessed for the selective detection of APIs relative to common pharmaceutical excipients. Active pharmaceutical ingredients (APIs) compose only a small percentage of most tabulated formulations, yet the API distribution within the tablet can affect drug release and tablet stability. Complementary measurements using either UV-SONICC (266 nm detection) or TPE-UVF were shown to generate signals >50-fold more intense for a model API (griseofulvin) than those produced by common pharmaceutical excipients. The combined product of the measurements produced signals >10(4)-fold greater than the excipients studied. UV-SONICC or TPE-UVF produced greater selectivity than analogous measurements with visible-light detection, attributed to the presence of aromatic moieties within the API exhibiting strong one and two photon absorption at ~266 nm. Complementary SONICC and fluorescence measurements allowed for the sensitive detection of the three-dimensional distribution of tadalafil within a Cialis tablet to a depth of >140 μm.

A validated capillary electrophoresis method for simultaneous determination of ezetimibe and atorvastatin in pharmaceutical formulations

A simple, precise, and sensitive capillary electrophoresis technique coupled with a diode array detector has been developed for the separation and simultaneous determination of ezetimibe and atorvastatin in pharmaceutical formulations. Separation of both ezetimibe and atorvastatin was achieved utilizing fused silica capillary (58cm×75μm ID) and background electrolyte solution that consisted of phosphate buffer (2.5mM, pH 6.7): methanol (70:30 v/v). The proposed method was validated by testing its specificity, linearity, precision, accuracy, recovery, and detection limit/quantitation limit values. The method was linear over the range 2.5–50μg/ml for ezetimibe (r=0.9992) and 1–100μg/ml for atorvastatin (r=0.9999). Within-day and between-day RSD for ezetimibe and atorvastatin were ⩽5.6% and ⩽2.9%, respectively. The detection limit was 0.07μg/ml for ezetimibe and 0.06μg/ml for atorvastatin. The validated method was successfully employed for the determination of ezetimibe and atorvastatin in tablets with no interfering peaks from common pharmaceutical excipients. The percentage recoveries of the two drugs from their tablets were 99.80±1.76 and 100.19±1.83, respectively.

Physiochemical interactions of praziquantel, oxamniquine and tablet excipients.

A differential scanning calorimetry and infrared spectrophotometry study of potential interactions between oxamniquine and praziquantel, two synergistic anti-parasitic drugs, indicated that they did not interact on fusion. Mixtures of the two drugs with each of nine common pharmaceutical excipients (Ac-Di-Sol, Avicel, Crospovidone, calcium phosphate, magnesium stearate, starch, lactose, PEG 6000, stearic acid) appeared to interact only with stearic acid. These results suggested that a combination solid dosage form was feasible.

Tribo-Electrification and Associated Segregation of Pharmaceutical Bulk Powders

Powder handling operations can give rise to the tribo-electrification of particles, causing a number of problems such as risk of fire and explosion, particle adhesion to the walls of processing equipment and segregation. Current methods available for measuring the dynamic charging of bulk powders are unsuitable for testing/handling small quantities of powders, some of which are highly active. Furthermore, very little work has been reported on the effect of tribo-electrification on the segregation of components of mixtures. A methodology has recently been developed for investigating the tribo-electrification of small quantities of bulk powders using a shaking device. Two common pharmaceutical excipients, namely α -lactose monohydrate (α -LM) and hydroxypropyl cellulose (HPC) were used as model materials. The electric charge transferred to the particles was quantified as a function of shaking time,frequency and container material. The temporal trend follows a first-order rate process. Using numerical simulations based on the Distinct Element Method (DEM), the charge accumulation of an assemblage of alumina beads inside the shaking device was analysed based on the single particle contact charge obtained from the experiments. It was shown that the inclusion of electrostatic mechanisms into the DEM model leads to an improved prediction of the charge buildup, but the difference with experimental data is still notable. Using the above method, segregation induced by tribo-electric charging was characterised for binary mixtures comprising α -LM and HPC. The bulk and wall-adhered particles were analysed for the mass fraction of each component using selective dissolution of one component and filtration of the non-dissolving component, followed by a gravimetric analysis. The findings reveal that a considerable level of segregation can take place on the wall-adhered particles. The method described here has the potential to be used to characterise small quantities of pharmaceutical powders including active pharmaceutical ingredients (API), which are sparse in the early development stages.

Spectrophotometric Determination ofN-Acetyl-L-Cysteine andN-(2-Mercaptopropionyl)-Glycine in Pharmaceutical Preparations

A simple spectrophotometric method for the determination of N-acetyl-L-cysteine (NAC) and N-(2-mercaptopropionyl)glycine (MPG) in pharmaceutical preparations was developed, validated, and used. The proposed equilibrium method is based on a coupled two-step redox and complexation reaction. In the first step, Fe(III) is reduced to Fe(II) by NAC or MPG. Subsequently, Fe(II) is complexed with 2,4,6-tripyridyl-s-triazine (TPTZ). Several analytical parameters of the method were optimized for NAC and MPG analysis in the concentration range from 1.0 μM to 100.0 μM. Regression analysis of the calibration data showed a good correlation coefficient (0.9999). The detection limit of the method was 0.14 μM for NAC and 0.13 μM for MPG. The method was successfully applied to quantify NAC and MPG in pharmaceutical preparations. No interferences were observed from common pharmaceutical excipients.

Tablet Tensile Strength: An Adhesion Science Perspective

Tablets are the most common dosage form employed by the pharmaceutical industry. They are both inexpensive to produce and convenient to patients. Active pharmaceutical ingredients, particularly those incorporated into innovator company products, are new chemical substances whose chemical and physical properties are incompletely known and are sometimes present in large amounts in the manufactured products. Excipients present in the formulation can, at least partially, offset undesirable properties of active ingredient. Successful tablet formulations must, in addition to having desirable medicinal properties, must be manufacturable. In order to be manufacturable tablets must have sufficient tensile strength to survive handling, processing and packaging. In this paper the tensile strength of common pharmaceutical excipients mixed with sodium dodecyl sulfate is investigated. Sodium dodecyl sulfate, if incorporated into formulations, usually has an undesirable effect on tensile strength. A model, based on adhesion science principles is proposed that allows the tensile strength of candidate formulations to be calculated from the Ryshkewitch–Duckworth parameters of the component materials. Both the model and the Ryshkewitch–Duckworth equation suggest that tablet porosity is the principal measure of the outcome of the tableting process.