Taste masking analysis in pharmaceutical formulation development using an electronic tongue

The purpose of this study is to assess the feasibility for taste masking and comparison of taste intensity during formulation development using a multichannel taste sensor system (e-Tongue). Seven taste sensors used in the e-Tongue were cross-selective for five basic tastes while having different sensitivity or responsibility for different tastes. Each of the individual sensors concurrently contributes to the detection of most substances in a complicated sample through the different electronic output. Taste-masking efficiency was evaluated using quinine as a bitter model compound and a sweetener, acesulfame K, as a bitterness inhibitor. In a 0.2 mM quinine solution, the group distance obtained from e-Tongue analysis was reduced with increasing concentration of acesulfame K. This result suggests that the sensors could detect the inhibition of bitterness by a sweetener and could be used for optimization of the sweetener level in a liquid formulation. In addition, the bitterness inhibition of quinine by using other known taste-masking excipients including sodium acetate, NaCl, Prosweet^® flavor, and Debittering^® powder or soft drinks could be detected by the e-Tongue. These results further suggest that the e-Tongue should be useful in a taste-masking evaluation study on selecting appropriate taste-masking excipients for a solution formulation or a reconstitution vehicle for a drug-in-bottle formulation. In another study, the intensity of the taste for several drug substances known to be bitter was compared using the e-Tongue. It was found that the group distance was 695 for prednisolone and 686 for quinine, which is much higher than that of caffeine (102). These results indicate that the taste of prednisolone and quinine is stronger or more bitter than that of caffeine as expected. Based on the group distance, the relative intensity of bitterness for these compounds could be ranked in the following order: ranitidine HCl > prednisolone Na > quinine HClphenylthiourea > paracetamol  sucrose octaacetate > caffeine. In conclusion, the multichannel taste sensor or e-Tongue may be a useful tool to evaluate taste-masking efficiency for solution formulations and to compare bitterness intensity of formulations and drug substances during pharmaceutical product development.     

Rapid separation of desloratadine and related compounds in solid pharmaceutical formulation using gradient ion-pair chromatography

We reported the development of an ion-pair chromatographic method to separate desloratadine and all known related compounds in Clarinex Tablets, which use desloratadine as active pharmaceutical ingredient (API). For the first time, baseline separation for desloratadine and all known related compounds was achieved by utilizing a YMC-Pack Pro C₁₈ column (150 mm × 4.6 mm I.D., 3 μm particle size, 120 Å pore size) and a gradient elution method. The mobile phase A contains 3 mM sodium dodecylsulfate (SDS), 15 mM sodium citrate buffer at pH 6.2, and 40 mM sodium sulfate, while the mobile phase B is acetonitrile. Chromsword^®, an artificial intelligence method development tool, was used to optimize several key chromatographic parameters simultaneously including buffer pH/solvent strength, and temperature/gradient profile. The resolution of desloratadine and desloratadine 3,4-dehydropiperidine derivative, one of the critical pairs was improved by adding 40 mM sodium sulfate. Ultraviolet detection at 267 nm was used to achieve the detection for desloratadine and all compounds. This method has been successfully validated according to ICH guidelines in terms of linearity, accuracy, quantitation limit/detection limit, precision, specificity and robustness. It could be used as a stability indicating method for desloratadine drug substances or drug products that use desloratadine as active pharmaceutical ingredient.     

Opportunities and challenges of three-dimensional printing technology in pharmaceutical formulation development

Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.     

Quantitative analysis of bucillamine and its pharmaceutical formulation using FT-IR spectroscopy

A Fourier transform infrared (FT-IR) spectrometric method was developed for the rapid, direct measurement of bucillamine. Conventional KBr-spectra and DRIFTS spectra were compared for best determination of active substance in its tablet formulation. Two chemometric approaches, partial least squares (PLS) and principal component regression (PCR+) methods were used in data processing. Similar results were obtained with both chemometric methods.     

Multivariate cluster analysis of pharmaceutical formulation data using Andrews plots

A multivariate clustering technique known as the Andrews Plot was applied to a set of previously published data describing a series of pharmaceutical tablet formulations. Dependent variable data were subjected to a trigonometric transform algorithm and unique sinusoidal patterns were obtained for each of 18 formulations characterized by a total of 12 granulation and tablet parameters. Three main formulation clusters were observed in close agreement with a previously published analysis of the same data set using principal components methodology. Interpretation of cluster behavior lead to conclusions closely aligned to those of the original investigators, although some alternate hypotheses also arise. Limitations of the Andrews plotting technique were explored. The method appears to have value in the analysis of complex data sets derived from pharmaceutical formulation characterizations.     

Flavor analysis in a pharmaceutical oral solution formulation using an electronic-nose

Flavors are commonly used in pharmaceutical oral solutions and oral suspensions to mask drug bitterness and to make the formulation more palatable. Flavor analysis during product development is typically performed by human organoleptic analysis, which is often expensive and less objective. A novel approach using a metal oxide sensor-based instrument (electronic-nose) for headspace analysis was explored to replace human sensory perception for consistent qualitative and quantitative analysis of flavors in a pharmaceutical formulation. The use of the electronic-nose technique to qualitatively distinguish among six common flavoring agents (raspberry, red berry, strawberry, pineapple, orange, and cherry) in placebo formulations was demonstrated. The instrument was also employed to identify unknown flavors in drug formulation placebos. Raspberry flavor samples from different lots made by the same manufacturer, as well as freshly prepared and aged samples, were also distinguished by electronic-nose. Therefore, the instrument can potentially be used for identity testing of different flavor raw materials and the flavored solution formulations. The electronic-nose was also employed successfully for quantitative analysis of flavors in an oral solution formulation. The quantitative method might be used to assay the flavor concentration during release testing of the oral solution formulation or to monitor flavor shelf-life in the marketed container. It can also be implemented for packaging selection for the formulation in order to ensure the flavor shelf-life. Chemometric methodologies including principal component analysis (PCA), discriminant factorial analysis (DFA), and partial least squares (PLS), were used for data processing and identification.     

Profiling of medium chain glycerides used in pharmaceutical formulation development by reversed-phase HPLC

Medium chain length (C8, C10) mono-, di- and triacylglycerols (MCGs) are used in pharmaceutical formulation development of poorly soluble compounds, as a means to increase their oral bioavailability. The ratios of C8 and C10 fatty acid components along with the ratio of monoglycerides, diglycerides and triglycerides can significantly impact overall solubilizing characteristics both in vitro and in vivo. Existing literature methods either do not have the desired selectivity or simplicity to adequately characterize these MCGs. A reversed-phase HPLC method has been developed utilizing a Waters Symmetry C18 (150 mm x 4.6 mm, 3.5 microm particle size) column with a gradient of acetonitrile and water. The effluent was monitored using a UV detector at 220 nm and relative response factors were determined for all components with available standards to allow for accurate quantitation. The RP-HPLC method was optimized for selectivity, sensitivity and efficiency and was successfully applied to the characterization of commercial samples yielding superior sensitivity and ease of preparation compared to existing compendial methods.     

A comparative study on two electronic tongues for pharmaceutical formulation development

Electronic tongues are sensor array systems which are able to determine single substances as well as complex mixtures of various substances. They are increasingly used for taste assessment of pharmaceutical formulations. Two systems are available on the market, the AlphaMOS electronic tongue Astree2 and the Insent taste sensing system TS-5000Z. Both systems measure based on potentiometry but sensor technologies are different. Therefore, these electronic tongue systems were compared to each other with respect to general aspects like software handling, sensors, and measurement procedure, but also on the basis of analytical experiments in order to figure out the applicability and limitations for use in the pharmaceutical field. By investigation of substances with different ionic character, like sodium saccharin, acetaminophen, ibuprofen, quinine, and caffeine, it was shown for both systems that ionic substances are easier to detect than neutral ones. Further, the performance qualification could only be done for the TS-5000Z, whereas the validation step, a correlation to human taste assessment, was passed by both systems. The results were even more reproducible than those from the panel. Taste masking by complexation of ibuprofen and quinine hydrochloride by maltodextrin, could be evaluated by both systems. Data from the Astree2 system have to be normalized in order to compare inter-day results, while the Insent taste sensing system refers each measurement to a standard solution and therefore reaches better inter-day results. Both systems offer the opportunity to be used for the development of taste-masked pharmaceutical formulations.     

Electrochemical analysis of sparfloxacin in pharmaceutical formulation and biochemical screening of its Co(II) complex

The electrochemical reduction of meloxicam has been studied at a mercury electrode using various electrochemical methods in aqueous solutions over a wide pH range. The reduction of the drug produced a single reduction step in acidic media, whereas in slightly acidic and neutral media two reduction steps were observed. In alkaline media meloxicam shows a single pH-independent reduction step. The irreversibility of the electrode process was verified by different criteria. At all pH values, reactant adsorption at mercury electrode was observed. The mechanism of reduction was discussed. Using differential-pulse voltammetry, the drug yielded a well-defined voltammetric response in Britton-Robinson buffer solution, pH 4.0 at -1.286 V (vs. Ag/AgCl). This process could be used to determine meloxicam concentration in the range 1.0 x 10(-8)-5.0 x 10(-6) M. The method was successfully applied for the analysis of meloxicam in the tablet dosage form.     

Voltammetric assay of Guaifenesin in pharmaceutical formulation

The electrochemical oxidation of Guaifenesin in a pharmaceutical formulation containing Guaifenesin has been carried out in Britton-Robinson buffer (BRB) (0.04 mol L-1) on platinum electrode. Guaifenesin exhibits a well-defined irreversible oxidation peak at 0.924 V/ref. The influence of pH on the oxidation of Guaifenesin was studied in BRB (pH range 2-5). A method for the analysis of Guaifenesin in BRB (0.04 mol L-1, pH 2), which allows quantification over the range 20-60 microg mL-1, was proposed and successfully applied to the determination of Guaifenesin in syrup with mean recovery and relative standard deviation of 103.3% and 1.32%, respectively.     

Colorimetric determination of gabapentin in pharmaceutical formulation

Three accurate, simple and precise colorimetric methods for the determination of gabapentin in capsules are developed. The first method is based on the reaction of gabapentin with vanillin (Duquenois reagent) in the presence of McIlvain buffer pH 7.5 and the color developed was measured at 376 nm. The linearity range was found to be 80-360 microg ml(-1). The second is based on the reaction of the primary amino group of gabapentin with ninhydrin reagent in N,N'-dimethylformamide (DMF) medium producing a colored product which absorbs maximally at 569 nm. Beer's law is obeyed in the concentration range 40-280 microg ml(-1) of gabapentin. The third method is based on the reaction of gabapentin with p-benzoquinone (PBQ) to form a colored product with lambda(max) at 369 nm. The products of the reaction were stable for 2 h at 30 degrees C, shifts of the wavelength of maximum absorbance were not observed for up to 24 h after starting the reaction. The absorbance is proportional to gabapentin concentration in the range 80-320 microg ml(-1). The optimum experimental parameters for the reactions have been studied. The validity of the described procedures was assessed. Statistical analysis of the results has been carried out revealing high accuracy and good precision. The suggested procedures could be used for the determination of gabapentin in capsules. The procedures were rapid, simple and suitable for quality control application.     

Polarographic determination of propranolol in pharmaceutical formulation

Propranolol was reacted with nitric acid to give nitropropranolol and was then measured in Britton-Robinson solutions in the pH range 2.0-12.0 by differential-pulse polarography. Nitropropranolol gave rise to a well-resolved differential-pulse polarographic peak at pH 2.0. A linear calibration graph in the range 5.0 x 10(-7)-5.0 x 10(-5) M and a detection limit of 5 nM was obtained. The relative standard deviation was 1.95% (n = 10) at 5 x 10(-6) M. The effect of common exceipient on the peak height was evaluated. The method was applied for the determination of the drug in the tablet dosage form.     

Novel approach of cyclodextrin-based pharmaceutical formulation

The α-, β-, and γ-CyDs are the most common natural CyDs, consisting of six, seven, and eight glucose units, respectively. Among the natural CyDs, bioadaptable γ-cyclodextrin (γ-CyD) is useful to improve the undesired properties of drug molecules through the formation of inclusion complex. Recently, various kinds of CyD derivatives such as hydrophilic, hydrophobic, amphiphatic and anionic CyDs have been developed, anticipating the design of CyD-based drug delivery system. The objective of this contribution is to outline our recent findings on the combinational use of γ-CyD and functional ingredients, focusing on the ability to increase the drug absorption, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site. In addition, the multi-functional characteristic of hydroxyalkylated CyDs, in particular, 2-hydroxypropyl-β-CyD (HP-β-CyD) is applicable to design the novel pharmaceutical formulation, focusing on the ability to form hydrophilic nano-particles. Moreover, some amphiphatic CyDs such as 2,6-di-O-methyl-β-CyD (DM-β-CyD) and 2-hydroxybutyl-β-CyD (HB-β-CyD) are useful to control the crystallization and polymorphic transition of solid drugs and will provide an opportunity to isolate labile intermediate metastable polymorphs. On the basis of above-mentioned knowledge, this review explores the use of CyDs to better understand their pharmaceutical applications as well as their limitations in the approach of CyD-based drug delivery system.     

LC determination of rosiglitazone in bulk and pharmaceutical formulation

An isocratic reversed phase liquid chromatographic (RP-LC) method has been developed and subsequently validated for the determination of rosiglitazone and its related impurities. Separation was achieved with a Symmetry C18 column and sodium phosphate buffer (pH adjusted to 6.2):acetonitrile (50:50, v/v) as eluent, at a flow rate of 1.0 ml/min. UV detection was performed at 245 nm. The method is simple, rapid, selective and stability indicating. Indole was used as internal standard for the purpose of quantification of rosiglitazone. The described method is linear over a range of 0.45-10 microg/ml for related impurities and 180-910 microg/ml for assay of rosiglitazone. The method precision for the determination of assay and related compounds was below 1.0 and 3.6% RSD, respectively. The mean recoveries of impurities were found to be in the range of 95-102%. The percentage recoveries of Active Pharmaceutical Ingredient (API) from dosage forms ranged from 99.02 to 101.30. The method is useful in the quality control of bulk manufacturing and also in pharmaceutical formulations.     

Flow injection amperometric determination of procaine in pharmaceutical formulation using a screen-printed carbon electrode

A rapid and simple method for procaine determination was developed by flow injection analysis (FIA) using a screen-printed carbon electrode (SPCE) as amperometric detector. The present method is based on the amine/hydroxylamine oxidation from procaine monitored at 0.80 V on SPCE in sodium acetate solution pH 6.0. Using the best experimental conditions assigned as: pH 6.0, flow rate of 3.8 mL min(-1), sample volume of 100 microL and analytical path of 30 cm it is possible to construct a linear calibration curve from 9.0x10(-6) to 1.0x10(-4) mol L(-1). The relative standard deviation for 5.0x10(-5) mol L(-1) procaine (15 repetitions using the same electrode) is 3.2% and detection limit calculated is 6.0x10(-6) mol L(-1). Recoveries obtained for procaine gave a mean values from 94.8 to 102.3% and an analytical frequency of 36 injections per hour was achieved. The method was successfully applied for the determination of procaine in pharmaceutical formulation without any pre-treatment, which are in good accordance with the declared values of manufacturer and an official method based on spectrophotometric analysis.     

Spectrophotometric determination of vitamin B1 in a pharmaceutical formulation using triphenylmethane acid dyes

A highly sensitive colour reaction has been developed, based on the fact that vitamin B(1) reacted with a triphenylmethane acid dye such as thymol blue, bromothymol blue, bromophenol blue, bromocresol green, phenol red or cresol red to form an ion-association complex in a weak-base aqueous solution in the presence of some solubilization agents e.g. polyvinyl alcohol, emulgent OP, Triton X-100 or Tween-20. The wavelengths of maximum absorbance of the six ion-association complexes were between 420 and 450 nm, and fading reaction appeared at the longer wavelength and the maximum fading wavelengths were between 550 and 620 nm. The reactions had highly sensitivities and their apparent molar absorptivities of the colour reactions were (0.82-1.65) x 10(5) l mol(-1) cm(-1) and those of fading reactions were (1.26-3.92) x 10(5) l mol(-1) cm(-1) depending on the different dye systems. The composition ratio of the ion-association complex was vitamin B(1):dye = 1:1 as established by Job's and equilibrium shift methods. The method had good selectivity and could be applied to direct spectrophotometric determination of vitamin B(1) in aqueous phase without using organic solvent extraction. Therefore, the method was simple and rapid. The colour reaction mechanism was discussed with the quantum chemistry method.     

Voltammetric determination of vitamins in a pharmaceutical formulation

Direct current polarography and differential pulse polarographic methods have been developed for the qualitative as well as quantitative analysis of vitamin B₁, B₂ and B₆. Thiamin (Vitamin B₁) produced a well-defined wave in 0.1 M KCl at pH 5.2 with E_1/2=−1.2 V and E_p=−1.22 V versus saturated calomal electrode (SCE). Riboflavin (Vitamin B₂) gave two distinct waves in Britton Robinson buffer at pH 1.8 with E_1/2 VALUES=−0.13 and −0.34 V versus SCE and at pH 6.5 with E_1/2=−1.10 V and E_p=−1.2 V versus SCE. Pyridoxin (Vitamin B₆) produced a well-defined wave in Britton Robinson buffer at pH 6.5 with E_1/2=−1.7 V and E_p=−1.68 V versus SCE. All the three Vitamins under study are reversibly reduced at the electrode surface. The number of electrons involved in the electrode process for vitamin B₁ and B₆ is one in each case where as for the two waves of B₂ it is one and two, respectively. This has been confirmed by the measurement of E_3/4–E_1/4 values and also from the log plot slopes for the reduction waves. The wave height of polarogram was found to be proportional to the vitamin concentration. The developed methods have been standardised for the determination of these compounds in pharmaceutical formulation. The concentration of Vitamin B₁, B₂ and B₆ are found to be 9.96, 9.92 and 3.01 mg, respectively in 240 mg of capsule powder of a standard company (name has not been disclosed due to secrecy purpose). The results have been found to be in excellent agreement to that claimed by the manufacturer. The observed data has been subjected to statistical analysis, which revealed high reliability and precision.     

Rapid, simultaneous determination of headspace oxygen and moisture in pharmaceutical packages using muGC

The rapid, accurate determination of headspace oxygen and moisture in various pharmaceutical packages is important for both product packaging development and the implementation of new packaging technologies. Current headspace oxygen measurement techniques suffer from serious drawbacks in terms of potential sampling contamination, lengthy analysis times, and large required analysis volumes. In addition, relatively few techniques currently exist for the convenient determination of headspace moisture in packaging systems. Efforts herein focused on the development and application of a new method for the rapid and simultaneous determination of headspace oxygen and moisture in pharmaceutical packages using micro-gas chromatography (muGC). Studies showed that both headspace oxygen and moisture could be simultaneously quantified in <90 s on sample volumes of 50-100 microL by employing muGC with dual chromatographic analysis modules. Sampling issues common to manual syringe-based injections were also alleviated in the current studies by use of the built-in diaphragm pump sampling interface of the portable muGC system. The performance of the analytical approach was evaluated and shown to exhibit excellent linearity, accuracy, and precision for both analytes. High sensitivity for headspace oxygen was demonstrated, allowing for levels of oxygen as low as 0.03% to be accurately quantified. The subject method was applied to measure the headspace oxygen and moisture in pharmaceutical blister packaging and glass vials.     

Systematical approach of formulation and process development using roller compaction

The roller compaction process has gained heightened interest in the pharmaceutical industry. In this review, common excipients and equipment used for dry granulation are described. Roller compaction process parameters and their impact on the critical quality attributes of the final product, as well as evaluation methods for roller compaction product such as ribbons and granules, are discussed. Overall, a systematical approach of formulation and process development has been proposed for excipient selection, critical process parameter identification, and necessary tests.