Pharmaceutical Drug Products Research Articles

Metabolic engineering to enhance the value of plants as green factories

The promise of plants to serve as the green factories of the future is ever increasing. Plants have been used traditionally for construction, energy, food and feed. Bioactive compounds primarily derived from specialized plant metabolism continue to serve as important scaffold molecules for pharmaceutical drug production. Yet, the past few years have witnessed a growing interest on plants as the ultimate harvesters of carbon and energy from the sun, providing carbohydrate and lipid biofuels that would contribute to balancing atmospheric carbon. How can the metabolic output from plants be increased even further, and what are the bottlenecks? Here, we present what we perceive to be the main opportunities and challenges associated with increasing the efficiency of plants as chemical factories. We offer some perspectives on when it makes sense to use plants as production systems because the amount of biomass needed makes any other system unfeasible. However, there are other instances in which plants serve as great sources of biological catalysts, yet are not necessarily the best-suited systems for production. We also present emerging opportunities for manipulating plant genomes to make plant synthetic biology a reality.

Distribution of a low dose compound within pharmaceutical tablet by using multivariate curve resolution on Raman hyperspectral images

In this work, Raman hyperspectral images and multivariate curve resolution-alternating least squares (MCR-ALS) are used to study the distribution of actives and excipients within a pharmaceutical drug product. This article is mainly focused on the distribution of a low dose constituent. Different approaches are compared, using initially filtered or non-filtered data, or using a column-wise augmented dataset before starting the MCR-ALS iterative process including appended information on the low dose component. In the studied formulation, magnesium stearate is used as a lubricant to improve powder flowability. With a theoretical concentration of 0.5% (w/w) in the drug product, the spectral variance contained in the data is weak. By using a principal component analysis (PCA) filtered dataset as a first step of the MCR-ALS approach, the lubricant information is lost in the non-explained variance and its associated distribution in the tablet cannot be highlighted. A sufficient number of components to generate the PCA noise-filtered matrix has to be used in order to keep the lubricant variability within the data set analyzed or, otherwise, work with the raw non-filtered data. Different models are built using an increasing number of components to perform the PCA reduction. It is shown that the magnesium stearate information can be extracted from a PCA model using a minimum of 20 components. In the last part, a column-wise augmented matrix, including a reference spectrum of the lubricant, is used before starting MCR-ALS process. PCA reduction is performed on the augmented matrix, so the magnesium stearate contribution is included within the MCR-ALS calculations. By using an appropriate PCA reduction, with a sufficient number of components, or by using an augmented dataset including appended information on the low dose component, the distribution of the two actives, the two main excipients and the low dose lubricant are correctly recovered.

Pattern of Acute Poisoning in Al Majmaah Region, Saudi Arabia

Background: Acute poisoning is a common situation in emergency departments all over the world. It may cause severe complications and death. Treatment of these cases requires great medical care and significant costs. There are many differences with respect to the pattern and cause of acute poisoning between geographical regions, even within the same country. Objective: This study was carried out to assess the pattern of acute poisoning with drugs, chemicals and natural toxins in both adults and children in Al Majmaah region, Saudi Arabia. Methods: The study was conducted at King Khaled Hospital in Al Majmaah region. The medical records of cases who were admitted due to acute poisoning from January 2009 to December 2012 were reviewed retrospectively. Results: This study included 591 acute poisoned cases presented to ED. There were 79.4% more than 12 years old and 20.6% under 12 years old. .Number of males with toxic exposure was 435 while that of females was 156. Animal envenomation contributed to most of these cases. Unfortunately, other data of these cases could not be followed as 422 cases were observed and discharged from ED. Of them 188 were observed, received no treatment and discharged from ED. The other 234 cases were treated and discharged from ED. The medical record of 169 cases who were admitted to pediatric and internal medicine department could be retrieved and studied completely. There were 5.6% infants, 74.4% between 1–6 years old, 20% between 6-12 years old, 15.2% between 12-18 years old, 83.5 between 18-60 years old and 1.3% more than 60 years old. Pharmaceutical drugs and household products were the main causes of poisoning in cases under 12 years old ( 84.4%) while, animal envenomation; mainly scorpion stings contributed to most cases over 12 years old (62%). Conclusion: Accidental poisoning is still a significant cause of morbidity. Regarding the high prevalence of pharmaceutical drug and household products poisoning in children, implementation of legislations to ban over the counter selling of medications and to sell potentially dangerous chemicals in childproof containers is recommended. Improving proper and complete medical record-keeping is also suggested for a better information access.

Enzymes in the dissolution testing of gelatin capsules.

Gelatin capsules are a widely used dosage form both for pharmaceutical drug products as well as dietary supplements. Gelatin in the presence of certain compounds, mainly aldehydes, or in high humidity and high temperature conditions can cross-link. Cross-linking involves covalent bonding of the amine group of a lysine side chain of one gelatin molecule to a similar amine group on another molecule. The covalent bonding is, for practical purposes, irreversible. Cross-linking results in the formation of a pellicle on the internal or external surface of the gelatin capsule shell that prevents the capsule fill from being released. In vitro dissolution testing of cross-linked gelatin capsules can result in slower release of the drug or no release at all. The data obtained by the Gelatin Capsule Working Group, created in the early 90s to investigate noncompliance of gelatin capsules, was used to establish the type and amounts of enzymes that can be added to the dissolution medium in the case of test failure to the presence of cross-linking in the gelatin. The two-tier dissolution testing was included in the US Pharmacopeia and it recommends the addition of pepsin (pH below 6.8) or pancreatin (pH above 6.8) to the medium depending on its pH. Pepsin shows good protease activity up to pH 4 and pancreatin above pH 6 leaving a gap where neither one has good activity. Possible proteolytic enzymes that could be used for the pH range 4-6.8 could be papain or bromelain.

Development, optimization and validation of a rapid colorimetric microplate bioassay for neomycin sulfate in pharmaceutical drug products

Microbiological assays have been used to evaluate antimicrobial activity since the discovery of the first antibiotics. Despite their limitations, microbiological assays are widely employed to determine antibiotic potency of pharmaceutical dosage forms, since they provide a measure of biological activity. The aim of this work is to develop, optimize and validate a rapid colorimetric microplate bioassay for the potency of neomycin in pharmaceutical drug products. Factorial and response surface methodologies were used in the development and optimization of the choice of microorganism, culture medium composition, amount of inoculum, triphenyltetrazolium chloride (TTC) concentration and neomycin concentration. The optimized bioassay method was validated by the assessment of linearity (range 3.0 to 5.0μg/mL, r=0.998 and 0.994 for standard and sample curves, respectively), precision (relative standard deviation (RSD) of 2.8% and 4.0 for repeatability and intermediate precision, respectively), accuracy (mean recovery=100.2%) and robustness. Statistical analysis showed equivalency between agar diffusion microbiological assay and rapid colorimetric microplate bioassay. In addition, microplate bioassay had advantages concerning the sensitivity of response, time of incubation, and amount of culture medium and solutions required.

A New Simple and Rapid Method for the Determination of Sodium Hyaluronate in Active Pharmaceutical Ingredient and Ophthalmic Formulations by DP5 Photorode

A new, simple, rapid and reliable turbidimetric routine method for the determination of sodium hyaluronate in active pharmaceutical ingredient and ophthalmic solution is described by using DP5 Phototrode. The turbidity of an aqueous ophthalmic sample solution was measured using a DP5 Phototrode™ for photometric indicated titration. Near the equivalence point, a precipitate between titrant and analyte is formed, and the solution becomes turbid. The method involves measurement of the equivalence point at minimum light transmission through the sample, containing cationic quaternary ammonium compound, cetylpyridinium chloride (CPC) solution as a dispersing agent, is measured at 520 nm. The results obtained for in-house prepared formulation and other marketed ophthalmic solution are compared with those obtained by the published HPLC method. A calibration curve was obtained from 0.08 to 0.122 mg mL–1 (r > 0.9998). Within-day % RSD was 1.08 and between-day % RSD was 1.10. Specificity/ selectivity experiments revealed the absence of interference from excipients, recovery from spiked samples for sodium hyaluronate was 98.3–100.9%. The developed method was applied to the determination of sodium hyaluronate in pharmaceutical drug substance and drug product.

Polyoxylglycerides and glycerides: Effects of manufacturing parameters on API stability, excipient functionality and processing

Lipid-based formulations are a viable option to address modern drug delivery challenges such as increasing the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), or sustaining the drug release of molecules intended for chronic diseases. Esters of fatty acids and glycerol (glycerides) and polyethylene-glycols (polyoxylglycerides) are two main classes of lipid-based excipients used by oral, dermal, rectal, vaginal or parenteral routes. These lipid-based materials are more and more commonly used in pharmaceutical drug products but there is still a lack of understanding of how the manufacturing processes, processing aids, or additives can impact the chemical stability of APIs within the drug product. In that regard, this review summarizes the key parameters to look at when formulating with lipid-based excipients in order to anticipate a possible impact on drug stability or variation of excipient functionality. The introduction presents the chemistry of natural lipids, fatty acids and their properties in relation to the extraction and refinement processes. Then, the key parameters during the manufacturing process influencing the quality of lipid-based excipients are provided. Finally, their critical characteristics are discussed in relation with their intended functionality and ability to interact with APIs and others excipients within the formulation.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on 13–14 October 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies without compromising quality. The workshop comprised four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that affect drug impurities and drug degradation products, the control of impurities, and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development approach that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses issues of safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in active Pharmaceutical Ingredient (API) and Drug Products Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms published separately.

Application of independent component analysis on Raman images of a pharmaceutical drug product: Pure spectra determination and spatial distribution of constituents

Independent component analysis (ICA) was used as a blind source separation method on a Raman image of a pharmaceutical tablet. Calculations were performed without a priori knowledge concerning the formulation. The aim was to extract the pure signals from the initial data set in order to examine the distribution of actives and major excipients within the tablet. As a method based on the decomposition of a matrix of mixtures of several components, the number of independent component to choose is a critical step of the analysis. The ICA_by_blocks method, based on the calculation of several models using an increasing number of independent components on initial matrix blocks, was used. The calculated ICA signals were compared with the pure spectra of the formulation compounds. High correlations between the two active principal ingredient spectra and their corresponding calculated signals were observed giving a good overview of the distributions of these compounds within the tablet. Information from the major excipients (lactose and avicel) was found in several independent components but the ICA approach provides high level of information concerning their distribution within the tablet. However, the results could vary considerably by changing the number of independent components or the preprocessing method. Indeed, it was shown that under-decomposition of the matrix could lead to better signal quality (compared to the pure spectra) but in that case the contributions due to minor components or effects were not correctly identified and extracted. On the contrary, over-decomposition of the original dataset could provide information about low concentration compounds at the expense of some loss of signal interpretability for the other compounds.

Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products. Part 1: Predicting Degradation Related Impurities and Impurity Considerations for Pharmaceutical Dosage Forms

The American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues was held on October 13–14, 2012 at the McCormick Place in Chicago, IL, USA. The goal of the workshop was to discuss control strategies of chemical and physical changes of active pharmaceutical ingredients (API) and drug products in the drug development process. These changes can affect both the safety and efficacy of drugs; therefore, the ability to rapidly predict and assess the potential for drug product performance changes for impurity formation and the associated safety concerns are important parts of speeding the development of innovative drug therapies. The workshop consisted of four different sessions. Each session focused on separate fundamental issues to build a comprehensive understanding of the physical and chemical processes that impact drug degradation, the control of impurities and the impact of these factors on safety and regulatory areas. Taken together, this comprehensive understanding is used to achieve a more robust development process that enables predictability with a concomitant assurance of safety and efficacy. Innovative methodologies for development of effective stability control strategies were also presented. This article summarizes Sessions 1 and 2 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues and addresses of predicting degradation related impurities and impurity considerations for pharmaceutical dosage forms. Sessions 3 and 4 of the American Association for Pharmaceutical Scientists (AAPS) Workshop on Predicting and Monitoring Impurities in API and Drug Products: Product Development and Regulatory Issues are summarized in Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient (API) and Drug Products Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying the Impurity Landscape published separately.

A computer aided optimal inventory selection system for continuous quality improvement in drug product manufacture

The multivariate interaction of the raw materials’ physical properties can be critical to the quality of the final drug product. Although an elegant solution to this problem is the establishment of multivariate specifications this becomes difficult (if not impossible) to implement when the interactions take place across materials that are sourced by different vendors. As an alternate solution, this work presents a feed-forward corollary approach to model predictive control (MPC) to improve the product quality from a lot-driven-operation; where there are no available manipulated variables (MV) in the process. In these special cases the only degree of freedom available to be used as a MV for control is the lot-to-lot variability in the raw materials. This work presents an extension to our earlier work (Ind. Eng. Chem. Res. 2013, 52 (17), pp. 5934–5942) to consider a horizon of n lots to be manufactured. By considering this horizon of future lots (rather than just the next one) our method allows the discretionary use of all materials to ensure that the quality of all the future n lots is within specification. This paper presents a detailed discussion of the objective function used and also reports the results of implementing this method to the manufacture of a pharmaceutical drug product in a commercial manufacturing setting.

Population Balance Model Validation and Predictionof CQAs for Continuous Milling Processes: toward QbDin Pharmaceutical Drug Product Manufacturing

Continuous tablet manufacturing has been investigated for its potential advantages (e.g., cost, efficiency, and controllability) over more conventional batch processes. One avenue for tablet manufacturing involves roller compaction followed by milling to form compactible granules. A better understanding of these powder processes is needed to implement Quality by Design in pharmaceutical manufacturing. In this study, ribbons of microcrystalline cellulose were produced by roller compaction and milled in a conical screen mill. A full factorial experiment was performed to evaluate the effects of ribbon density, screen size, and impeller speed on the product size distribution and steady-state mass holdup of the mill. A population balance model was developed to simulate the milling process, and a parameter estimation technique was used to calibrate the model with a subset of experimental data. The calibrated model was then simulated at other processing conditions and compared with additional unused experimental data. Statistical analyses of the results showed good agreement, demonstrating the model’s predictive capability in quantifying milled product critical quality attributes within the experimental design space. This approach can be used to optimize the design space of the process, enabling Quality by Design.

Determination of sodium hyaluronate in pharmaceutical formulations by HPLC–UV

A liquid chromatography (HPLC) method with UV detection was developed for determination of sodium hyaluronate in pharmaceutical formulation. Sodium hyaluronate is a polymer of disaccharides, composed of d-glucuronic acid and d-N-acetylglucosamine, linked via alternating β-1, 4 and β-1, 3 glycosidic bonds. Being a polymer compound it lacks a UV absorbing chromophore. In the absence of a UV absorbing chromophore and highly polar nature of compound, the analysis becomes a major challenge. To overcome these problems a novel method for the determination of sodium hyaluronate was developed and validated based on size exclusion liquid chromatography (SEC) with UV detection. An isocratic mobile phase consisting of buffer 0.05M potassium dihydrogen phosphate, pH adjusted to 7.0 using potassium hydroxide (10%) was used. Chromatography was carried out at 25°C on a BioSep SEC S2000, 300mm×7.8mm column. The detection was carried out using variable wavelength UV–vis detector set at 205nm. The compounds were eluted isocratically at a steady flow rate of 1.0mL/min. Sodium hyaluronate retention time was about 4.9min with an asymmetry factor of 1.93. A calibration curve was obtained from 1 to 38g/mL (r>0.9998). Within-day % RSD was 1.0 and between-day % RSD was 1.10. Specificity/selectivity experiments revealed the absence of interference from excipients, recovery from spiked samples for sodium hyaluronate was 99–102. The developed method was applied to the determination of sodium hyaluronate in pharmaceutical drug substance and product.

Multi-scale flowsheet simulation of an integrated continuous purification–downstream pharmaceutical manufacturing process

Properties of active pharmaceutical ingredients influence the critical quality attributes (CQAs) of final solid dosage forms (e.g. tablets). In the last decade, continuous manufacturing has been shown to be a promising alternative to batch processing in the pharmaceutical industry. Therefore, a quantitative model-based analysis of the influence of upstream API properties on downstream processing quality metrics will lead to enhanced QbD in pharmaceutical drug product manufacturing (Benyahia et al., 2012). In this study, a dynamic flowsheet simulation of an integrated API purification step (crystallization), followed by filtration and drying, with a downstream process (powder mixing) is presented. Results show that the temperature profile of a cooling crystallization process influences the crystal size distribution which in turn impacts the RSD and API concentration of the powder mixing process, which in turn has a direct effect on tablet properties (Boukouvala et al., 2012). A hybrid PBM-DEM model is also presented to demonstrate the coupling of particle-scale information with process-scale information leading to enhanced elucidation of the dynamics of the overall flowsheet simulation.

Methodology for the validation of analytical methods involved in uniformity of dosage units tests

Validation of analytical methods is required prior to their routine use. In addition, the current implementation of the Quality by Design (QbD) framework in the pharmaceutical industries aims at improving the quality of the end products starting from its early design stage. However, no regulatory guideline or none of the published methodologies to assess method validation propose decision methodologies that effectively take into account the final purpose of developed analytical methods. In this work a solution is proposed for the specific case of validating analytical methods involved in the assessment of the content uniformity or uniformity of dosage units of a batch of pharmaceutical drug products as proposed in the European or US pharmacopoeias. This methodology uses statistical tolerance intervals as decision tools. Moreover it adequately defines the Analytical Target Profile of analytical methods in order to obtain analytical methods that allow to make correct decisions about Content uniformity or uniformity of dosage units with high probability. The applicability of the proposed methodology is further illustrated using an HPLC-UV assay as well as a near infra-red spectrophotometric method.

Benefits and Limitations of Infrared Technologies in Omics Research and Development of Natural Drugs and Pharmaceutical Products

Abstract Preclinical Research Properties related to individual or bioactive compounds that constitute the matrix of pharmaceutical and natural drug products (e.g., essential oils, terpenoids, flavonoids, volatile compounds, and other chemicals) are present at low concentrations (e.g., parts per million or parts per billion). Classical separation, chromatographic, and spectrometric techniques such as high‐performance liquid chromatography, gas chromatography, liquid chromatography, and mass spectrometry have been used for the elucidation of isolated compounds in research and development (R&D) of drugs and pharmaceutical products. Hence, the use of standard separation, chromatographic, and spectrometric methods were found useful for fingerprinting and comparing natural and synthetic samples, as well as for identifying single active compounds. However, these methods are time consuming and require some level of preprocessing of the sample before analysis. Over the last four decades, infrared (IR) spectroscopy became one of the most attractive and used methods for analysis of agricultural‐related products and plant materials providing simultaneous, rapid, and nondestructive tool to quantify major constituents in such samples. This review describes the benefits and limitations of IR spectroscopy combined with multivariate data analysis for high‐throughput screening and R&D of natural drugs and pharmaceutical products.

The Application of Uniplex, Duplex, and Multiplex PCR for the Absence of Specified Microorganism Testing of Pharmaceutical Excipients and Drug Products

Notable progress has been made in methods that encourage the use of polymerase chain reaction (PCR) as a rapid and accurate tool in microbiological testing of pharmaceuticals. In this study, the detection of the four main specified microorganisms according to the pharmacopeial recommendations, Salmonella spp, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, was optimized in different pharmaceutical dosage forms and raw materials. Uniplex PCR was performed for the detection of each microorganism individually targeting the conserved region in each bacterial genome. Further optimizations were done to perform duplex and multiplex PCR assays considering relative concentrations of competitor primers used in the reaction. The uniplex PCR amplicons were successfully sequenced, confirming the conservation of used primers. Other validation parameters such as specificity, sensitivity, and robustness were examined closely. The method provides a high-throughput screening method to test different pharmaceutical preparations for specified microorganisms for the detection of microbiological contamination. Strict regulations govern the production of pharmaceutical products whether they are sterile or nonsterile. Certain official tests are carried out in microbiology testing laboratory in any pharmaceutical production facility to ensure the pharmaceuticals microbiological quality according to the standard pharmacopeial recommendations. Nonsterile products must be free of specified microorganisms that are used as a check for their quality. Topical preparations must be free of Pseudomonas aeruginosa and Staphylococcus aureus, and oral preparations must be free of Salmonella spp and Escherichia coli. Conventional microbiological methods are time-consuming, labor-intensive, and require long incubation times, resulting in delaying the release of the products. In this study, we tested and validated a polymerase chain reaction identification approach to detect indicator bacteria in pharmaceutical preparations. The method depends on amplification of certain conserved genes located in the four specified bacteria. The method is optimized to be carried out individually or collectively to detect all indicator bacteria in a single reaction in different forms of pharmaceutical products.

A General Strategy for the Chemical Aspects of the Safety Assessment of Extractables and Leachables in Pharmaceutical Drug Products: The Chemical Assessment Triad

During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. In order to properly assess the risk and manage the hazard posed by migratory substances, it is necessary to establish the identities of the migratory substances and the levels to which they will accumulate in the finished drug product, as these two pieces of information establish the hazard posed by an individual substance and the magnitude of the patient exposure (dose). The process by which migrating compounds are discovered and identified, and by which their accumulation levels in a finished drug product are established, is termed chemical assessment. Because the development of a finished drug product is a long and complicated process, chemical assessment is most typically not a single action but rather a series of actions that together establish a process of risk management. It is the purpose of this manuscript to establish a high-level strategy, illustrated in the chemical assessment triad, which can be applied to such a risk management process. During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. It is the purpose of this manuscript to outline a high-level strategy, illustrated in the chemical assessment triad, to chemically establish the safety risk related to the migrating substances.

Evaluating the taste masking effectiveness of various flavors in a stable formulated pediatric suspension and solution using the Astree™ electronic tongue

Pediatric formulation development requires an understanding of the physico-chemical stability and the taste of the pharmaceutical drug product. Two model active pharmaceutical ingredients (compound X and compound Y) were used to develop a powder for reconstitution to a suspension and a solution dosage form after dilution with purified water. X-ray powder diffraction was used to monitor the physical stability of compound X in the suspension and high pressure liquid chromatography was used to monitor the chemical stability of compound Y in the solution. The most stable suspension (formulation T) and solution (formulation Z) were used to assess the change in taste-perception by different flavors using the Astree™ electronic tongue. The suspension was determined to be stable for 43days and 21days respectively at 5°C and 25°C/60% RH. Compound Y solution was chemically stable for up to 30days at 25°C/60% RH. The taste of the suspension was improved by Lemon and Cherry flavors. The taste of the solution was made better by Vanilla, Cherry, and Strawberry flavors. The significance of these results is that the e-Tongue can be used in the early stages of formulation development to eliminate flavors that do little to improve the palatability of a formulation.

Rapid Simultaneous Determination of Olmesartan, —Amlodipine and Hydrochlorothiazide in Combined Pharmaceutical Dosage form by Stability-Indicating Ultra Performance Liquid Chromatography

A simple, precise and rapid stability-indicating ultra-performance liquid chromatography (UPLC) method was devel-oped for the simultaneous quantitative determination of Olmesartan, Amlodipine and Hydrochlorothiazide from their innovative Pharmaceutical combination drug product, with the presence of degradation products. It involved a 50 mm × 2.1 mm, 1.8 μm Phenyl column. The separation was achieved on simple gradient method. The mobile phase A contains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 90:10, v/v, and mobile phase B con- tains a mixture of sodium perchlorate buffer pH 3.2(0.053M): acetonitrile in the ratio 10:90, v/v. The flow rate was 0.7 mL?min–1 and column temperature was maintained at 55?C.The gradient program (T/%B) was set as 0/10, 2/50, 4/80, and 6.0/10. The detector wavelength was 271 nm for Hydrochlorothiazide, 215 for Olmesartan and 237 nm for Amlodipine. The retention times of Olmesartan, Amlodipine, and Hydrochlorothiazide are 3.5, 3.3 and 0.9 minutes; respectively. The total runtime was 6.0 minutes within which three active compounds and their degradation products were separated. The described method was validated with respect to system suitability, specificity, linearity, precision and accuracy. The precision of the assay method was evaluated by carrying out six independent assays of Olmesartan, Amlodipine, and Hydrochlorothiazide (0.004 mg?mL–1, 0.001 mg?mL–1, 0.0025 mg?mL–1). The accuracy of the method was evaluated in triplicate at three concentration levels, i.e. 50%, 100%, and 150% of target test concentration. The described method was linear over the range, 2 to 6 μg?mL–1 for Olmesartan, 0.5 to 1.5 μg?mL–1 Amlodipine and 1.25 to 3.75 μg?mL–1 for Hydrochlorothiazide. The method is fast and is suitable for high-throughput analysis of the drug and one can analyze about 240 samples per working day, facilitating the processing of large-number batch samples.