Commercial Drug Products Research Articles

Production of salidroside and polysaccharides in Rhodiola sachalinensis using airlift bioreactor systems

Rhodiola sachalinensis is widely used in traditional Chinese medicine, and salidroside and polysaccharides are its important bioactive compounds. This study used airlift bioreactor systems to produce mass bioactive compounds through callus culture. Several factors affecting callus biomass and bioactive compound accumulation were investigated. Callus growth was vigorous in a bioreactor system, and the growth ratio was 2.8-fold higher in bioreactor culture than in agitated-flask culture. Callus biomass and polysaccharide content were favorable at 0.1 air volume per culture volume per min (vvm), whereas favorable salidroside content was observed at a high air volume (0.2 vvm). The maximum yields of salidroside (7.90 mg l−1) and polysaccharide (2.87 g l−1) were obtained at 0.1 vvm. Inoculum density greatly affected callus biomass and bioactive compound accumulation, and the highest biomass and contents or yields of salidroside and polysaccharide were determined at a high inoculum density of 12.5 g l−1. The level of hydrogen ion concentration (pH) at 5.8 improved callus biomass accumulation. Acidic medium (pH 4.8) stimulated salidroside synthesis but higher pH level (7.8) promoted polysaccharide accumulation. The highest yields of both bioactive compounds were obtained at pH 5.8. Methyl jasmonate (MeJA) participated in synthesis promotion of bioactive compounds, and the contents and yields of salidroside [4.75 mg g−1 dry weight (DW), 58.43 mg l−1] and polysaccharides (392.41 mg g−1 DW, 4.79 g l−1) were at maximum at 125 and 150 μmol of MeJA. Therefore, bioreactor systems can be used to produce R. sachalinensis bioactive compounds, and callus culture in a bioreactor can be as an alternative method for supplying materials for commercial drug production.

Quantification of impurities in commercial drug products containing montelukast and evaluation of the impurities’ cytotoxic effects

Quantification of impurities in commercial drug products containing montelukast and evaluation of the impurities’ cytotoxic effects

The Assessment of Impurities for Genotoxic Potential and Subsequent Control in Drug Substance and Drug Product

The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.

In Vitro and In Vivo Evaluation of Oxatomide β -Cyclodextrin Inclusion Complex.

The objective of this study was to evaluate the influence of oxatomide β-cyclodextrin inclusion complex on the physicochemical properties and bioavailability of the drug. Oxatomide β-cyclodextrin solid complex was prepared with equimolar ratio of both oxatomide and β-cyclodextrin in presence or absence of water soluble polymers using different techniques. The coevaporated complex prepared in presence of PVP-K15 showed a prompt drug release and significantly increased % dissolution efficiency (P < 0.05) compared to the pure oxatomide. Moreover, the results of bioavailability evaluation of this complex in rabbits compared to commercial drug product indicated a 73.15% increase in the oral bioavailability of oxatomide. In conclusion, inclusion complex of oxatomide with β-cyclodextrin prepared by coevaporation in presence of PVP-K15 not only results in an enhancement of the oxatomide dissolution rate but also improves the bioavailability of oxatomide.

Physicochemical Interactions in Solid Dosage Forms

Complete characterization and mechanistic understanding of physicochemical interactions in solid dosage forms are not only important for consistent manufacturability, stability, and bioavailability of the drug product, but are also expected under the quality-by-design paradigm of drug development. Lack of this understanding can impact successful and timely development, scale-up, and commercial manufacture of dosage forms. This article highlights the stability and bioavailability implications of physicochemical interactions in dosage forms citing a couple of examples where such interactions necessitated the recall of commercial drug products.

Nanoparticles in the Pharmaceutical Industry and the Use of Supercritical Fluid Technologies for Nanoparticle Production

Poor aqueous solubility of drug candidates is a major challenge for the pharmaceutical scientists involved in drug development. Particle size reduction appears as an effective and versatile option for solubility improvement. Nanonization is an attractive solution to improve the bioavailability of the poorly soluble drugs, improved therapies, in vivo imaging, in vitro diagnostics and for the production of biomaterials and active implants. In drug delivery, application of nanotechnology is commonly referred to as Nano Drug Delivery Systems (NDDS). In this article, commercially available nanosized drugs, their dosage forms and proprietors, as well as the methods used for preparation like milling, high pressure homogenization, vacuum deposition, and high temperature evaporation were listed. Unlike the traditional methods used for the particle size reduction, supercritical fluid-processing techniques offer advantages ranging from superior particle size control to clean processing. The primary focus of this review article is the use of supercritical CO2 based technologies for small particle generation. Particles that have the smooth surfaces, small particle size and distribution and free flowing can be obtained with particular SCF techniques. In almost all techniques, the dominating process variables may be thermodynamic and aerodynamic in nature, and the design of the particle collection environment. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three groups of processes which lead to the production of fine and monodisperse powders. Few of them may also control crystal polymorphism. Among the aforementioned processes, RESS involves dissolving a drug in a supercritical fluid (SCF) and passing it through an appropriate nozzle. Rapid depressurization of this solution causes an extremely rapid nucleation of the product. This process has been known for a long time but its application is limited. Carbon dioxide, which is the only supercritical fluid that is preferentially used in pharmaceutical processes, is not a good solvent for many Active Pharmaceutical Ingredients (API). Various researchers have modified the RESS process to overcome its solubilizing limitations, by introducing RESOLV, RESAS, and RESS-SC. Overall, all RESS based processes are difficult to scale up. The SAS processes are based on decreasing the solvent power of a polar organic solvent in which the substrate (API & polymer of interest) is dissolved, by saturating it with carbon dioxide (CO2) at supercritical conditions. CO2 causes precipitation and recrystalization of the drug. SAS is scalable and can be applied to a wide variety of APIs and polymers. Minor modifications of basic SAS process include GAS, ASES, SAS-DEM and SAS-EM. Processes where SCF is used as an anti solvent and dispersing agent include SEDS, SAA, and A-SAIS. The mechanisms and applications of these processes were briefly discussed. In PGSS, CO2 is dissolved in organic solutions or melted compounds and it is successfully used for manufacturing drug products as well as for drying purposes. The two widely used methods, PGSSdrying and CAN-BD SCF, were also included in discussions. Among the limitations of the techniques involved, the poor solvent power of CO2, the cost and necessity of voluminous usage of the CO2 can be mentioned. There is still confusion in contribution of each variable on the particle morphology and properties regardless of the number of mechanistic studies available. The advantages of especially SAS and PGSS based techniques are the production of the nano or micro sized spherical particles with smooth surfaces and narrow particle size distribution. Regardless of its advantages, the reasons why 25 years of active research, and more than 10 years of process development could not promote the use of (SCF) technology, and produced only few commercial drug products, necessitate further evaluation of this technique.

Capillary Electrophoresis for Simultaneous Analysis of Heparin, Chondroitin Sulfate and Hyaluronic Acid and its Application in Preparations and Synovial Fluid

A simple and accurate capillary electrophoresis (CE) method was developed to simultaneously separate and quantify heparin, chondroitin sulfate and hyaluronic acid. The relative standard deviations (intra-day) of migration time, peak height and peak area for heparin, chondroitin sulfate and hyaluronic acid were lower than 1.11, 5.45 and 2.82%, respectively. The limits of detection of heparin, chondroitin sulfate and hyaluronic acid were 0.91, 0.12 and 9.04 × 10(-3) mg/mL, respectively. The developed electrophoretic method was successfully applied to the analysis of commercial drug products and biological samples containing chondroitin sulfate and/or hyaluronic acid. The recoveries for chondroitin sulfate and hyaluronic acid were in the range of 95.9 ~107.0%. This was the first time the content of hyaluronic acid in the synovial fluids from osteoarthritic rabbits was investigated by CE. The results suggested that hyaluronic acid in the synovial fluids from osteoarthritic rabbits may be further metabolized and the administration of chondroitin sulfate or hyaluronic acid could affect the content and metabolism of hyaluronic acid in the synovial fluids. The developed CE method was simple to implement without sample pretreatment such as depolymerisation, very repeatable and easily transferred from lab to lab.

Ion Beam Analysis and PD-MS As New Analytical Tools for Quality Control of Pharmaceuticals: Comparative Study from Fluphenazine in Solid Dosage Forms

In order to evaluate the potential of accelerator based analytical techniques ((particle induced X-ray emission (PIXE), particle induced gamma-ray emission (PIGE), and particle desorption mass spectrometry (PD-MS)) for the analysis of commercial pharmaceutical products in their solid dosage form, the fluphenazine drug has been taken as a representative example. It is demonstrated that PIXE and PIGE are by far the best choice for quantification of the active ingredient (AI) (certification with 7% precision) from the reactions induced on its specific heteroatoms fluorine and sulfur using pellets made from original tablets. Since heteroatoms cannot be present in all types of drugs, the PD-MS technique, which makes easily the distinction between AI(s) and excipients, has been evaluated for the same material. It is shown that the quantification of AI is obtained via the detection of its protonated molecule. However, calibration curves have to be made from the secondary ion yield variations since matrix effects of various nature are characteristics of such mixtures of heterogeneous materials (including deposits from soluble components). From the analysis of solid tablets, (either transformed into pellets and even as received), it is strongly suggested that the physical state of the grains in the mixture is a crucial parameter in the ion emission and accordingly for the calibration curves. As a result of our specific (but not optimized) conditions the resulting precision is <17% with an almost linear range extending from 0.04 to 7.87 mg of AI in a tablet made under the manufacturer conditions (the commercial drug product is labeled at 5 mg).

Creation and application of psychoactive designer drugs data library using liquid chromatography with photodiode array spectrophotometry detector and gas chromatography–mass spectrometry

In order to quickly confirm a potentially hazardous psychoactive designer drug (a compound in which part of the molecular structure of a stimulant or narcotic has been modified), we created a psychoactive drugs data library by performing analysis using liquid chromatography with photodiode array spectrophotometry (LC/PDA) and gas chromatography–mass spectrometry (GC/MS). The data in this library consist of the LC capacity factor ( k′) ratios in relation to the internal standard, the ultraviolet (UV) spectra and the MS spectra of 104 compounds. By performing a comparative study of the data in this report with the analytical data for commercial and illegal drug products, it is possible to quickly identify the psychoactive designer drugs in 205 purchased products by using the library. Further, it is possible to analogize the structure of drugs for which there is no matching data in the library using similar data. Furthermore, when structural isomers of controlled substances have detected from the presented library, similarity of their biological effects on human will be predicted, thus leading to regulate their public circulation. Examples of these types of isomers include, for instance, the narcotic 3,4,5-trimethoxyamphetamine (TMA) and its positional isomers 2,4,5-trimethoxyamphetamine (TMA-2) and 2,4,6-trimethoxyamphetamine (TMA-6), or the narcotic 1-(3-chlorophenyl)piperazine (3CPP) and its isomers 1-( o-chlorophenyl)piperazine (2CPP) and 1-( p-chlorophenyl)piperazine (4CPP). Differentiation of these compounds is necessary in regulating them, and we report here the results of a study of a method to confirm these compounds using the present library.

Evaluation of mean arterial blood pressure, heart rate, and sympathetic nerve activity in rabbits after administration of two formulations of etomidate

ObjectiveTo evaluate and compare the effects of the aqueous sulfobutyl ether β-cyclodextrin (SBE-CD) etomidate formulation and the commercial etomidate formulation on mean arterial pressure (MAP), heart rate, and sympathetic outflow using neuraxis-intact and baro-denervated rabbits. Study designProspective experimental study. AnimalsTwenty-seven male New Zealand white rabbits. MethodsUnder basal anesthesia (urethane) and ventilation with intermittent positive pressure (IPPV), the New Zealand white rabbits underwent surgical preparation including isolation of the left renal sympathetic nerve and, in the baro-denervated models, additional combined denervation of bilateral carotid sinus, aortic, and vagal nerves. After hemodynamic stabilization, both neuraxis-intact and baro-denervated animals received bolus intravenous (IV) injection (0.6 mg kg−1) of either the SBE-CD or commercial etomidate formulation over 5 seconds (n = 6 animals per group). ResultsMean arterial pressure decreased significantly in all four groups to the same extent. However, the rate of MAP decrease was lower in the SBE-CD-treated groups relative to the commercial formulation. Renal sympathetic nerve activity was decreased significantly less in the SBE-CD group in the baro-denervated studies. Independent pharmacokinetic evaluation demonstrated that the two formulations had comparable plasma concentration–time profiles. Conclusions and Clinical relevanceEtomidate in the commercial drug product is solubilized with propylene glycol, a cosolvent associated with adverse side effects on injection. An aqueous formulation of etomidate has been developed, which utilizes SBE-CD as a solubilizing agent. The data suggest that the SBE-CD etomidate formulation may be a safer IV induction formulation than the commercial etomidate drug product.

Tetrazole compounds: The effect of structure and pH on Caco-2 cell permeability

A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate.

In vitro and in vivo evaluation of a sulfobutyl ether β‐cyclodextrin enabled etomidate formulation

In this study, we report the formulation and in vivo evaluation of etomidate in an aqueous solution using sulfobutyl ether‐7 β‐cyclodextrin (SBE‐CD, Captisol®) as a solubilizing agent. The phase‐solubility behavior of etomidate as a function of SBE‐CD concentration was evaluated, and accelerated solution stability studies of 2mg/mL etomidate in a 5% w/v SBE‐CD solution were conducted. The intravenous administration of the SBE‐CD etomidate formulation in dogs was compared with Amidate®, the commercial etomidate drug product formulated with propylene glycol as a cosolvent. The etomidate plasma concentration‐time data were fit to a three‐compartment mamillary model and the derived standard pharmacokinetic parameters were not statistically different between the two formulations (n = 4, p > 0.050). Concurrent pharmacodynamic analysis provided statistically equivalent maximum effects and median inhibitory concentrations for the two formulations. In vivo hemolysis after intravenous administration of Amidate® was 10‐fold higher than the SBE‐CD formulation. Whereas Amidate® cannot be given subcutaneously because of the cosolvent in the formulation, a 12mg/mL aqueous solution of etomidate in 20% (w/v) SBE‐CD was well tolerated by this route. The results suggest that the SBE‐CD formulation is a viable clinical drug product with a reduced side‐effect profile.

Qualitative and quantitative study of polymorphic forms in drug formulations by near infrared FT-Raman spectroscopy

Near infrared FT-Raman spectroscopy was applied for the determination of polymorphic forms in a number of commercial drug products containing the polymorphic drug compounds sorbitol, mannitol, famotidine, acemetacin, carbamazepine, meprobamate and phenylbutazone. The crystal forms present in the drug products were identified based on the position, intensity and shape of characteristic bands. Quantitative analysis of a mixture of two crystal forms of mannitol in a drug product was carried out using a partial least-squares method. In drug products containing meprobamate, sorbitol, and carbamazepine, the thermodynamically stable form was found exclusively, whereas metastable polymorphs were found in solid dosage forms of acemetacin, phenylbutazone, famotidine and mannitol. A mixture of two polymorphic forms of mannitol in Lipobay tablets was determined to consist of 30.8±3.8% of the metastable modification I. The simple sample preparation, the occurrence of sharp bands in the spectra as well as the high reproducibility and accuracy qualifies FT-Raman spectroscopy for the identification and quantification of crystal forms in drug products. The method is perfectly suited to meet the regulatory requirements of monitoring crystal forms during processing and storage and often succeeds in detecting the present crystal form in drug products even when the used excipients are not known.

Gas turbine installations with divided expansion : Cårdu, M. and Baica, M. Energy Conversion and Management, 2002, 43, (13), 1747–1756

The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.

Rare wild plants of potential or current economic importance in Canada — a list of priorities

A priorization system based on dollar value of plant, degree of relationship to economic genotype, and rarity status was applied to rare plants in Canada. This resulted in priorization of 56 taxa, approximately 1% of wild plants of Canada. Most of these taxa are native species, but a few are infraspecific taxa, and some are introduced. Most of the priorized taxa are plants of the Carolinian region of extreme southern Ontario, which is part of the Mixedwood Plains Ecozone. The provinces with the highest numbers were Ontario with 38, British Columbia with 9, Quebec with 8 and Manitoba with 7. Crops, crop relatives and forages accounted for 38 of the taxa. Twelve were plants providing ingredients for commercial drug products or health foods. Nine were sources of wood. Five were plants used in landscape gardening, land reclamation or erosion control. Native berry producing plants, i.e. relatives of clonal crops for which Canada contains significant germplasm on a world scale, were the largest economic group with 18 taxa. Twenty-six of the priorized plants were herbs, 17 were shrubs and 13 were trees. The genera Amelanchier and Linum were the largest taxonomic groups, each with four taxa. The list and related geographic data can be used to orient monitoring and management, to select and acquire material for ex situ protection, and to select and priorize sites for in situ protection. Key words: Germplasm, protection, rare plants, crops, pharmaceuticals, ornamentals, medicinal plants

Validation in Research and Development —What is Appropriate?

Validation is a concept that has expanded considerably in scope since the mid-1970s (1–5). It has a nebulous quality caused by differing definitions, interpretations of guidelines, nomenclature and perceived changes in application. Initially introduced to assure the processes used in commercial drug product manufacture, validation requirements inexorably began to include the equipment, facilities and utilities supporting those processes. Subsequently, the need for validation has spread to both earlier in the production chain (drug substance manufacture) and to earlier in the development process (research, development and pilot operations and supporting analytical laboratories). It is now established that validation is required for the manufacture of drug substances and drug products according to Good Manufacturing Practices (GMPs), for use in clinical trials and also to assure the data from preclinical studies conducted to Good Laboratory Practices (GLPs). The problem is to translate the rules devised for routine production and apply them to research and development (R&D). This paper describes the hierarchical structure of validation as applied to GMP operations, details how programmes are administered and executed and suggests how much validation is expected by the regulatory authorities for both GMP and GLP activities. Also included are brief accounts of computer and cleaning validation as applied to research and development.

Investigation of Dissolution Profiles from Suspensions Containing Benzoyl Metronidazole Using a Statistical Model with Repeated Measurements

AbstractThe Mexican Pharmacopeia (MP) dissolution general test was carried out on one and two lots of suspensions from each one of three commercial drug products, containing benzoyl metronidazole, and using water or 0.1 N hydrochloric acid as dissolution medium. When we used paddles at 100 rpm, and water as dissolution medium, 72 to 99% of the active substance was dissolved after 60 minutes, showing differences between the dissolution profiles from these drug products. When testing conditions were changed to 0.1 N hydrochloric acid at 75 r.p.m., the amount dissolved of active substance varied from 25 to 100%, showing different dissolution rate profiles for all 6 drug products.The ANOVA for the statistical model with repeated measurements was applied to the observed dissolution rate data, showing no parallel behaviour between each dissolution profile. Using the ANOVA for nested models, and the hydrochloric acid data to investigate the dissolution efficiency, we found intraclass difference but no interclass...

Collaborative Study of the Analysis of Acetaminophen and Salicylamide in Tablets and Capsules

Abstract A column chromatographic procedure has been developed for separating acetaminophen and salicylamide in combination with a variety of other drug ingredients in tablets and capsules. Strongly acidic and basic Celite columns are used to trap acetaminophen and salicylamide, respectively. Quantitation is performed using UV spectrophotometry. Identifications are made by the infrared KBr technique on a portion of the column eluates. A collaborative study of the method was conducted. Average recoveries of 99.45% for acetaminophen and 100.9% for salicylamide were obtained for a synthetic standard mixture. The study also included 3 commercial drug products which were assayed for acetaminophen and salicylamide.