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Drug Substance (drug + substance)
Selected AbstractsDrug substances presented as sulfonic acid salts: overview of utility, safety and regulationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2009David P. Elder Abstract Objectives Controlling genotoxic impurities represents a significant challenge to both industry and regulators. The potential for formation of genotoxic short-chain alkyl esters of sulfonic acids during synthesis of sulfonic acid salts is a long-standing regulatory concern. This review provides a general overview of the utility of sulfonic acids as salt-forming moieties and discusses strategies for effectively minimizing the potential for alkyl sulfonate formation during the synthesis and processing of sulfonate salt active pharmaceutical ingredients. The potential implications of the recent establishment of a substantial human threshold dose for ethyl methanesulfonate for the safety assessment of alkyl sulfonates in general are also discussed. Key findings The formation of alkyl sulfonates requires highly acidic conditions, possibly combined with long reaction times and/or elevated temperatures, to generate significant amounts, and these conditions are most unlikely to be present in the synthesis of active pharmaceutical ingredient sulfonate salts. It is possible to design salt formation conditions, using a short-chain alcohol as solvent, to manufacture sulfonate salts that are essentially free of alkyl sulfonate impurities. Processes using non-acidic conditions such as ethanol recrystallization or wet granulation should not raise any concerns of alkyl sulfonate formation. Summary An understanding of the mechanism of formation of alkyl sulfonates is critical in order to avoid restricting or over-controlling sulfonic acid salts, which have many technical advantages as pharmaceutical counterions. Recent regulatory acceptance of a human threshold limit dose of 2 mg/kg per day for ethyl methanesulfonate, indicating that its toxicological risks have previously been considerably overestimated, could signal the beginning of the end over safety concerns on alkyl sulfonate residues, thus removing a major constraint from the exploitation of sulfonic acid counterions. [source] Cyclodextrin-based nonaqueous electrokinetic chromatography with UV and mass spectrometric detection: Application to the impurity profiling of amiodarone,ELECTROPHORESIS, Issue 17 2008Roelof Mol Abstract The potential of nonaqueous electrokinetic chromatography (NAEKC) using cyclodextrins (CD) for the analysis of basic drugs and related compounds was evaluated. Both UV absorbance and mass spectrometric (MS) detection were employed. Addition of neutral CD to the NA background electrolyte did not significantly enhance the separation of a test mixture of basic drugs, and no change in selectivity was observed. In contrast, anionic single-isomer-sulfated CD strongly added to the selectivity of the NAEKC system inducing an improved resolution among the test compounds and increasing the migration time window. The applicability of the NAEKC system using anionic CD is demonstrated by the profiling of a sample of the drug amiodarone that had been stored for 1,year at room temperature. Amiodarone is poorly soluble in water. NAEKC-UV analysis indicated the presence of at least seven impurities in the amiodarone sample. In order to identify these compounds, the NAEKC system was coupled directly to electrospray ionization (ESI) ion-trap MS. The total of detected impurities increased to 12 due to the added sensitivity and selectivity of MS detection. Based on the acquired MS/MS data, three sample constituents could be identified as ,known' impurities (British Pharmacopoeia), whereas for three unknown impurities molecular structures could be proposed. Estimated limits of detection for amiodarone using the NAEKC method were 1,,g/mL with UV detection and 15,ng/mL with ESI-MS detection (full-scan). Based on relative responses, the impurity content of the stored drug substance was estimated to be 0.33 and 0.47% using NAEKC-UV and NAEKC-ESI-MS, respectively. [source] Chiral separation of cetirizine by capillary electrophoresisELECTROPHORESIS, Issue 12 2006Ann Van Eeckhaut Abstract Chiral separation of cetirizine, a second-generation H1 -antagonist, was studied by CD-mediated CE. Several parameters, including pH, CD type, buffer concentration, type of co-ion, applied voltage and temperature, were investigated. The best conditions for chiral separation were obtained using a 75,mM triethanolamine-phosphate buffer (pH,2.5) containing 0.4,mg/mL heptakis(2,3-diacetyl-6-sulfato)-,-CD and 10%,ACN. Online UV detection was performed at 214,nm, a voltage of 20,kV was applied and the capillary was temperature controlled at 25°C by liquid cooling. Hydrodynamic injection was performed for 1,s. The method was validated for the quantification of levocetirizine in tablets and for enantiomeric purity testing of the drug substance. Selectivity, linearity, LOD and LOQ, precision and accuracy were evaluated for both methods. The amount of levocetirizine dihydrochloride in the commercially available tablets was quantified and was found to be within the specification limits of the claimed amount (5,mg). The amount of distomer in levocetirizine drug substance was found to be 0.87 ± 0.09%,w/w, which is in agreement with the certificate of analysis supplied by the company. [source] A randomized, double-blind trial demonstrating bioequivalence of the current recombinant activated factor VII formulation and a new robust 25°C stable formulationHAEMOPHILIA, Issue 5 2007B. V. BYSTED Summary., Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven®) and a new rFVIIa formulation (VII25) stable at up to 25°C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 ,g kg,1, in a randomized order 2,3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89,0.96), within the predefined bioequivalence range (0.80,1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25°C. VII25's ,user-friendly' formulation removes the inconvenience of storing/transporting at 2,8°C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained. [source] In-line measurement of a drug substance via near infrared spectroscopy to ensure a robust crystallization processJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2006George X. Zhou Abstract The crystallization of Etoricoxib, a polymorphic compound, has been optimized and controlled by seeding with the desired polymorph at a moderate supersaturation condition. To enhance the process robustness, near infrared spectroscopy (NIRS) has been evaluated as an inline measurement method for the concentration of Etoricoxib prior to seeding in the crystallization process. In this NIRS method, a spectral discriminant analysis based on principal component analysis (PCA) was established to detect the presence of solids produced by premature crystallization, or bubbles in the path of light. Once a spectrum was qualified as that of clear solution, concentration of Etoricoxib was calculated by a NIRS calibration model built with partial least squares (PLS) regression and with offline HPLC analysis as the reference method. This model was accurate with a standard error of cross validation (SECV) less than 1.2 mg/g Etoricoxib and a standard error of prediction (SEP) less than 1.7 mg/g over the concentration range from 50 to 170 mg/g, temperature range from 49 to 65°C, and different sources of materials. In addition, all aspects of the offline HPLC method, especially the sampling procedure, were optimized to provide an accurate reference for NIRS calibration models. The application of this method at a pilot plant has demonstrated its capability of accurately measuring the process concentration of Etoricoxib as well as detecting the presence of solids produced by premature crystallization before seeding. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:2337,2347, 2006 [source] Immediate drug release from solid oral dosage formsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2005Thomas Schreiner Abstract Fast drug release from solid dosage forms requires a very fast contact of the vast majority of the drug particles with the solvent; this, however, is particularly delayed in tablets and granulations. Starch and cellulose substances favor the matrix disintegration during the starting phase and the generation of the effective dissolution surface of the drug substance, thereby. To investigate the very complex interrelation between the functionality of commonly used excipients and the structural effects of the production processes, wettability, porosity, water uptake, and drug release rates of several ketoprofen-excipient preparations (powder blends, granulations, tablets) were measured. Significant linear correlation between these parameters, however, was not achieved; only qualitative tendencies of the effects could be detected. In consequence, a general mathematical model describing the mechanistic steps of drug dissolution from solid dosage forms in a fully correct way was not realized. However, the time-dependent change of the effective dissolution surface follows stochastic models: a new dissolution equation is based on the differential Noyes-Whitney equation combined with a distribution function, e.g. the lognormal distribution, and numerically solved with the software system EASY-FIT by fitting to the observations. This new model coincides with the data to a considerably higher degree of accuracy than the Weibull function alone, particularly during the starting, matrix disintegration, and end phases. In combination with a procedure continuously quantifying the dissolved drug, this mathematical model is suitable for the characterization and optimization of immediate drug release by the choice and modification of excipients and unit operations. The interdependence of some characteristic effects of excipients and production methods is discussed. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:120,133, 2005 [source] General pharmaceutics,The new physical pharmacyJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2003E. F. "Gene" Fiese Abstract General Pharmaceutics is proposed as the broad study of the biopharmaceutical and physical chemical properties of each potential drug substance. When the first quality bulk lot is delivered, usually the first GMP bulk lot, an extensive profiling of the potential drug substance should commence. This profile should include solid-state characterization as well as thorough analyses of solubility, stability, and absorption properties of the drug substance that could affect the development of a viable medicine. As a result of these studies, a number of initial specifications could be developed: the preferred polymorphic or crystalline form identified, the preferred particle size to optimize absorption/development, and an initial biopharmaceutics classification with a dose limit to identify those cases in which the formulation can be expected to improve absorption and exposure. The broad topic of General Pharmaceutics is discussed in this Minireview including many advances in technology in this field as well as the rationale behind the proposed initial specifications. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1331,1342, 2003 [source] Formulation and food effects on the oral absorption of a poorly water soluble, highly permeable antiretroviral agentJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2002Bruce J. Aungst Abstract DPC 961 is a low-solubility, high-permeability, second-generation non-nucleoside reverse transcriptase inhibitor. The purpose of these studies was to evaluate the effects of drug substance and formulation variables on DPC 961 oral absorption, and to compare fed and fasted state oral absorption. To accomplish this, groups of four to six dogs were dosed with various formulations of DPC 961 under fasted or fed conditions, and DPC 961 pharmacokinetics were examined. Absolute oral bioavailability, based on i.v. AUC in the same dogs, was 24% after a suspension dose in fasted dogs and was 51% in fed dogs. Bioavailability with an unoptimized tablet formulation was 30% in fasted dogs and 86% in fed dogs. DPC 961 oral absorption was shown to be dependent on drug substance particle size in fasted dogs, after dosing with a tablet formulation where only the drug substance particle size was varied, but there was no difference in fed dogs. AUC and Cmax increased in proportion with increases in tablet strength from 100 to 400 mg, using tablets manufactured from a common granulation. Tablets made with 50 and 66% drug loadings showed similar relative oral bioavailabilities. Tablets prepared with two different polymorphic forms of DPC 961 were also compared, and these were found to be equivalent. These studies provided a useful component of the formulation development process, to help identify and control the variables affecting oral absorption of this potential new therapeutic agent. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1390,1395, 2002 [source] Method for enantiomeric purity of a quinuclidine candidate drug by capillary electrophoresisJOURNAL OF SEPARATION SCIENCE, JSS, Issue 13 2006Tore Ramstad Abstract A chiral procedure based on EKC was developed and validated for determination of the enantiomeric purity of PHA-543613, a drug candidate that was under development for treatment of the cognitive deficits of Alzheimer's disease and schizophrenia. Separation of enantiomers is accomplished via differential, enantiospecific complexation with a single-isomer, precisely sulfated beta-CD and heptakis-6-sulfato-,-CD (HpS-,-CD). Both neutral and sulfated CDs were screened before selecting HpS-,-CD as the chiral selector. The separation is conducted in a 61 cm×50 ,m uncoated fused silica capillary with 25 mM HpS-,-CD in pH 2.50, 25 mM lithium phosphate as the separation buffer with detection at 220 nm. Application of reverse polarity at ,30 kV results in an elution time of about 12 min for PHA-543613 and 13 min for the undesired S -enantiomer. Quantification is versus an authentic reference S -enantiomer as an external standard in combination with an internal standard. The procedure was validated over the range 0.1,2.0% w/w. The detection limit is 0.01,0.02%. The amount of distomer intrinsic to the drug substance is about 0.1% or less. The developed method was used to generate stability data on multiple lots: in one case for up to 3 years. [source] (203) Manufacturing Process for a Highly Purified, Stable Liquid Formulation of Botulinum Toxin Type B (MyoblocÔ)PAIN MEDICINE, Issue 3 2001Andrew Grethlein Botulinum toxin type B (BoNT-B; MyoblocÔ) is a new botulinum toxin with demonstrated efficacy in patients with cervical dystonia, and has been found to decrease neck pain associated with this disorder. Developmental work has led to the commercial-scale production of a uniform, highly purified toxin complex in a liquid formulation. Production of BoNT-B involves fermentation, recovery and purification from Clostridium botulinum. The reliability and robustness of the process were tested by altering critical process parameters (eg, pH, temperature) and showing that a high-quality product resulted even in conditions detrimental to C botulinum fermentation. Consistency and key quality attributes (purity, complex integrity, percent nicking, specific activity) of the toxin were assessed using a series of biochemical tests, which were validated as precise and accurate and are now routinely used in quality control analysis. Results confirmed production of an intact, uniform toxin complex with consistent purity, percentage nicking (a measure of toxin activation) of over 70%, and specific activity over 90 U/ng in three manufacturing runs. BoNT-B is manufactured as a slightly acidic liquid formulation that maintains complex integrity, reducing the potential for generating neutralizing antibodies. The potency of drug substance, dilute bulk solution, and finished product was shown to be reliable using the validated mouse intraperitoneal LD50 potency assay. The liquid formulation of BoNT-B was found to be stable for at least 9 months at 25°C and at least 3 years at 2,8°C. BoNT-B has a long shelf-life and may be produced on a commercial scale reliably and reproducibly, making it readily available and convenient to store and use. Support of Elan Pharmaceuticals is gratefully acknowledged. [source] The use of particle beam mass spectrometry for the measurement of impurities in a nabumetone drug substance, not easily amenable to atmospheric pressure ionisation techniquesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 4 2001Jean-Claude Wolff Liquid chromatography/particle beam mass spectrometry (LC/PB-MS) was used for the structural elucidation of some impurities in nabumetone as this compound poorly ionises by atmospheric pressure ionisation (API) techniques. PB-MS was optimised for nabumetone and a sensitivity study was carried out. To obtain full scan electron ionisation spectra a minimum of 100,ng of compound on column was needed. By using 20,mg/mL solutions of nabumetone, impurities at levels of about 250,ppm mass fraction relative to nabumetone could be detected. Results were compared with LC/API-MS and previous GC/MS. Copyright © 2001 John Wiley & Sons, Ltd. [source] Variability and Impact on Design of Bioequivalence StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Achiel Van Peer Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75,133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003,2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe. [source] Skin disposition of menthol after its application in the presence of drug substancesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Krzysztof Cal Abstract Many drug products that are applied onto the skin contain menthol. Menthol plays a dual role in the analgesic and anti-inflammatory drugs: it causes cooling and local anesthetic effects and, being a penetration enhancer, it increases the skin permeation of the drug substances. However, there are no data concerning the skin penetration of menthol after its application in the most commonly used vehicles and in the presence of drug substances. Therefore, this study evaluated the ex vivo skin disposition of menthol after application of the commercially available drug products containing aluminum acetotartrate, methyl salicylate, ibuprofen and naproxen, using full human-skin mounted in flow-through diffusion cells. After 15, 30 and 60,min of application, the skin was progressively tape-stripped into three fractions of stratum corneum and the remaining epidermis with dermis. The content of menthol in the skin layers was determined by GC method. Varying degrees of penetration of menthol into the skin layers was observed, depending on its amount in the vehicle and the presence of drug substance. In the presence of aluminum acetotartrate, the skin penetration of menthol was limited only to the outer fraction of the stratum corneum. In the case of drug products containing naproxen, the concentration of the drug substance significantly influenced the skin penetration of menthol. Copyright © 2008 John Wiley & Sons, Ltd. [source] Impact of freezing on pH of buffered solutions and consequences for monoclonal antibody aggregationBIOTECHNOLOGY PROGRESS, Issue 3 2010Parag Kolhe Abstract Freezing of biologic drug substance at large scale is an important unit operation that enables manufacturing flexibility and increased use-period for the material. Stability of the biologic in frozen solutions is associated with a number of issues including potentially destabilizing pH changes. The pH changes arise from temperature-associated change in the pKas, solubility limitations, eutectic crystallization, and cryoconcentration. The pH changes for most of the common protein formulation buffers in the frozen state have not been systematically measured. Sodium phosphate buffer, a well-studied system, shows the greatest change in pH when going from +25 to ,30°C. Among the other buffers, histidine hydrochloride, sodium acetate, histidine acetate, citrate, and succinate, less than 1 pH unit change (increase) was observed over the temperature range from +25 to ,30°C, whereas Tris-hydrochloride had an ,1.2 pH unit increase. In general, a steady increase in pH was observed for all these buffers once cooled below 0°C. A formulated IgG2 monoclonal antibody in histidine buffer with added trehalose showed the same pH behavior as the buffer itself. This antibody in various formulations was subject to freeze/thaw cycling representing a wide process (phase transition) time range, reflective of practical situations. Measurement of soluble aggregates after repeated freeze,thaw cycles shows that the change in pH was not a factor for aggregate formation in this case, which instead is governed by the presence or absence of noncrystallizing cryoprotective excipients. In the absence of a cryoprotectant, longer phase transition times lead to higher aggregation. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] 2165: Microplasmin as an antiscarring agent for glaucoma surgery: translation into clinical applicationACTA OPHTHALMOLOGICA, Issue 2010E VANDEWALLEArticle first published online: 23 SEP 2010 Purpose Previously Microplasmin was investigated in a rabbit model for trabeculectomy. The combination of intracameral injections and topical drops of Microplasmin improved surgical outcome. The aqueous solution of Microplasmin used, was not optimized for use as drops or injections. Microplasmin is an autocatalytic enzyme which has a short half life when it is brought in conditions of 37°C and physiological pH. Therefore there is need for a more stable and longer acting formulation. Methods Firstly we will do pharmacological experiments to determine the rheological characterization of drug carriers with Carrier-med rheometer. Then we will define the purity of Microplasmin bulk drug substance by RP-HPLC. Finally, we will check the Microplasmin activity in the new obtained solutions by spectrophotometer. Secondly we will perform trabeculectomy in a rabbit model and administer the most qualified and optimized formulations. Postoperative clinical evaluation of IOP, bleb area, conjunctival vascularity and anterior chamber assessment will be performed. The eyes will be immunohistological investigated for collagen and inflammation. Conclusion Our previous data learned that the combination therapy of Microplasmin improved surgical outcome in a rabbit model, despite the fact that the formulation of Microplasmin was not optimized for use as drops or injections. Our proposed research project will optimize the formulation of Microplasmin for extended drug delivery and determine the optimal administration route and regimen. We believe that this project will allow us to further improve the positive animal data, translate this novel antifibrotic adjunctive therapy into clinical application, and thus improve the outcome after trabeculectomy in patients. [source] An in,vitro Assay to Measure Targeted Drug Delivery to Bone MineralCHEMMEDCHEM, Issue 5 2010Wolfgang Jahnke Dr. Abstract Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in,vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance. [source] Determination of the enantiomeric excess of an M3 antagonist drug substance by chemometric analysis of the IR spectra of different guest-host complexesCHIRALITY, Issue 5 2006Lili Zhou Abstract A novel approach for the potential on-line determination of the enantiomeric excess (ee) of an M3 antagonist drug substance combining attenuated total reflectance infrared (ATR-IR) spectroscopy, guest-host complexes, and chemometric data analysis is described. Chiral recognition through a formation of diastereomeric complexes was measured by ATR-IR. Small changes on the IR spectra reflect the interaction between the guest (M3) and host (chiral selector). These changes are measured as a function of M3 enantiomer excess. The standard error of prediction is 1.3 ee%. The prediction results based on the IR method were in good agreement with the gravimetric method. The robustness of the calibration model was evaluated by varying the concentration of the chiral selector, the pH of the solution, and the organic solvents. The stability of the calibration model was also demonstrated through measuring different sets of samples on different days. Chirality, 2006. © 2006 Wiley-Liss, Inc. [source] Differentiation of structural isomers in a target drug database by LC/Q-TOFMS using fragmentation predictionDRUG TESTING AND ANALYSIS, Issue 6 2010Elli Tyrkkö Abstract Isomers cannot be differentiated from each other solely based on accurate mass measurement of the compound. A liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/Q-TOFMS) method was used to systematically fragment a large group of different isomers. Two software programs were used to characterize in silico mass fragmentation of compounds in order to identify characteristic fragments. The software programs employed were ACD/MS Fragmenter (ACD Labs Toronto, Canada), which uses general fragmentation rules to generate fragments based on the structure of a compound, and SmartFormula3D (Bruker Daltonics), which assigns fragments from a mass spectra and calculates the molecular formulae for the ions using accurate mass data. From an in-house toxicology database of 874 drug substances, 48 isomer groups comprising 111 compounds, for which a reference standard was available, were found. The product ion spectra were processed with the two software programs and 1,3 fragments were identified for each compound. In 82% of the cases, the fragment could be identified with both software programs. Only 10 isomer pairs could not be differentiated from each other based on their fragments. These compounds were either diastereomers or position isomers undergoing identical fragmentation. Accurate mass data could be utilized with both software programs for structural elucidation of the fragments. Mean mass accuracy and isotopic pattern match values (SigmaFit; Bruker Daltonics Bremen, Germany) were 0.9 mDa and 24.6 mSigma, respectively. The study introduces a practical approach for preliminary compound identification in a large target database by LC/Q-TOFMS without necessarily possessing reference standards. Copyright © 2010 John Wiley & Sons, Ltd. [source] Dual CD system-modified MEEKC method for the determination of clemastine and its impuritiesELECTROPHORESIS, Issue 19 2010Serena Orlandini Abstract A dual system of CDs was used for the first time in MEEKC with the aim of determining clemastine and its three main related impurities in both drug substances and tablets. The addition of methyl-,-cyclodextrin and heptakis(2,6-di- O -methyl)-,-cyclodextrin to the microemulsion pseudo-stationary phase was essential to increase the resolving power of the system to obtain a baseline separation among the compounds. The best microemulsion composition was identified by mixture design and the effects of the factors concentrations of CDs and voltage were investigated by a response surface study applying a Central Composite Design. In both cases, Derringer's desirability function made it possible to find the global optimum, which corresponded to the following combination: microemulsion, 89.8% 10,mM borate buffer pH 9.2, 1.5% n -heptane and 8.7% of SDS/n -butanol in 1:2 ratio; 18,mM methyl-,-cyclodextrin, 38,mM heptakis(2,6-di- O -methyl)-,-cyclodextrin, 17,kV. By applying these conditions, the separation was completed in about 5.5,min. The method was validated following International Conference on Harmonisation guidelines and was applied to a real sample of clemastine tablets. [source] Drug,liposome distribution phenomena studied by capillary electrophoresis-frontal analysisELECTROPHORESIS, Issue 16 2008Jesper Østergaard Professor Abstract The potential of using CE frontal analysis (CE-FA) for the study of low-molecular-weight drug,liposome interactions was assessed. The interaction of bupivacaine, brompheniramine, chlorpromazine, imipramine, and ropivacaine with net negatively charged 80/20,mol% 1-oleoyl-2-palmitoyl- sn -glycero-3-phosphocholine/egg yolk phosphatidic acid liposome suspensions in HEPES buffer at pH,7.4 was investigated. The fraction of free drug as a function of lipid concentration was measured and apparent liposome , buffer distribution coefficients were determined for the basic drug substances. The distribution coefficients increased in the order ropivacaine, bupivacaine, brompheniramine, imipramine, and chlorpromazine. The developed CE method was relatively fast allowing estimates of drug,liposome affinity to be obtained within 15,min. CE-FA may have the potential to become a valuable tool for the characterization of drug,liposome interactions in relation to estimation of drug lipophilicity and for the evaluation of drug distribution in liposomal drug delivery systems. [source] CE frontal analysis based on simultaneous UV and contactless conductivity detection: A general setup for studying noncovalent interactionsELECTROPHORESIS, Issue 3 2007Henrik Jensen Dr. Abstract CE frontal analysis (CE-FA) has been established as a powerful tool to study noncovalent interactions between macromolecules and small molecules such as drug substances or pharmaceutical excipients. However, when using traditional commercial CE instrumentation, a serious drawback is related to the fact that only UV-active compounds can be studied. In recent years, contactless conductivity detection has become an attractive alternative to UV detection in CE due to its high versatility. In this study, we combine contactless conductivity detection and UV detection in a highly versatile setup for profiling noncovalent interactions between low-molecular-weight molecules and macromolecules. In the case of molecules having a chromophore the setup allows determination of binding constants using two independent detectors. The new contactless conductivity detection cell is compatible with commercial CE instrumentation and is therefore easily implemented in any analysis laboratory with CE expertise. [source] Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality?JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2009B. Glass BSc Hons BTech-Hons (Marketing) BPharm PhD Summary Background and objective:, Patients are increasingly requiring their medications to be repackaged into dose administration aids because of the positive outcomes associated with reduction in medication related hospitalization and adverse effects due to improved medicines management. Since the stability of these repackaged medications is not the responsibility of manufacturer, it is important that drug substances with potential stability issues be identified. Thus the objective of this study was to evaluate the stability of prochlorperazine, a light sensitive drug repackaged into dose administration aids (DAAs), in order to provide guidelines to the pharmacist and advice to the patient on appropriate storage. Methods:, Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging for 8 weeks at ambient (25 ± 1 °C; 60 ± 1·5% RH), accelerated (40 ± 1 °C; 75 ± 1·5% RH) and in-use conditions encountered in situ both in a pharmacy and the patients' home. They were assessed for both chemical (using a validated HPLC method) and physical stability according to British Pharmacopoeial (BP) standards. In addition, photostability testing was undertaken under ICH conditions. Results and discussion:, Chemical and physical stability was confirmed to be within BP Limits. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. Conclusion:, Despite the confirmation of physical and chemical stability within BP limits, the discoloration and the potential for photodegradants to cause adverse effects in patients must lead us to draw the conclusion that the quality of this medication has been compromised. Pharmacists thus need to take this into account in repackaging and storage of prochlorperazine in DAAs and advise patients to store their DAA protected from light, heat and humidity. [source] Quality specifications for peptide drugs: a regulatory-pharmaceutical approachJOURNAL OF PEPTIDE SCIENCE, Issue 11 2009Valentijn Vergote Abstract Peptide drugs, as all types of pharmaceuticals, require adequate specifications (i.e. quality attributes, procedures and acceptance criteria) as part of their quality assurance to ensure the safety and efficacy of drug substances (i.e. active pharmaceutical ingredients) and drug products (i.e. finished pharmaceutical dosage forms). Compendial monographs are updated regularly to keep up with the most recent advances in peptide synthesis (e.g. reduced by-products) and analytical technology. Nevertheless, currently applied pharmacopoeial peptide specifications are barely harmonized yet (e.g. large differences between the European Pharmacopoeia and the United States Pharmacopeia), increasing the manufacturers' burden of performing analytical procedures in different ways, using different acceptance criteria. Additionally, the peptide monographs are not always consistent within a single pharmacopoeia. In this review, we highlight the main differences and similarities in compendial peptide specifications (including identification, purity and assay). Based on comparison, and together with additional information from peptide drug substance manufacturers and public evaluation reports on registration files of non-pharmacopoeial peptide drugs, a consistent monograph structure is proposed. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [source] A critical assessment of the ICH guideline on photostability testing of new drug substances and products (Q1B): Recommendation for revisionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2010Steven W. Baertschi Abstract The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2934,2940, 2010 [source] Modeling the solubility of pharmaceuticals in pure solvents and solvent mixtures for drug process designJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2009Feelly Ruether Abstract The knowledge of the solubility of pharmaceuticals in pure solvents and solvent mixtures is crucial for designing the crystallization process of drug substances. The first step in finding optimal crystallization conditions is usually a solvent screening. Since experiments are very time consuming, a model which allows for solubility predictions in pure solvents and solvent mixtures based only on a small amount of experimental data is required. In this work, we investigated the applicability of the thermodynamic model perturbed-chain statistical associating fluid theory (PC-SAFT) to correlate and to predict the solubility of exemplary five typical drug substances and intermediates (paracetamol, ibuprofen, sulfadiazine, p -hydroxyphenylacetic acid, and p -aminophenylacetic acid) in pure solvents and solvent mixtures. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4205,4215, 2009 [source] A novel peroxy radical based oxidative stressing system for ranking the oxidizability of drug substancesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2006Paul A. Harmon Abstract A novel oxidative stressing system is described which generates high levels of peroxy radicals in solution at room temperature, without the use of azonitrile initiators. The oxidative stressing system is composed of a 10% solution of Tween 80 in water to which FeCl3,·,6H2O is added. The Tween 80 acts as a solubilizing agent for drug compounds, and also contains substantial amounts of organic hydroperoxides. It is shown that the Fe III/ Fe II couple operates on the hydroperoxide concentration to effectively generate new peroxy radicals, which then propagate in the Tween 80 solution. Key features of the Tween 80/Fe III system are investigated, and the oxidizability of seven known compounds and ten developmental compounds are examined. Relative reaction rates span a 300-fold range, from benzoic acid (nonreactive, defined as <0.5% reacted per day) to Vitamin D3 (7% reacted per hour). Oxidizability "rankings" thus generated are shown to agree well with azonitrile initiated oxidative stress. The potential for general correlations between this type of oxidizability data and actual oxidative performance in LFC and solid oral dosage forms is discussed. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 2014,2028, 2006 [source] Trends in solubility of polymorphsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2005Madhu Pudipeddi Abstract Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on solubility or dissolution of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on solubility? A large number of literature reports on solubility or dissolution of polymorphs were reviewed and the data were analyzed for trends in solubility ratio of polymorphs. The general trend reveals that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. A similar trend is also observed for anhydrate/hydrate solubility ratios, although anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to estimate the ratio of solubilities of polymorphs from thermal data. The trend in estimated solubility ratio shows good agreement with the one observed with experimentally determined solubility values. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:929,939, 2005 [source] Peak shape improvement of basic analytes in capillary liquid chromatographyJOURNAL OF SEPARATION SCIENCE, JSS, Issue 3 2005Anja Prüß Abstract The analysis of bases is of special interest in pharmaceutical research because numerous active substances contain basic functional groups. Capillary and conventional size LC separations of drug substances spiked with potential impurities were compared. In the case of the nonpolar drug levonorgestrel equal separation efficiency was readily attained by both techniques. The peaks of basic substances, however, showed extensive tailing when separated by capillary LC. The peak deformation was attributable to interactions of the basic substances with the polar inner surface of the fused silica capillaries employed in capillary LC and does not appear with the steel tubing generally used in conventional size LC. This drawback of capillary LC was overcome by use of deactivated fused silica capillaries for column hardware and transfer lines. [source] Variability and Impact on Design of Bioequivalence StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Achiel Van Peer Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75,133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003,2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe. [source] Skin disposition of menthol after its application in the presence of drug substancesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Krzysztof Cal Abstract Many drug products that are applied onto the skin contain menthol. Menthol plays a dual role in the analgesic and anti-inflammatory drugs: it causes cooling and local anesthetic effects and, being a penetration enhancer, it increases the skin permeation of the drug substances. However, there are no data concerning the skin penetration of menthol after its application in the most commonly used vehicles and in the presence of drug substances. Therefore, this study evaluated the ex vivo skin disposition of menthol after application of the commercially available drug products containing aluminum acetotartrate, methyl salicylate, ibuprofen and naproxen, using full human-skin mounted in flow-through diffusion cells. After 15, 30 and 60,min of application, the skin was progressively tape-stripped into three fractions of stratum corneum and the remaining epidermis with dermis. The content of menthol in the skin layers was determined by GC method. Varying degrees of penetration of menthol into the skin layers was observed, depending on its amount in the vehicle and the presence of drug substance. In the presence of aluminum acetotartrate, the skin penetration of menthol was limited only to the outer fraction of the stratum corneum. In the case of drug products containing naproxen, the concentration of the drug substance significantly influenced the skin penetration of menthol. Copyright © 2008 John Wiley & Sons, Ltd. [source] | ||||||||||||||||