Residual Solvent Content Research Articles

Determination of the content of residual solvents in Haikesu I by head-space gas chromatography.

To explore the usefulness of head-space gas chromatography for the determination of methanol and ethanol in Haikesu I,a raw material of artificial musk. The determination was performed on HP-5(30 m×0.53 mm,5 Μm)capillary column with an hydrogen flame ionization detector. The solvent was dimethyl sulfoxide and the internal standard was acetone. The injector temperature and the detector temperature were controlled at 180 ℃ and 250 ℃,respectively. The carrier gas was nitrogen. The containers of head-space injector were preheated at 90 ℃ for 15 minutes. The column temperature was programmed raised,which achieved baseline separation of the components. The results showed a good linear relationship for methanol and ethanol in their linearity range;and the limit of detection was 0.8 and 1.0 Μg/ml,respectively. The precision and average recoveries were satisfactory. The head-space gas chromatography is simple,rapid,and precise technique for the measurement of residual solvents in Haikesu I.

In-line NIR monitoring of key characteristics of enteric coated pellets

We describe the development of an in-line monitoring approach for the fluid-bed drying and coating steps for the production of enteric coated pellets by NIR. Our results show that key pellet characteristics can be monitored in-line. Likewise, the finished product acidic resistance is in excellent agreement to the in-line NIR predictions. Samples were collected at regular intervals and analyzed by several reference methods to characterize both process steps. In-line NIR models for pellets size sieve fractions, residual solvent content, and amount of coating layer have been constructed. Both the pellet coating layer amount and the in-vitro enteric performance demonstrate low variability which represents a challenge to the usual chemometric model development approach. To overcome this challenge a hierarchical PLS model for predicting acidic resistance was successfully constructed using time-evolving spectral data from 22 batches. Moreover, a novel multivariate meta-analysis of the PLS loadings of individual in-line models and the hierarchical PLS model has identified which pellet characteristics correlate most significantly with the observed enteric performance of the finished product. Additionally, the meta-analysis pointed toward the presence of further mechanisms unrelated to studied characteristics that also significantly influence the acidic resistance.

Drying of Multilayer Polymeric Coatings, Part I: An Experimental Study

Designing of multilayer coatings of poly(styrene)-tetrahydrofuran and poly(methyl methacrylate)-tetrahydrofuran has been studied. Multilayers were prepared by layer-by-layer and simultaneous methods. Several binary polymeric coatings of poly(styrene)-tetrahydrofuran and poly(methyl methacrylate)-tetrahydrofuran systems have been dried under quiescent drying conditions. Gravimetric analyses were performed using an analytical weighing balance. The initial amount of polymer was kept constant in both solution coatings. Coating which is likely to go through the glass transition temperature should be applied on the bottom side in order to minimize the residual solvent. For instance, residual solvent content is high in multilayer coating having poly(methyl methacrylate)-tetrahydrofuran coating on the top and poly(styrene)-tetrahydrofuran coating on the bottom, as compared to multilayer coatings having poly(styrene)-tetrahydrofuran on the top of poly(methyl methacrylate)-tetrahydrofuran coating.

Formation of nanocarrier systems by dense gas processing.

Nanocarrier systems, such as liposomes, polymersomes, and micelles, find applications in the delivery of a wide range of compounds, including targeted delivery of pharmaceuticals. Nanocarrier systems have the ability to increase the bioavailability, reduce toxicity, and avoid undesirable interactions of active pharmaceutical ingredients. In this work, a novel dense gas technique known as depressurization of an expanded solution into aqueous media (DESAM) was used to produce different types of nanocarrier systems. The effects of using different types of dense gases and different operating temperatures were investigated. Encapsulation of hydrophilic compounds in the vesicles (liposomes and polymersomes) was also studied. The highest encapsulation efficiencies in liposomes and polymersomes achieved were 10.2 and 9.7%, respectively. The DESAM process was also able to reduce the residual solvent content in the product to 2.2% (v/v), which is significantly lower than the solvent residual levels reported for conventional processing.

The Effect of Residual Solvent on the Morphology and Properties of Semi-Interpenetrating Polymer Network Membranes Based on Sulfonated Poly(Ether Ether Ketone) and Crosslinked Poly(2-Acrylamido-2-Methyl-1-Propanesulphonic Acid)

To further improve proton conductivity of semi-interpenetrating polymer network membranes based on sulfonated poly(ether ether ketone) (SPEEK) and crosslinked poly(2-acrylamido-2-methyl-1-propanesulphonic acid) (CrPAMPS), the attempt was made to photo-initiate the polymerization and crosslinking of AMPS in a swollen state of SPEEK membranes, where the residual solvent (RS) content was carefully controlled during the synthesis. The effect of RS on membrane structure and properties were investigated. The proton conductivity of the membrane with 33 wt% RS was found to increase more than 60% than that of the “dry” membrane which actually contained 13 wt% RS. It was suggested the existence of RS content might help the formation of large and well-connected hydrophilic domains that facilitate proton transport.

The effect of film thickness on the depth‐wise chain orientation of rod‐shaped polyimide

ABSTRACTControlling the chain orientation of polyimide is important because it affects the physical and electrical properties of the film. When a polyimide film is thick, the chain orientation has an inhomogeneous distribution along the thickness direction. In this study, poly(amic acids), the precursor of polyimide, with different coating thicknesses are dried, and the distribution of chain orientation in the thickness direction is investigated by measuring the residual solvent content with Raman spectroscopy. The effect of film thickness on the imidization rate is also studied by measuring the depth‐wise degree of imidization at the curing step. With the final cured polyimide film, the depth‐wise chain orientation is quantified by introducing the Fraser distribution function using polarized Raman spectroscopy. The thicker film has a lower degree of in‐plane orientation of polyimide chains, particularly near the substrate. This distribution of polyimide chain orientation in the thickness direction is similar to that of poly(amic acid) after drying. Fast imidization with higher solvent content for thick polyimide retards the formation of a well‐ordered structure with a high degree of in‐plane orientation. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2014, 52, 848–857

A fast method for the determination of residual solvents in 18FDG and 11C-methionine samples

A method for the determination of residual solvents in the commonly used radiopharmaceuticals 18F-fluorodeoxyglucose (18F-FDG) and 11C-methionine is proposed. This method is applicable to formulations even with high ethanol content up to 10% and offers a low detection limit: 3mg/L for methanol, 3mg/L for ethanol and 0.4mg/L for acetonitrile. Other advantages include short sample preparation and chromatographic separation times and minimum manual operation. To test the performance of the method 18F-FDG and 11C-methionine were synthesized in a number of consecutive runs and the residual solvent content was checked.

Analysis and Standardization of Levofloxacin Substance

Amethod for the analysis and standardization of levofloxacin substance synthesized using an original method was developed. The physicochemical properties of batch samples of levofloxacin substance were studied; IR and UV spectra were recorded for identification; contents of contaminants and R-ofloxacin in substance were determined by HPLC; residual solvent contents were determined by GLC. Samples of substance were assayed by HPLC. The shelf life was determined and quality norms were specified for levofloxacin substance; the results were used to prepare a draft pharmacopoeia monograph for levofloxacin substance.

Headspace-gas chromatographic fingerprints to discriminate and classify counterfeit medicines.

Counterfeit medicines are a global threat to public health. These pharmaceuticals are not subjected to quality control and therefore their safety, quality and efficacy cannot be guaranteed. Today, the safety evaluation of counterfeit medicines is mainly based on the identification and quantification of the active substances present. However, the analysis of potential toxic secondary components, like residual solvents, becomes more important. Assessment of residual solvent content and chemometric analysis of fingerprints might be useful in the discrimination between genuine and counterfeit pharmaceuticals. Moreover, the fingerprint approach might also contribute in the evaluation of the health risks different types of counterfeit medicines pose. In this study a number of genuine and counterfeit Viagra(®) and Cialis(®) samples were analyzed for residual solvent content using headspace-GC-MS. The obtained chromatograms were used as fingerprints and analyzed using different chemometric techniques: Principal Component Analysis, Projection Pursuit, Classification and Regression Trees and Soft Independent Modelling of Class Analogy. It was tested whether these techniques can distinguish genuine pharmaceuticals from counterfeit ones and if distinct types of counterfeits could be differentiated based on health risks. This chemometric analysis showed that for both data sets PCA clearly discriminated between genuine and counterfeit drugs, and SIMCA generated the best predictive models. This technique not only resulted in a 100% correct classification rate for the discrimination between genuine and counterfeit medicines, the classification of the counterfeit samples was also superior compared to CART. This study shows that chemometric analysis of headspace-GC impurity fingerprints allows to distinguish between genuine and counterfeit medicines and to differentiate between groups of counterfeit products based on the public health risks they pose.

Thermal analysis of epoxy-based nanocomposites: Have solvent effects been overlooked?

Analysis of the available published data calls into question some of the reported effects of silver, graphene, and boron nitride nanoparticles on the cure behavior and glass transition temperature (Tg) of epoxy-based conductive nanocomposites. The usefulness of most studies is limited, as the final Tg value is only reported for a single composition. More useful studies provide a comparison of Tg across compositions and/or to the Tg of the neat matrix material. However, the main focus is on nanoparticle effect, while the presence of residual solvent is generally overlooked. Although the data are too sparse for firm conclusions, reductions in Tg seem to correlate with a known residual solvent or mild degas conditions (low temperature, unagitated), while increases are more likely when no solvent is used or after rigorous degassing. Using solvent control groups to differentiate solvent effects from filler effects, we conducted our own differential scanning calorimetry experiments. It was found that silver microparticles have no statistically significant effect on Tg, but appeared to when solvent content was not accounted for. The erroneous apparent effect is very similar to reported effects for nanoparticles in the literature. If a solvent must be used, we recommend that the residual solvent content be quantified and provide the Tg of a control sample with a representative solvent content without nanoparticles. Analysis of the present literature also suggests that (i) nanoparticle surface chemistry has a significant effect and (ii) poor dispersion/aggregation results in a reduction in Tg.

Final report on key comparison CCQM-K55.c (L-(+)-Valine): Characterization of organic substances for chemical purity

Under the auspices of the Organic Analysis Working Group (OAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM K55.c, was coordinated by the Bureau International des Poids et Mesures (BIPM) in 2012. Twenty National Measurement Institutes or Designated Institutes and the BIPM participated. Participants were required to assign the mass fraction of valine present as the main component in the comparison sample for CCQM-K55.c. The comparison samples were prepared from analytical grade L-valine purchased from a commercial supplier and used as provided without further treatment or purification.Valine was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of organic compounds of low structural complexity [molecular weight range 100–300] and high polarity (pKOW > −2).The KCRV for the valine content of the material was 992.0 mg/g with a combined standard uncertainty of 0.3 mg/g. The key comparison reference value (KCRV) was assigned by combination of KCRVs assigned from participant results for each orthogonal impurity class. The relative expanded uncertainties reported by laboratories having results consistent with the KCRV ranged from 1 mg/g to 6 mg/g when using mass balance based approaches alone, 2 mg/g to 7 mg/g using quantitative 1H NMR (qNMR) based approaches and from 1 mg/g to 2.5 mg/g when a result obtained by a mass balance method was combined with a separate qNMR result.The material provided several analytical challenges. In addition to the need to identify and quantify various related amino acid impurities including leucine, isoleucine, alanine and α-amino butyrate, care was required to select appropriate conditions for performing Karl Fischer titration assay for water content to avoid bias due to in situ formation of water by self-condensation under the assay conditions. It also proved to be a challenging compound for purity assignment by qNMR techniques.There was overall excellent agreement between participants in the identification and the quantification of the total and individual related structure impurities, water content, residual solvent and total non-volatile content of the sample. Appropriate technical justifications were developed to rationalise observed discrepancies in the limited cases where methodology differences led to inconsistent results.The comparison demonstrated that to perform a qNMR purity assignment the selection of appropriate parameters and an understanding of their potential influence on the assigned value is critical for reliable implementation of the method, particularly when one or more of the peaks to be quantified consist of complex multiplet signals.Main text.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

A Process Analytical Technology (PAT) approach to control a new API manufacturing process: Development, validation and implementation

Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses.

On-line near infrared spectroscopy as a Process Analytical Technology (PAT) tool to control an industrial seeded API crystallization

The final step of an active pharmaceutical ingredient (API) manufacturing synthesis process consists of a crystallization during which the API and residual solvent contents have to be quantified precisely in order to reach a predefined seeding point. A feasibility study was conducted to demonstrate the suitability of on-line NIR spectroscopy to control this step in line with new version of the European Medicines Agency (EMA) guideline [1]. A quantitative method was developed at laboratory scale using statistical design of experiments (DOE) and multivariate data analysis such as principal component analysis (PCA) and partial least squares (PLS) regression. NIR models were built to quantify the API in the range of 9–12% (w/w) and to quantify the residual methanol in the range of 0–3% (w/w). To improve the predictive ability of the models, the development procedure encompassed: outliers elimination, optimum model rank definition, spectral range and spectral pre-treatment selection. Conventional criteria such as, number of PLS factors, R2, root mean square errors of calibration, cross-validation and prediction (RMSEC, RMSECV, RMSEP) enabled the selection of three model candidates. These models were tested in the industrial pilot plant during three technical campaigns. Results of the most suitable models were evaluated against to the chromatographic reference methods. Maximum relative bias of 2.88% was obtained about API target content. Absolute bias of 0.01 and 0.02% (w/w) respectively were achieved at methanol content levels of 0.10 and 0.13% (w/w). The repeatability was assessed as sufficient for the on-line monitoring of the 2 analytes. The present feasibility study confirmed the possibility to use on-line NIR spectroscopy as a PAT tool to monitor in real-time both the API and the residual methanol contents, in order to control the seeding of an API crystallization at industrial scale. Furthermore, the successful scale-up of the method proved its capability to be implemented in the manufacturing plant with the launch of the new API process.

Evaluation of the residual solvent content of counterfeit tablets and capsules

A group of counterfeit samples of Viagra® and Cialis® were screened for their residual solvent content and compared to the content of the genuine products.It was observed that all counterfeit samples had higher residual solvent contents compared to the genuine products. A more diverse range of residual solvents was found as well as higher concentrations. In general these concentrations did not exceed the international imposed maximum limits. Only in a few samples the limits were exceeded.A Projection Pursuit analysis revealed clusters of samples with similar residual solvent content, possibly enabling some future perspectives in forensic research.

Polyvinylpyrrolidone–LiClO4 solid polymer electrolyte and its application in transparent thin film supercapacitors

Films of PVP (polyvinylpyrrolidone) and LiClO4 have been obtained by dip coating to be used as solid ionic conductors in transparent energy storage systems. The dependence of the ionic conductivity of PVP/LiClO4 films on temperature, lithium salt concentration, and residual solvent content or humidity has been studied. The films were used in a symmetrical supercapacitor (PEDOT/PVP/PEDOT). Whose behaviour with the aging time was analysed as well. It was observed that the experimental differences in the performance of a lithium ion based energy storage devices using these films as solid electrolyte may be due to changes in the residual content of the solvent used in their preparation or the hygroscopic nature of the electrolyte.

Soluble Itraconazole in Tablet Form Using Disordered Drug Delivery Approach: Critical Scale-up Considerations and Bio-equivalence Studies

The present research work explores formulation design, critical scale-up considerations and bio-equivalence studies of soluble itraconazole (ITZ) in a tablet form using disordered drug delivery approach. Disordered system of ITZ with a lower viscosity grade of hydroxypropyl methyl cellulose (Pharmacoat 603) was developed for the first time and extensively characterised at three different stages, namely development of glass system, pellet coating and tablet compression using advanced analytical techniques. Complete molecular embedment of ITZ resulting in amorphisation was observed and found to be sustained until end of the real-time and accelerated stability studies. Developed formulation exhibited comparative in vitro dissolution profile (similarity factor>70) with reference product (Sporanox, Janssen Pharmaceutica) in simulated gastric fluid without enzymes. Formulation was scaled up in three batches (50,000 tablets/batch) with detailed validation of critical process parameters using process capability index method. Critical scale-up considerations like control of residual solvent content, effect of pellet size on dissolution, process variables in pellet coating, compressibility of coated pellets and cushioning effect required for desired compressibility were thoroughly discussed. Bioequivalence study of single dose of test and reference product in seven healthy human volunteers under fed condition exhibited significant bioequivalence with results (AUClast and AUC∞) lying between 90% confidence interval. With increase in number of subjects to 24, a significant effect on pharmacokinetic parameters of both reference as well as developed ITZ tablets was observed.

Comparison of FASTlab 18F-FDG Production Using Phosphate and Citrate Buffer Cassettes

The objective of this research is to determine whether there are significant differences in the (18)F-FDG produced by either the phosphate or the citrate buffer cassettes in the FASTlab synthesizer. Forty batches of (18)F-FDG were produced with each cassette and analyzed retrospectively. The analysis consisted of determining the mean radiochemical yield (RCY)-uncorrected and corrected for decay-radiochemical purity (RCP), pH, and residual solvent content (ethanol and acetonitrile). An independent t test (alpha error [α], 0.05) was performed to determine whether the differences were statistically significant. The mean decay-corrected RCYs for (18)F-FDG produced by phosphate and citrate cassettes were 82.9% ± 17.4% and 79.2% ± 5.0%, respectively. The uncorrected RCY was 57.5% ± 16.7% for phosphate- and 58.8% ± 6.0% for citrate-buffered (18)F-FDG, leading to a difference of 4.4% and P value of 0.11 for corrected RCY and a difference of 2.2% and P value of 0.32 for uncorrected RCY. Thus, the RCY differences are neither statistically nor clinically significant. The mean RCPs were 99.4% ± 0.2% for the phosphate-buffered (18)F-FDG and 99.0% ± 1.1% for the citrate-buffered (18)F-FDG. There was a 0.5% difference and a P value of 0.021, meaning that the difference was statistically significant. The average pHs for (18)F-FDG produced by phosphate and citrate buffer cassettes were 5.9 ± 0.1 and 5.3 ± 0.2, respectively, resulting in a 9.6% difference and a P value close to zero (2.6 × 10(-19))-a statistically significant difference. The difference between ethanol content was also dramatic. Phosphate-buffered (18)F-FDG contained 0.08% ± 0.02% ethanol, whereas the citrate-buffered (18)F-FDG contained 0.20% ± 0.07%. No difference was found in the acetonitrile content of the 2 cassettes. The differences in yield between cassettes are due to statistical variability. The results confirm our hypothesis that there is no significant difference in RCY. The differences seen in the statistically significant data (those with a P value > 0.05) turn out to be insignificant in a real-world setting because all values fell within the limits set by the United States Pharmacopeia and Food and Drug Administration. Therefore, determining which cassette to use is a matter of the preference of the institution.

Solvent screening for non‐aqueous extraction of Alberta oil sands

AbstractNon‐aqueous extraction of bitumen from oil sands has the potential to reduce fresh water demand of the extraction process and eliminate tailings ponds. In this study, different light hydrocarbon solvents, including aromatics, cycloalkanes, biologically derived solvents and mixtures of solvents were compared for extraction of bitumen from Alberta oil sands at room temperature and ambient pressure. The solvents are compared based on bitumen recovery, the amount of residual solvent in the extracted oil sands tailings and the content of fine solids in the extracted bitumen. The extraction experiments were carried out in a multistage process with agitation in rotary mixers and vibration sieving. The oil sands tailings were dried under ambient conditions, and their residual solvent contents were measured by a purge and trap system followed by gas chromatography. The elemental compositions of the extraction tailings were measured to calculate bitumen recovery. Supernatants from the extraction tests were centrifuged to separate and measure the contents of fine solid particles. Except for limonene and isoprene, the tested solvents showed good bitumen recoveries of around 95%. The solvent drying rates and residual solvent contents in the extracted oil sands tailings correlated to solvent vapour pressure. The contents of fine solids in the extracted bitumen (supernatant) were below 2.9% for all solvents except n‐heptane‐rich ones. Based on these findings, cyclohexane is the best candidate solvent for bitumen extraction, with 94.4% bitumen recovery, 5 mg of residual solvent per kilogram of extraction tailings and 1.4 wt% fine solids in the recovered bitumen. © 2012 Canadian Society for Chemical Engineering

Microencapsulation of Alpha Interferons in Biodegradable Microspheres

The immunomodulatory, antiproliferative, and antiviral properties of interferons alpha (IFN-α) have made these cytokines attractive for numerous clinical applications. However, most of the current available IFN pharmaceutical dosage forms need to be injected frequently and may provoke adverse reactions in patients. This problem might be overcome by using biodegradable microspheres loaded with IFN. The encapsulation of IFN-α in microspheres and the current status of this technology are the main subjects reviewed here. To this end, we describe (i) the main methods and experimental parameters used to obtain IFN-loaded microspheres and (ii) characterization of these microspheres in terms of morphology, particle size, loading/encapsulation efficiency, residual water content, residual solvent content, release profile, and sterility. Also, we discuss both the characterization of the encapsulated IFN and the stabilization/protection of IFN during microencapsulation. Finally, a brief overview of preclinical and clinical studies using IFN-containing microspheres is given.

Impact of process variables on the micromeritic and physicochemical properties of spray-dried microparticles – Part II. Physicochemical characterisation of spray-dried materials

In this work we investigated the residual organic solvent content and physicochemical properties of spray-dried chlorothiazide sodium (CTZNa) and potassium (CTZK) salts. The powders were characterised by thermal, X-ray diffraction, infrared and dynamic vapour sorption (DVS) analyses. Solvent levels were investigated by Karl-Fischer titration and gas chromatography. Spray-drying from water, methanol (MeOH) and mixes of MeOH and butyl acetate (BA) resulted in amorphous microparticles. The glass transition temperatures of CTZNa and CTZK were ∼192 and ∼159°C, respectively. These materials retained their amorphous nature when stored at 25°C in dry conditions for at least 6 months with no chemical decomposition observed. DVS determined the critical relative humidity of recrystallisation of CTZNa and CTZK to be 57% RH and 58% RH, respectively. The inlet temperature dependant oxidation of MeOH to formaldehyde was observed; the formaldehyde was seen to deposit within the amorphous matrix of spray-dried product. Spray-drying in the open blowing mode coupled with secondary drying resulted in a three-fold reduction in residual BA (below pharmacopoeial permitted daily exposure limit) compared to spray-drying in the closed mode. Experiments showed that recirculation of recovered drying gas increases the risk of deposition of residual solvents in the spray-dried product.