Residual Solvent Research Articles

Large-scale synthesis of galeterone and lead next generation galeterone analog VNPP433-3β

VNPP433-3β (compound 2, (3β-(1H-imidazole-1-yl)-17-(1H-benzimidazole-1-yl)-androsta-5,16-diene), a multitarget anticancer agent has emerged as our lead next generation galeterone analogs (NGGA). Here, we describe a large multi-gram (92 g) scale synthesis of compound 2 starting from the commercially available dehydroepiandrosterone-3-acetate (DHEA, 6) via Galeterone (Gal, 1), in 8 steps with a 26% overall yield and 99.5% purity. The overall yield for the synthesis of Gal from DHEA improved from previously reported 47% to 59%. The advantages of this synthesis are as follows: (1) In the first two steps of Scheme 2, the change of solvents and reagents enabled the isolation of compounds 7 and 8 from heptane triturations, as column chromatography was eliminated in both steps. (2) In step 3 (deformylation) the catalyst required was reduced from 50% to 10% (wt/wt) of compound 8 which enable easy purification of compound 9, with modest increased yield. (3) The fourth step to produce Gal (1) was improved by using methanol, eliminating the use of tetrahydrofuran (THF) and dichloromethane, solvent which may be a problem as residual solvent contaminant. (4) In the final step 8, the imidazole-ring formation, inexpensive glyoxal (40% aqueous solution) was used in the reaction instead of expensive glyoxal trimer dihydrate. The structure of the target product (2, VNPP433-3β) was established by NMR spectroscopy, mass spectrometry and elemental analysis. Gal and VNPP433-3β exhibit more potent antiproliferative activities against CWR22Rv1 human prostate cancer cells compared to clinical drugs, Abiraterone and Enzalutamide.

Dynamic self-stabilization in the electronic and nanomechanical properties of an organic polymer semiconductor

The field of organic electronics has profited from the discovery of new conjugated semiconducting polymers that have molecular backbones which exhibit resilience to conformational fluctuations, accompanied by charge carrier mobilities that routinely cross the 1 cm2/Vs benchmark. One such polymer is indacenodithiophene-co-benzothiadiazole. Previously understood to be lacking in microstructural order, we show here direct evidence of nanosized domains of high order in its thin films. We also demonstrate that its device-based high-performance electrical and thermoelectric properties are not intrinsic but undergo rapid stabilization following a burst of ambient air exposure. The polymer’s nanomechanical properties equilibrate on longer timescales owing to an orthogonal mechanism; the gradual sweating-out of residual low molecular weight solvent molecules from its surface. We snapshot the quasistatic temporal evolution of the electrical, thermoelectric and nanomechanical properties of this prototypical organic semiconductor and investigate the subtleties which play on competing timescales. Our study documents the untold and often overlooked story of a polymer device’s dynamic evolution toward stability.

Development and Validation of a Procedure for the Quantitative Determination of Residual Organic Solvents in Allergen Preparations by GC

Introductio n. One of the requirements for the quality of pharmaceuticals, including allergens, is the determination of residual organic solvents in them. In the production of allergen preparations, in a number of cases in the technological process, organic solvents of the third toxicity class are used, diethyl ether and acetone, which are solvents of low toxicity and their maximum content is allowed up to 0.5 % (5000 ppm). Since diethyl ether or acetone, and in some cases both solvents can be used simultaneously in the production process of allergen preparations for degreasing and cleaning, it is therefore advisable to develop and use a unified technique to determine them. Aim. The aim of the study was to develop and validate a method for the quantitative determination of residual organic solvents in allergen preparations. Materials and methods. The studies were carried out by gas-liquid chromatography with a flame ionization detector with injection of the test samples using an autosampler on a Zebron ZB-624 capillary quartz column (G43, 6 % cyanopropylphenyl / 94 % dimethylpoly siloxane). Results and discussion. The conditions for the chromatographic separation of acetone and diethyl ether on a capillary quartz column were selected. The parameters of the suitability of the chromatographic system have been determined. The developed method was validated according to the following characteristics: specificity, linearity, limit of quantitative determination, correctness and precision at the level of repeatability and intra-laboratory precision. The content of acetone and diethyl ether in 26 preparations of allergens was determined. The results of the quantitative determination of diethyl ether and acetone in allergen preparations, in the technological process of which OOP are used, are in the range of 0.0053–0.0524 % for diethyl ether and 0.0029–0.0994 % for acetone. Thus, the content of diethyl ether and acetone in all tested allergen preparations was below the established norm (less than 0.5 %). Conclusion. An analytical method has been developed for determining the quantitative content of diethyl ether and acetone in allergen preparations using the GLC method; the method has been validated according to characteristics that meet the requirements of General Pharmacopoeia Monograph 1.1.0012.15 "Validation of analytical methods". The analysis of allergen preparations was carried out in accordance with the methodology. In all preparations, the content of diethyl ether and acetone was no more than 0.5 %.

Formulation and optimization of polymeric agglomerates of Bosentan monohydrate by crystallo-co-agglomeration technique

BackgroundThe polymeric spherical agglomerate of Bosentan monohydrate was prepared by crystallo-co-agglomeration technique, for enhancing the micrometric properties and solubility of the drug. The agglomerates were developed using two distinct solvents, DCM as a good solvent and bridging liquid and water as a weak solvent, respectively. Hydrophilic polymer like HPMC K100M is used as a hardening agent which gives mechanical strength to the agglomerates, and PEG6000 is used as a wetting agent. Other excipients like talc which was used as a size enhancer, and PVA was used as an emulsifier agent. The formulation was optimized by Box–Behnken design. The concentration of talc and PEG6000, as well as rotation speed, was considered as independent variables. The particle size, angle of repose, and % drug content were used as dependent variables to investigate the effect of independent variables on dependent variables. The spherical crystal agglomerates were subjected to various physicochemical evaluations.ResultsThe results revealed that as the concentration of talc and PEG6000 increases, the sphericity and particle size of the agglomerates increase, and at a low agitation, speed agglomerates become more spherical and coarser, which is confirmed by FESEM. The characterization like FTIR confirms no interaction with excipients, while XRPD confirms the polymorphic changes, and gas chromatography (GC) confirms the concentration of residual organic solvents in PDE limits. The optimized formulation of SAs showed a good angle of repose which is 30.33 ± 0.35, and the % cumulative drug release at 20 min was 94.14 ± 0.628%. Finally, the FDTs of the optimized batch were prepared.ConclusionsThe comparison of the in vitro release study of pure drugs with agglomerates and fast dispersible tablets of agglomerates confirms the solubility improvement. Finally, it can be concluded that the polymorphic crystal agglomerates enhance the solubility and micrometric properties of Bosentan monohydrate.

Supercritical CO2 Extraction of Carotenoids (Astaxanthin, Adonirubin, and Adonixanthin) from Paracoccus carotinifaciens: Improved Z‐Isomer Ratio and Recovery of Carotenoids via High‐Temperature Extraction

AbstractThe effects of high‐temperature supercritical CO2 (SC‐CO2) extraction on Z‐isomerization and recovery of carotenoids (astaxanthin, adonirubin, and adonixanthin) from Paracoccus carotinifaciens are investigated. The high‐temperature extraction, especially at >100 °C, not only increases the total Z‐isomer ratio of carotenoids in the resulting extracts but also improves carotenoid recovery. For example, when the SC‐CO2 extraction is performed at 60 °C and 30 MPa with an entrainer (ethanol), the total Z‐isomer ratio and the recovery of astaxanthin are 11.1% and 28.4%, respectively, whereas at 120 °C, the values increase to 54.2 and 56.4%, respectively. The significant improvement in the extraction efficiency of carotenoids at high temperatures can be attributed to the increase in the ratio of carotenoid Z‐isomers with high solubility in SC‐CO2. Moreover, the effects of extraction pressure and entrainer content on Z‐isomerization and recovery of carotenoids are also investigated. The results show that higher pressure and ethanol content resulted in lower Z‐isomer ratios and higher recoveries of carotenoids. As the Z‐isomers of carotenoids have greater bioavailability and potentially exhibit superior biological activities than the all‐E‐isomers, high value‐added carotenoids, and higher yield can be simultaneously achieved with high‐temperature extraction.Practical applications: As carotenoid extraction is usually performed using toxic organic solvents, residual solvents are a serious concern. In addition, naturally occurring carotenoids (mainly the all‐E‐isomers) have low bioavailability. These are important issues that need to be overcome for the industrial use of carotenoids. The Z‐isomer‐rich carotenoids obtained by SC‐CO2 extraction under high‐temperature conditions have great potential to solve these issues simultaneously.

Kinetics of CO2 gas bubbling for the separation of residual solvent from waste solids: Effects of bubble size

Solvent loss in the residual solids has been considered as a major challenge during the solvent extraction processes of unconventional oil ores (oil sands, asphalt rocks, etc.) or similar liquid-solid extraction. Meanwhile, the residual solvent in the solvent-extracted solids also causes serious environmental problems. The gas (CO2) bubbling process is proved to be an effective method for the removal and recovery of residual solvents from solvent-extracted solids. Herein, the kinetic model of the solvent removal by the gas bubbling has been built after considering the bubbling process as quasi vapor-liquid equilibrium. It is found that the solvent removal by gas bubbling matches well with the first-order kinetic model. Based on the fitting of gas bubbling experimental data under different water volumes, the quasi Henry’s constant and separation rate constant were obtained. At this time, all the related parameters of gas bubbling kinetic model were determined. Then the effect of bubble size on the gas bubbling kinetics was systematically analyzed, a potential strengthening method of connecting micro-nano bubbles and large bubbles is proposed for improving the solvent removal from the residual solids. Finally, the molecular dynamic (MD) simulation and gas bubbling experiments combined with large bubbles and micro-nano bubbles prove micro-nano could well accelerate the solvent removal in the residual solids. This work provides the fundamental basis for the industrialization of the gas bubbling process for the solvent removal from residual solids, which also provides a new idea for the treatment of environmental problems, such as the treatment of solvent-containing waste solids.

Installation of First Medium Energy Medical Cyclotron in Bangladesh at National Institute of Nuclear Medicine and Allied Sciences (NINMAS) for PET radiopharmaceuticals Production

PET-CT (positron emission tomography and computed tomography) is a gold-standard cancer imaging tool for diagnosis and management, as well as prognostic information based on treatment. Positron-emitting radionuclide 18F (Fluorine) is generated by accelerating particles to energies high enough to cause a certain nuclear reaction 18O(p,n)18F within the particle accelerator, the cyclotron. Mannose triflate is converted to 2-[18F] Fluoro-2-deox-D-yglucose ([18F]FDG) via nucleophilic reaction. Under the ownership of Bangladesh Atomic Energy Commission installed a medium energy (18/9 MeV, IBA) Cyclotron at National Institute of Nuclear Medicine and Allied Sciences (NINMAS). The facility was established in the oncology Building (Block F) of Bangabandhu Sheikh Mujib Medical University (BSMMU). Cyclotron vault and the Control room are located in the underground i.e. basement floor. Each wall of the cyclotron vault and ceiling is made of concrete with a density of 2.35 g/cm3 and a thickness sufficient to shield gamma and neutron radiation. On the ground floor, there are Synthesis room, Quality control laboratory, and the Decontamination room. PET-CT rooms are located on the first floor. Identification, Radionuclide purity (Gamma spectrum detection and half-life measurement), Radiochemical Purity, Chemical purity, Residual solvent measurement, pH measurement, Sterility, and bacterial endotoxins (LAL test) are performed to maintain the quality of the product. The current uses of the Cyclotron are mostly for the synthesis of 18F-FDG. Bangladesh J. Nuclear Med. 24(1&2): 48-50, 2021

Minimizing the initial burst of octreotide acetate from glucose star PLGA microspheres prepared by the solvent evaporation method

Sandostatin long-acting release (SLAR) depot for 1-month controlled release of octreotide is a somatostatin analogue product that has been used extensively in the pharmacological treatment of acromegaly. The complexities in the SLAR coacervation manufacturing processes and the use of a unique glucose-starpoly(lactic-co-glycolic acid) (PLGA-glu) may have contributed to the lack of US FDA-approved generic products referencing SLAR in the USA. To address this challenge, we encapsulated octreotide acetate by the commonly used solvent evaporation method in microspheres of a similar composition to SLAR, including the use of a comparable PLGA-glu. Based on our previous study that identified key formulation variables to prepare octreotide acetate/PLGA-glu microspheres, including lowering initial peptide pH and introducing an annealing step post loading, here we added NaCl to the external water phase to further improve the formulation. The resulting microspheres exhibited highly similar release and stability performance in vitro to SLAR, including an exceptionally low initial burst. The very low initial burst was also confirmed by pharmacokinetics in rats. Full erosion behavior analysis (polymer MW, water uptake and mass loss) revealed a slightly faster degradation of SLAR than the solvent evaporation formulations. Analysis of kinetics of dry Tg of the formulations reflected (a) the elevated residual solvent in SLAR and was not duplicated in the solvent evaporation formulations, and (b) the slightly higher Tg of peptide loaded formulations relative to than blank microspheres, consistent with the interaction of the acetate salt of octreotide with linear PLGA chains in the PLGA-glu. These data indicate that it is possible to prepare peptide loaded microspheres by the solvent evaporation method with extraordinarily similar performance to microspheres, such as those in SLAR, that are prepared by the low-burst release coacervation method.

Over 12% Efficient CuIn(S,Se)2 Solar Cell with the Absorber Fabricated from Dimethylformamide Solution by Doctor‐Blading in Ambient Air

Solution‐processed chalcopyrite copper indium gallium sulfoselenide (Cu(In,Ga)(S,Se)2, CIGSSe) thin‐film solar cells have achieved efficiency beyond 18% and have great potential as an alternative to vacuum‐based ones. However, most of the efficient solution‐based CIGSSe solar cells are fabricated by spin‐coating in an inert atmosphere, which limits the transfer from lab protocol to industrial large‐scale production. Herein, a scalable doctor‐blading technique is applied to fabricate CuIn(S,Se)2 (CISSe) absorbers from N,N‐dimethylformamide molecular precursor solution in ambient air. With the optimization of the precursor concentration to reduce the residue solvent and change the thermal annealing process from one‐step to two‐step to separate solvent evaporation and complex decomposition to suppress fluidity, high‐quality absorber films with densely packed large grains have been fabricated and a champion CISSe solar cell with a power conversion efficiency of 12.54% has been achieved. Importantly, unlike the spin‐coating technique which may cause composition change due to the different solubilities of the precursors, the doctor‐bladed film has a composition very close to the precursor solution, which is very important for precise control of the absorber composition for industrial production.

Exploiting the full advantages of colloidal perovskite nanocrystals for large-area efficient light-emitting diodes.

Cost-effective, high-throughput industrial applications of metal halide perovskites in large-area displays are hampered by the fundamental difficulty of controlling the process of polycrystalline film formation from precursors, which results in the random growth of crystals, leading to non-uniform large grains and thus low electroluminescence efficiency in large-area perovskite light-emitting diodes (PeLEDs). Here we report that highly efficient large-area PeLEDs with high uniformity can be realized through the use of colloidal perovskite nanocrystals (PNCs), decoupling the crystallization of perovskites from film formation. PNCs were precrystallized and surrounded by organic ligands, and thus they were not affected by the film formation process, in which a simple modified bar-coating method facilitated the evaporation of residual solvent to provide uniform large-area films. PeLEDs incorporating the uniform bar-coated PNC films achieved an external quantum efficiency (EQE) of 23.26% for a pixel size of 4 mm2 and an EQE of 22.5% for a large pixel area of 102 mm2 with high reproducibility. This method provides a promising approach towards the development of large-scale industrial displays and solid-state lighting using perovskite emitters.

Thermostructural evaluation of poly(butylene adipate-co-terephthalate) /molybdenum trioxide nanocomposites through time domain nuclear magnetic resonance and other conventional techniques / Avaliação termo-estrutural de nanocompósitos de poli(adipato-co-tereftalato de butileno) / trióxido de molibdénio através de ressonância magnética nuclear no domínio do tempo e outras técnicas convencionais

In present study, poly(butylene adipate-co-terephthalate) (PBAT) nanocomposites films were prepared by solvent casting technique, using chloroform (CHCl3) and containing different percentages (0-0.5 wt %) of molybdenum trioxide (MoO3) nanoparticles (NPs). The microstructure and molecular dynamics of the PBAT and PBAT/MoO3 films were characterized by X-ray diffraction (XRD) and time-domain nuclear magnetic resonance (TD-NMR). Films’ thermal degradation was studied by using thermogravimetric analysis (TGA). Fourier transform infrared spectroscopy (FTIR) confirmed: no residual solvent or contaminants and polymer matrix integrity after the casting process. The results' matchup indicated that filler–polymer interaction was suitable and, thus, MoO3NPs are potential candidates to be used as filler in PBAT matrices, especially in concentrations around 0.3 %.

The Effect of Residual Solvent in Carbon-Based Filler Reinforced Polymer Coating on the Curing Properties, Mechanical and Corrosive Behaviour.

Solution mixing, which is one of the standard methods of producing Graphene−based Nanocomposites (GPC) may not be as efficient as it is expected due to the presence of residual solvent in the cured product. Therefore, the influence of including acetone in the preparation of Graphene Oxide−based epoxy coating (GO−EP) on the curing behaviour, mechanical and corrosive behaviour was studied. FTIR and TGA analysis confirmed that the GO−EP prepared by ultrasonication (GO−EP U) indicated the presence of more low−molecular−weight/low crosslinked (LMW/LC) sites than GO−EP prepared by stirring (GO−EP MS). Meanwhile, the tensile strength and hardness of GO−EP MS was 20% and 10% better than GO−EP U which confirmed that the presence of a lower number of LMW/LC could prevail over the agglomeration of GO sheets in the GO−EP MS. Pull−off adhesion tests also confirms that the presence of remaining acetone would cause the poor bonding between metal and coating in GO−EP U. This is reflected on the electrochemical impedance spectroscopy (EIS) results, where the GO−EP U failed to provide substantial barrier protection for carbon steel after 140 days of immersion in 3.5 wt% NaCl. Therefore, it is essential to consider the solvent effect when solvent is used in the preparation of a coating to prevent the premature failure of high−performance polymer coatings.

Impurity Profiling: A Review

Impurities are any substances, such as starting materials or intermediates, that coexist with the parent drug or arise from side reactions. Interest in impurities present in APIs continues to grow. Nowadays, not only purity profile but also impurity profile is mandated by various regulatory agencies. Impurity profiling is a generic name for a group of analytical working groups such as describing, quantifying and characterizing identified and unidentified impurities present in a new drug substance. Impurity profiling is a novel approach aimed at detecting, identifying, structuring and quantifying organic and inorganic impurities and residual solvents in pharmaceuticals. Various regulatory bodies, such as ICH, USFDA, UKMHRA, and India's CDSCO, focus on impurity profiling and have formulated guidelines for impurity management and restriction. Impurities are classified into different categories based on their origin, type of composition, and biological safety. The presence of these unwanted chemicals or substances may affect the safety and effectiveness of the final medicinal product. This review focuses on the sources of impurities, their classification, and various analytical methods for the identification and quantification of impurities. Terms such as residual solvent, by-product, transformation product, decomposition product, reaction product, and related products are often used to define impurities.

High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

High-Throughput GC-FID Method for the Determination of Residual Solvents in Early-Phase Drug Discovery Samples

Design of low cost waterborne polyvinyl alcohol coatings using plasticizer polyethylene glycol to minimize the residual solvent and coating defects

AbstractWaterborne coatings provide nontoxicity and flame‐retardance but exhibit inefficient drying. The literature on drying enhancers is limited for the want of residual solvent minimization study. Here, we use polyethylene glycol‐6000 (PEG), a low cost biodegradable plasticizer, to minimize the residual solvent in polyvinyl alcohol (PVA)‐water coatings. Coatings were prepared at different PEG loadings (0, 0.50, 1.00, 2.50, 5.00, and 7.50 wt%) and initial conditions. The maximum drop in the residual solvent was 87% at 0.50 wt% PEG loading in the coating of initially 5% PVA and 1000 μm thickness. The effect of doubling the initial wet thickness from 500 to 1000 μm was first examined. The minimum residual solvent significantly reduced from 1.30% to 0.59%, and occurred at the same PEG loading of 0.50 wt%. However, the drying time increased and drying rate slowed down remarkably. SEM results also revealed that at the optimum PEG loading a smooth and dense coating was obtained. Thermogravimetric analysis/derivative thermogravimetric studies showed improved thermal stability and differential scanning calorimetry showed little decrease in Tg at optimized PEG loading. When the initial polymer concentration was doubled from 5% to 10%, the optimum PEG loading lowered from 0.50 to 0 wt%. Simultaneously, a marked increase in the minimum residual solvent from 1.30% to 3.27% occurred, caused by the hydrophilicity of PVA and enhanced solution viscosity. On comparison with a fluorosurfactant (FS) modifier, PEG yields significantly better maximum reduction in residual solvent at substantially lower optimum loading by employing higher wet film thickness. Furthermore, PEG is significantly lower in cost and environmentally friendly than FS.

Towards a holistic view of tablet quality, an extensive study on paracetamol tablets with nuclear magnetic resonance using similarity calculations, differential NMR and hierarchical cluster analysis

The 1H NMR spectra obtained from 56 different paracetamol tablets were thoroughly investigated to analyse and quantify besides paracetamol, the excipients and eventual minor components present in the formulations. In the NMR spectra the amide-iminol tautomerism of paracetamol was observed, with the iminol form present at a quantity of only 0.80% of the amide form. Furthermore, seventeen different components of the tablets were identified, ranging from major excipients like starch and polyvinylpyrrolidone (PVP) to minor components like different parabens, sorbate and triacetin. The similarity from all spectra in relation to each of the other spectra was calculated and based on the similarity table a hierarchical cluster analysis (HCA) was performed. Each of the components of the DMSO extracts of the tablets was quantified, providing a component table, which also was used for HCA. The quantitative analysis of paracetamol was determined to have a precision of 0.2% using the residual solvent signals as internal standard. The HCA of the similarity data and the component table were compared with the HCAs obtained by analysis of the crude NMR data. This clearly shows the limitations of multivariate data analysis and the strength of similarity calculations combined with differential NMR, especially in relation to the analysis of trace components. In fact, the spectrum is not a series of unrelated variables, but a superposition of a limited number of component spectra, and the quantities of these components were determined.

Application of Online NIR Spectroscopy to Enhance Process Understanding and Enable In-process Control Testing of Secondary Drying Process for a Spray-dried Solid Dispersion Intermediate

Near infrared spectroscopy (NIRS) was utilized to determine the endpoint of secondary drying process (post primary spray drying) of Spray-Dried Intermediates (SDI). In addition, NIR methods have been developed to quantify residual solvents (acetone and water), which are in-process controls (IPCs), and assay on the spray dried intermediate, thereby minimizing the need for off-line sample testing. NIRS calibration models were built with Partial Least Squares (PLS) regression for samples from several statistically designed experiments. Standard errors of prediction (SEP) of 0.1 wt. % for acetone, 0.2 wt. % for water, and 3.0 mg API/g SDI for API potency were obtained from validation of the models. When these methods were transferred to commercial scale on a different analyzer at a different site, additional updates to the NIR models were successfully made to overcome the impact from the differences in instrumentation and scale. Not only could real-time, in-process release be achieved, but also consistency and quality of data could be improved by minimizing or eliminating sample handling issues for off-line sample analysis. These NIR methods for secondary drying might also be used to optimize the drying process cycle time and study the effect of agitation rate, jacket temperature, and drying gas sweep rate on drying cycle time.

Protein folding stabilities are a major determinant of oxidation rates for buried methionine residues

The oxidation of protein-bound methionines to form methionine sulfoxides has a broad range of biological ramifications, making it important to delineate factors that influence methionine oxidation rates within a given protein. This is especially important for biopharmaceuticals, where oxidation can lead to deactivation and degradation. Previously, neighboring residue effects and solvent accessibility have been shown to impact the susceptibility of methionine residues to oxidation. In this study, we provide proteome-wide evidence that oxidation rates of buried methionine residues are also strongly influenced by the thermodynamic folding stability of proteins. We surveyed the Escherichia coli proteome using several proteomic methodologies and globally measured oxidation rates of methionine residues in the presence and absence of tertiary structure, as well as the folding stabilities of methionine-containing domains. These data indicated that buried methionines have a wide range of protection factors against oxidation that correlate strongly with folding stabilities. Consistent with this, we show that in comparison to E. coli, the proteome of the thermophile Thermus thermophilus is significantly more stable and thus more resistant to methionine oxidation. To demonstrate the utility of this correlation, we used native methionine oxidation rates to survey the folding stabilities of E. coli and T. thermophilus proteomes at various temperatures and propose a model that relates the temperature dependence of the folding stabilities of these two species to their optimal growth temperatures. Overall, these results indicate that oxidation rates of buried methionines from the native state of proteins can be used as a metric of folding stability.

Development and Validation of Head-Space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual Solvents in Letermovir API synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography / flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: ethyl acetate, MTBE, Toluene and isopropyl acetatein Letermovir API. HS-GC method in a simple and selective manner is delineated for the quantification and determination of Residual Solvents in Letermovir API. The separation of solvents along with drug on Chromatographic chamber was processed on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30 m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 10-50µg/ml for ethyl acetate, MTBE, Toluene and isopropyl acetate (r2>0.999) for the amount of solvent determined through sophisticated methods was in good agreement. The proposed methods were validated. The method of accuracy was assessed by recovery studies at three different levels.The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for ethyl acetate, MTBE, Toluene and isopropyl acetate. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of ethyl acetate, MTBE, Toluene and isopropyl acetate in Letermovir. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity (micrograms/mL) and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

Release of Ropinirole in Acrylate Transdermal Patches: Mutual Interactions Between Formulation Variables

The aim of this study is to evaluate the cooperative interactions between formulation variables of ropinirole transdermal patches and characterize the effects of drug loading and crystallinity, degree of ionization and drug-polymer solubilization, functionalization of acrylate polymeric basis, and the addition of permeation enhancers over the release profiles. Several series of transdermal films based on carboxylic or hydroxylic acrylates (DuroTak®) and containing 1 to 10% ropinirole hydrochloride were laminated by mold-casting and evaporation. Formulations were characterized for crystallinity, drug particle size, drug assay, and residual solvents. Release profiles were obtained at different drug ionization state using paddle over disk apparatus. Mechanisms were elucidated with nonlinear data fitting of relevant release equations. Fickian and erosion processes were evaluated with the Peppas–Sahlin equation, and burst release risks were estimated as an independent term added to Higuchi kinetics. X-ray diffraction and microscopy evidenced differences in drug-polymer solubilization and density of drug crystals. Concerning drug release, area under the curve of dissolved quantities and release percentage were discriminant variables in mutual influence. Peppas–Shalin equation was the majority descriptor of release suggesting a combination of Fickian and erosion processes, revealing a decrease in the Fickian component as drug loading increased. Major burst release risks were evidenced mostly with Higuchi kinetics with vinylacetate acrylates. The carboxylic polymer without vinylacetate provided the best release extent, being more highly efficient as lower the drug loading was. Permeation enhancers with carboxylic or aliphatic radicals have, additionally, modified the release properties of ropinirole. Chemical interactions between the drug and acrylic polymers have been demonstrated. Only the effect with carboxylic polymer is pH dependent. The vinyl acetate comonomer reduces the drug release rate most effectively in formulations with low drug loads. The acrylic polymers without vinylacetate achieved the highest drug solubilization and thus the highest degree of release, providing a release of approximately 15% of the drug load.