Drying of an active pharmaceutical ingredient, in the form of a crystalline hydrate, was investigated using a small-scale flow cell methodology. A new laboratory tool was developed and demonstrated ...using a simple segregated column technique to quickly distinguish different drying mechanisms using a minimal number of experiments. For the case studied here, increasing vacuum levels improved the removal of solvents while use of nitrogen flow through the solids facilitated water removal. Additional results are presented from experiments conducted to assess the impact of the crystallization solvent system and washing on drying behavior and cake properties. A system was identified which avoided issues associated with poor cake handling and improved overall drying performance. This article provides details on the new experimental method used that helped lead to the rapid development of an improved drying process and presents results demonstrated through the pilot plant scale.
Exposure of wildlife to Active Pharmaceutical Ingredients (APIs) is likely to occur but studies of risk are limited. One exposure pathway that has received attention is trophic transfer of APIs in a ...water-fish-osprey food chain. Samples of water, fish plasma and osprey plasma were collected from Delaware River and Bay, and analyzed for 21 APIs. Only 2 of 21 analytes exceeded method detection limits in osprey plasma (acetaminophen and diclofenac) with plasma levels typically 2–3 orders of magnitude below human therapeutic concentrations (HTC). We built upon a screening level model used to predict osprey exposure to APIs in Chesapeake Bay and evaluated whether exposure levels could have been predicted in Delaware Bay had we just measured concentrations in water or fish. Use of surface water and BCFs did not predict API concentrations in fish well, likely due to fish movement patterns, and partitioning and bioaccumulation uncertainties associated with these ionizable chemicals. Input of highest measured API concentration in fish plasma combined with pharmacokinetic data accurately predicted that diclofenac and acetaminophen would be the APIs most likely detected in osprey plasma. For the majority of APIs modeled, levels were not predicted to exceed 1 ng/mL or method detection limits in osprey plasma. Based on the target analytes examined, there is little evidence that APIs represent a significant risk to ospreys nesting in Delaware Bay. If an API is present in fish orders of magnitude below HTC, sampling of fish-eating birds is unlikely to be necessary. However, several human pharmaceuticals accumulated in fish plasma within a recommended safety factor for HTC. It is now important to expand the scope of diet-based API exposure modeling to include alternative exposure pathways (e.g., uptake from landfills, dumps and wastewater treatment plants) and geographic locations (developing countries) where API contamination of the environment may represent greater risk.
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•21 pharmaceuticals analyzed in DE Bay and River water, fish and osprey plasma.•8 were quantifiable in water, 7 in fish plasma but only 2 in osprey plasma.•Acetaminophen was detected in 22 of 29 osprey plasma samples.•Acetaminophen was 3 orders of magnitude below human therapeutic concentration.•Exposure levels for ospreys could be predicted using a read-across approach.
Low-level exposure of ospreys to pharmaceuticals via diet was detected in Delaware Bay, concentrations in plasma were predicted using a pharmacokinetic model.
A Balz-Schiemann reaction was developed to convert 2-cyano-5-aminopyridine to 2-cyano-5-fluoropyridine. The use of an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF4) as a ...solvent was found to be critical in achieving high assay yields and high selectivity for the fluorination vs. protonation. A process was developed to recycle and reuse the ionic liquid enabling its cost-effective use as a solvent. Finally, the optimal conditions were demonstrated under as a continuous process to address process safety risks associated with diazonium intermediates and the product was used to access a key intermediate in the synthesis of β-amyloid cleaving enzyme 1 inhibitor, verubecestat.
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The pharmaceutical industry has shown a strong interest in flow synthesis and continuous production. In general, solvent selection is performed based on solubility and reactivity/selectivity, but in ...heterogeneous reactions, solvent properties related to mass transfer can affect the reaction performance. This work presents a model-based analysis of the impact of solvent selection in batch and flow syntheses for heterogeneous hydrogenation, e.g., for doripenem, a commercialized antibiotic. Simulations of reaction conversions under different conditions were conducted. First, a sensitivity analysis was performed, where the effects of individual solvent properties (viscosity, density, Henry’s law constant, and concentration) were examined, followed by solvent selection from six existing candidates. The sensitivity analysis results showed that the individual properties had different impacts on reactions in batch and flow syntheses, and thus the optimal solvent choice varied in each case. The results can be useful for solvent design, such as computer-aided molecular design. A guideline for solvent selection was proposed to assist in reducing dedicated experimental burden and allowing for more deliberate and selective solvent selection.
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•Model-based analysis of solvent selection on batch and flow syntheses using heterogeneous hydrogenation.•Different impact of individual solvent property on batch and flow syntheses.•Variations in ideal solvents between batch and flow syntheses.•Guideline for better solvent selection when changing from batch to flow synthesis.
Excipients are important components of the final medicinal product. They perform many important functions as fillers, lubricants, disintegrating agents, stabilizers, emulsifiers, etc., and their ...presence in the formulation is essential. They facilitate the technological process and improve the drug bioavailability. Their proper selection is necessary to obtain the final product with appropriate physicochemical properties. The excipients are not inert compounds. They undergo many interactions with the drug. The occurrence of chemical interactions as a consequence of the chemical reaction of the active substance with the excipient or its impurities can lead to degradation of the drug (including the formation of toxic degradation products) or reduction of its therapeutic properties. Examples of chemical reactions are reactions with water molecules (including hydrolysis), oxidation, isomerization, and other complex chemical reactions such as Maillard reactions. Physical interactions involving changes in physicochemical parameters such as solubility, alteration in flavor, odor, or color lead to changes in the bioavailability of the drug. Physical drug-excipient interactions (adsorption or complex formation, etc.) are commonly used in the pharmaceutical industry e.g., to improve the solubility of lipophilic substances, thus achieving higher bioavailability. Sometimes they are unintentional, and the occurrence of these phenomena may have a detrimental effect on the final product (changes in color, odor, or flavor, difficult drug release from the excipient complex). Excipients may also affect the drug metabolism by enhancing or inhibiting the activity of cytochrome P450 and P-glycoprotein. In addition, they are also subject to a number of interactions with body fluids. The impurities of excipients are an important aspect of the formulation. The most common impurities are oxides, aldehydes, acids, and metals. Usually, these substances are highly reactive. Therefore, their presence is often the cause of incompatibility. In order to minimize the occurrence of interactions, so-called formulation compatibility tests are performed, and the most effective is the combination of thermoanalytical and non-thermoanalytical (spectroscopic, chromatographic) methods of analysis. Currently, there are no globally harmonized regulatory requirements for excipients, however, organizations such as IPEC are working towards harmonization.
A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from (R)-3-amino-1-butanol and establishes the BC ...ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2E/Z)-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr2·OEt2-mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48–51% isolated yield (HPLC purity of 99.7–99.9%) over six linear steps.
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Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug ...substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.
•Microchip isotachophoresis methods for pharmaceutical quality control developed.•Universal methods validated in accordance with the ICH guideline.•The greenness of the proposed methods ...evaluated.•Active ingredients and counterions determined in six commercial formulations.
Universal microchip isotachophoresis (μITP) methods were developed for the determination of cationic and anionic macrocomponents (active pharmaceutical ingredients and counterions) in cardiovascular drugs marketed in salt form, amlodipine besylate and perindopril erbumine. The developed methods are characterized by low reagent and sample consumption, waste production and energy consumption, require only minimal sample preparation and provide fast analysis. The greenness of the proposed methods was assessed using AGREE. An internal standard addition was used to improve the quantitative parameters of μITP. The proposed methods were validated according to the ICH guideline. Linearity, precision, accuracy and specificity were evaluated for each of the studied analytes and all set validation criteria were met. Good linearity was observed in the presence of matrix and in the absence of matrix, with a correlation coefficient of at least 0.9993. The developed methods allowed precise and accurate determination of the studied analytes, the RSD of the quantitative and qualitative parameters were less than 1.5% and the recoveries ranged from 98 to 102%. The developed μITP methods were successfully applied to the determination of cationic and anionic macrocomponents in six commercially available pharmaceutical formulations.
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