Purification Of Active Pharmaceutical Ingredients Research Articles

Organic Solvent Nanofiltration in Pharmaceutical Applications.

Separation and purification in organic solvents are indispensable procedures in pharmaceutical manufacturing. However, they still heavily rely on the conventional separation technologies of distillation and chromatography, resulting in high energy and massive solvent consumption. As an alternative, organic solvent nanofiltration (OSN) offers the benefits of low energy consumption, low solid waste generation, and easy scale-up and incorporation into continuous processes. Thus, there is a growing interest in employing membrane technology in the pharmaceutical area to improve process sustainability and energy efficiency. This Review comprehensively summarizes the recent progress (especially the last 10 years) of organic solvent nanofiltration and its applications in the pharmaceutical industry, including the concentration and purification of active pharmaceutical ingredients, homogeneous catalyst recovery, solvent exchange and recovery, and OSN-assisted peptide/oligonucleotide synthesis. Furthermore, the challenges and future perspectives of membrane technology in pharmaceutical applications are discussed in detail.

High-Degree Concentration Organic Solvent Forward Osmosis for Pharmaceutical Pre-Concentration.

Over half of the pharmaceutical industry's capital investments are related to the purification of active pharmaceutical ingredients (APIs). Thus, a cost-effective purification process with a highly concentrated solution is urgently required. In addition, the purification process should be nonthermal because most APIs and their intermediates are temperature-sensitive. This study investigated a high-degree concentration organic solvent forward osmosis (OSFO) membrane process. A polyketone-based thin-film composite hollow fiber membrane with a polyamide selective layer on the bore surface was used as the OSFO membrane to achieve a high tolerance for organic solvents and an effective concentration. MeOH, sucrose octaacetate (SoA), and 2M polyethylene glycol 400 (PEG-400)/MeOH solution were used as the solvent, model API, and a draw solution (DS), respectively. OSFO was performed at room temperature (23 ± 3 °C). Consequently, the 11 wt% SoA/MeOH solution was concentrated to 52 wt% without any SoA leakage into the DS. To our knowledge, there are no studies in which up to a 5 wt% concentration by OSFO has been demonstrated. However, the final feed solution contained 17 wt% PEG-400. This study demonstrates the promising potential of OSFO for pharmaceutical pre-concentration and the technical problems that need to be solved for social implementation.

Molecularly Imprinted Polymers for Pharmaceutical Impurities: Design and Synthesis Methods.

The safety of a medicinal product is determined by its pharmacological and toxicological profile, which depends not only on the active substance's toxicological properties, but also on the impurities it contains. Because impurities are a problem that must be considered to ensure the safety of a drug product, many studies have been conducted regarding the separation or purification of active pharmaceutical ingredients (APIs) and the determination of impurities in APIs and drug products. Several studies have applied molecularly imprinted polymers (MIPs) to separate impurities in active ingredients and as adsorbents in the sample preparation process. This review presents the design of MIPs and the methods used to synthesise MIPs to separate impurities in APIs and drug product samples, the application of MIPs to separate impurities, and a view of future studies involving MIPs to remove impurities from pharmaceutical products. Based on a comparison of the bulk and surface-imprinting polymerisation methods, the MIPs produced by the surface-imprinting polymerisation method have a higher adsorption capacity and faster adsorption kinetics than the MIPs produced by the bulk polymerisation method. However, the application of MIPs in the analysis of APIs and drug products are currently only related to organic compounds. Considering the advantages of MIPs to separate impurities, MIPs for other impurities still need to be developed, including multi-template MIPs for simultaneous separation of multiple impurities.

Solid-liquid phase equilibrium and thermodynamic properties analysis of Bazedoxifene acetate in fifteen kinds of mono-solvents

Crystallization is widely used for the isolation and purification of active pharmaceutical ingredients (APIs) in the final manufacturing stage. Bazedoxifene (BZD) acetate, classified as a third-generation selective estrogen receptor modulator, is employed in the treatment of postmenopausal osteoporosis. This work reports the equilibrium solubility data of BZD acetate in fifteen different mono-solvents, including methanol, ethanol, n-propanol, i-propanol, n-butanol, ethyl formate, methyl acetate, ethyl acetate, acetone, 2-butanone, cyclohexanone, tetrahydrofuran (THF), 2-methyltetrahydrofurane (2-MeTHF), 1,4-dioxane and acetonitrile (ACN), within the temperature range “T = 283.15–323.15 K” under p = 0.1 MPa. The solubilities of BZD acetate in various solvents increase with increasing temperature. Among the alcoholic solvents, the solubility order is as follows: methanol > ethanol > n-propanol > n-butanol > i-propanol. In esters solvent, the solubility of BZD acetate decreases in the following order: methyl acetate > ethyl acetate > ethyl formate. For ketones solvent, the solubility decreases in the following order: cyclohexanone > acetone > 2-butanone. The maximum value of BZD acetate solubility was 0.011 mol·mol−1 in tetrahydrofuran at T = 323.15 K, but the least data was found in ethyl formate at 283.15 K. Four thermodynamic models, i.e., the Yaws model, modified Apelblat model, λh model, and Wilson model were applied to fit the solubility data of BZD acetate in different solvents. Among them, the Wilson model represents the most accurate fitting outcomes. Finally, the thermodynamic functions of mixing (including enthalpy, entropy, and Gibbs energy) were calculated, and the results indicate a mixing process that is both spontaneous and driven by entropy. The solubility data, correlated models, and derived thermodynamic functions present essential thermodynamic fundamentals for the industrial production of BZD acetate crystallization, facilitating efficient separation and purification.

Optimization and troubleshooting of preparative liquid chromatography using statistical design of experiments: Four small-molecule case studies

Statistical design of experiments (DoE) is used to aid in the development and execution of preparative liquid chromatography (LC) for large-scale purification of active pharmaceutical ingredients (API) and pharmaceutical intermediates. Four purification case studies were undertaken. In case study 1, a normal phase preparative silica method is developed and modeled. After initial method screening, DoE results were used to set mobile phase composition, flowrate, and sample diluent. Of the three particle sizes studied (10 µm, 20 µm, 50 µm) only 10 µm silica resin was able to produce purified API at the yield (>96%) and productivity (> 1 kg/kg-resin/day) necessitated by the project. The second case study uses DoE studies to identify critical process parameters of column load, mobile phase solvent ratio and basic modifier level for a low-resolution, preparative, chiral separation. Trade-offs between purity, yield and productivity are quantified in a tight separation which made compromising on process outcomes a necessity. The third case study troubleshoots a loss of yield experienced during operation of a process-scale reverse-phase LC purification. DoE is used to identify a critical interaction between levels of acetonitrile and phosphoric acid in the mobile phase. An operating region which increased yield from around 85% to 97% was defined and implemented. The fourth case study was initially designed as a preparative chromatography purification of API. DoE was used to screen mobile phase solubility. These experiments uncovered conditions where API is soluble, and impurities are not. The solubility model in acetonitrile/water mixtures is further defined via a response surface DoE. The resulting targeted solvent mixture allows bulk purification via dissolution of API while three less-polar impurities remain in the solid phase and are removed by filtration. These four case studies demonstrate the efficiency of DoE and response surface modeling as tools for process development and optimization.

Crystallization Operation for Purification of Active Pharmaceutical Ingredients

Crystallization Operation for Purification of Active Pharmaceutical Ingredients

Continuous purification of active pharmaceutical ingredients utilizing polymer membrane surface wettability.

Continuous processing of pharmaceuticals opens opportunities for continuous separation based on wettability of polymer membranes. Dual use of hydrophobic and hydrophilic membranes realize in-line liquid-liquid extraction in the synthesis of four essential APIs. A secondary membrane with opposite wetting characteristics proves critical to phase separation of aqueous-organic reaction streams.

Johnson Matthey teams with Intrexon

Johnson Matthey and and Intrexon, a Budapest-based biopharmaceutical firm, will jointly develop microbial strains for the production of peptide-based active pharmaceutical ingredients (APIs) via fermentation. Intrexon will contribute its proprietary microbial hosts and fermentation processes to the initial fermentation, isolation, and purification of APIs. Johnson Matthey will be responsible for scale-up, formulation, and commercialization of microbial strains.

The achievements and problems of the production of generic drug substances for pharmaceutical industry

The key achievements, problems, and prospects of the pharmaceutical industry in the Russian Federation concerning the development, synthesis, and purification of active pharmaceutical ingredients (generic drugs) are considered.

Partition Coefficients of Pharmaceuticals as Functions of Temperature and pH

Liquid–liquid extraction is a potential separation process for the purification of active pharmaceutical ingredients (APIs). The design of an extraction step requires knowledge of the API partition coefficient, which strongly depends on the solvent system and process conditions. Usually, cost-intensive experiments have to be performed to select the most suitable solvent system and the best process conditions. The number of experiments can be reduced by predicting the partition coefficient using perturbed chain statistical associating theory (PC-SAFT). In this work, modeling results and experimental data were compared for the partition coefficients of the APIs nicotinamide and salicylamide in different solvent systems at temperatures from 293.15 to 328.15 K and at pH values varying between 5.2 and 10.3. The results show that PC-SAFT is able to predict the API partition coefficients for different solvent systems as functions of temperature and pH.

Continuous purification of active pharmaceutical ingredients using multistage organic solvent nanofiltration membrane cascade

Downstream processing accounts for a large fraction of the production costs in pharmaceutical manufacturing. Organic solvent nanofiltration performed in a membrane cascade offers an interesting possibility for a continuous downstream processing unit operation. This work demonstrates continuous purification of Active Pharmaceutical Ingredient (API) Roxithromycin from potential Genotoxic Impurity (GTI) 4-dimethylaminopyridine (DMAP) in a simple and efficient two stage membrane cascade. Cascade performance is initially evaluated via mathematical simulations, and then validated experimentally. We demonstrated that by careful selection of operating parameters, high purity of the API >99% could be achieved from feed stream purity of 78%. The continuous cascade could be easily coupled with an adsorption column, utilising an inexpensive non-selective adsorbent such as charcoal, as a solvent recovery stage. The combined continuous process generates orders of magnitude less waste than a batch diafiltration which makes it an attractive alternative purification process for pharmaceutical industry.

REMOVED: A Simple Closed-Loop Membrane Cascade System for Purification of Active Pharmaceutical Ingredients (API)

REMOVED: A Simple Closed-Loop Membrane Cascade System for Purification of Active Pharmaceutical Ingredients (API)

INDENA STEPS UP

READINESS TO ADAPT to changing times and market conditions has enabled Indena, a privately held Italian medicinal and nutritional plant extracts specialist, to survive for 90 years. The company’s annual sales grew to $200 million mainly by making custom active pharmaceutical ingredients (APIs) for drug firms and standardized plant extracts for nutritional supplement makers. Now it is conducting internal research programs to discover, patent, and license its own drugs. And it has started up a new business to make single-dose nutritional supplements for sale by prescription in Italy. Over many years, explains Dario Bonacorsi, the company’s president, Indena became expert in scaling up the extraction and purification of APIs from plant sources. Success led to a long list of process patents. But such patents are no guarantee that a customer will buy only from Indena. “As you know, others can develop processes of their own to compete at lower cost,” says Bonacorsi, a Ph.D. electrical ...