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1
Patil, Sayali T., Monika S. Mane, Kshitija S. Desai, Satyajeet R. Jagdale, Pankaj A. Jadhav, and Harshada A. Patil. "Co-Crystallization: Approaches, Characterization and Applications in Drug Delivery." Journal of Pharmaceutical Technology, Research and Management 10, no. 2 (November 10, 2022): 141–49. http://dx.doi.org/10.15415/jptrm.2022.102004.
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Co-crystals play a significant role in the pharmaceutical sector. Medicinal co crystals are multicomponent systems with at least one active therapeutic ingredient and the rest of the constituents being pharmaceutically acceptable. Co crystallization of a medicinal material with a coformer is a potential and growing method for improving pharmaceutical performance in areas such as solubility, dissolution profile, pharmacokinetics, and stability.. A key barrier to developing novel API compounds is poor bio availability and water solubility, which can limit the effectiveness of new drugs or prevent their approval for the market. In terms of the significant enhancement in solubility profiles compared to the single- active pharmaceutical ingredients, co-crystals provide a distinct and competitive edge over other traditional approaches.
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Pradeep Shetye, Ms Maitrayee. "A Study of Active Pharmaceutical Ingredients Disposition of Waste." MET Management Review 09, no. 02 (2022): 48–51. http://dx.doi.org/10.34047/mmr.2020.9206.
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API (Active Pharmaceutical Ingredient) means the active ingredient which is contained in medicine. For example, an active ingredient to relieve pain is included in a painkiller. Developing and producing Active Pharmaceutical Ingredients (APIs) includes various processing steps, such as reaction, crystallization, separation and purification, solvent swap, and solvent exchange. Active Pharmaceutical Ingredients or APIs are also known as bulk drugs and a term that is often heard in business news. An active ingredient is the ingredient in a pharmaceutical drug or pesticide that is biologically active. The similar terms active pharmaceutical ingredient and bulk active are also used in medicine, and the term active substance may be used for natural products. Active Pharmaceutical Ingredients are the active ingredients contained in a medicine. The issue of disposal of wastes from these API companies, as well as the development and implementation of efficient collection strategies, is an important concern. This research looks into the factors that have an impact on the disposition of wastes from these companies, and how are these addressed by local government bodies. The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients with the aim to cure them, vaccinate them, or alleviate symptoms. Pharmaceutical companies may deal in generic or brand medications and medical devices. They are subject to a variety of laws and regulations that govern the patenting, testing, safety, efficacy using drug testing and marketing of drugs.
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Joshi, Varda, Poonam Raut, and Nikita Bhosale. "A review Review on Co-Crystals New Approach to Modify the Physicochemical Characteristics of API." Asian Journal of Pharmaceutical Research and Development 11, no. 3 (June 15, 2023): 103–11. http://dx.doi.org/10.22270/ajprd.v11i3.1263.
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The expansion of a novel product is constrained by an active medicinal ingredient's poor solubility in aqueous solutions and limited oral bioavailability. A novel strategy to improve the physicochemical characteristics of the active medicinal ingredient is co-crystal formation. The pharmacological action of the API is unaffected by co-crystallization with pharmaceutically acceptable molecules, although it can enhance the physical characteristics like solubility, stability, and dissolution rate. Cocrystals are multi-component systems comprising active medicinal ingredients that also contain a stoichiometric amount of a coformer that is acceptable to the pharmaceutical industry. The pharmaceutical business has a significant chance to create new medicinal products since producing pharmaceutical co-crystals can enhance a drug's physicochemical qualities.The most major benefit of co-crystals is their ability to produce novel medications with improved solubility, which increases the effectiveness and safety of the treatment. The thermodynamic stability of the co-crystal preparation is the key influencing factor. Co-crystal screening provides information on the chemical composition and connection between the active medicinal ingredient and the coformer. This review discusses the many co-crystal synthesis techniques, including hot-melt extrusion, slurrying, antisolvent, grinding, and spray drying. Here is a quick explanation of the characteriszation methods frequently employed for co-crystals, as well as their uses in medicine. Here are some quick summaries of reported research on co-crystals that were evaluated in order to better grasp the notion of co-crystals.
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Rosenbaum, Tamar, Li Tan, and Joshua Engstrom. "Advantages of Utilizing Population Balance Modeling of Crystallization Processes for Particle Size Distribution Prediction of an Active Pharmaceutical Ingredient." Processes 7, no. 6 (June 10, 2019): 355. http://dx.doi.org/10.3390/pr7060355.
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Active pharmaceutical ingredient (API) particle size distribution is important for both downstream processing operations and in vivo performance. Crystallization process parameters and reactor configuration are important in controlling API particle size distribution (PSD). Given the large number of parameters and the scale-dependence of many parameters, it can be difficult to design a scalable crystallization process that delivers a target PSD. Population balance modeling is a useful tool for understanding crystallization kinetics, which are primarily scale-independent, predicting PSD, and studying the impact of process parameters on PSD. Although population balance modeling (PBM) does have certain limitations, such as scale dependency of secondary nucleation, and is currently limited in commercial software packages to one particle dimension, which has difficulty in predicting PSD for high aspect ratio morphologies, there is still much to be gained from applying PBM in API crystallization processes.
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Stocker, Michael, Matthew Harding, Valerio Todaro, Anne Healy, and Steven Ferguson. "Integrated Purification and Formulation of an Active Pharmaceutical Ingredient via Agitated Bed Crystallization and Fluidized Bed Processing." Pharmaceutics 14, no. 5 (May 14, 2022): 1058. http://dx.doi.org/10.3390/pharmaceutics14051058.
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Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.
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Amir, Md, Md Ashfaque Alam, Md Fauwaz Aftab, Md Gulam Nabi, Md Sadre Alam, Jagdeesh Rathi, and Sonpal Singh Thakur. "Effect of pH on Pharmaceutical Ingredients / Drugs / Chemicals." Asian Journal of Dental and Health Sciences 2, no. 3 (September 15, 2022): 9–11. http://dx.doi.org/10.22270/ajdhs.v2i3.17.
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The word excipient is derived from the Latin excipere meaning to except, which is simply explained as other than. Pharmaceutical excipients are basically everything other than the active pharmaceutical ingredient. Ideally, excipients should be inert, however, recent reports of adverse reactions have suggested otherwise. Pharmaceutical excipients are substances other than the active pharmaceutical ingredient (API) that have been appropriately evaluated for safety and are intentionally included in a drug delivery system. Solubility, which defines the liquid /solid equilibrium, is a key parameter to control a crystallization process. As the API is a weak acid (pKa = 3.7), its solubility increases with the pH. On the basis of the experimental curve of solubility, a model was defined to fit the evolution of the solubility as a function of pH. In the case of this compound, studies revealed a weak influence of the temperature in comparison with the pH. So, the solubility of the compound is slightly impacted by the temperature. Some experiments were carried out in order to compare the solubility of the API, at the same pH and temperature, for different concentrations of impurities found in the process. The results revealed a solubility increase in presence of acetic acid and a high solubility decrease in presence of sodium chloride. By carrying out experiments on common ions salts, the anion chloride Cl− has been identified as the cause of the solubility decrease. Keywords: Solubility, API, Impurity, Ph
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Ramos Ojeda, Nicolás Antonio, and Mathias Kind. "Transferring Crystallization Conditions from Small to Larger Scale for Achieving Targeted Crystal Morphologies of an Active Pharmaceutical Ingredient." Crystals 14, no. 1 (December 28, 2023): 42. http://dx.doi.org/10.3390/cryst14010042.
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Crystal morphology plays a critical role in the processability and physicochemical behavior of active pharmaceutical ingredients. Manipulating crystal morphology involves consideration of crystallization conditions such as temperature, supersaturation, and solvent choice. Typically, experimental screenings on a small scale are conducted to find targeted crystal morphologies. However, results from such small-scale experiments do not assure direct success at a larger scale, particularly if the small-scale setup differs significantly from a conventional stirred crystallizator. In this study, we successfully validated the morphologies observed in the small-scale experiments of an exemplary API, Bitopertin, when scaled up by a factor of 200, through the maintenance of identical process conditions and geometrical vessel relations. This successful scalability highlights the significant potential of small-scale crystallization studies to provide a reliable foundation for further exploration in large-scale endeavors.
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Bisht, Kamal Kumar, Priyank Patel, Yadagiri Rachuri, and Suresh Eringathodi. "Binary co-crystals of the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and camphoric acid." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 70, no. 1 (January 16, 2014): 63–71. http://dx.doi.org/10.1107/s2052520613031260.
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Co-crystals comprising the active pharmaceutical ingredient 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene, C12H10N4, and the chiral co-formers (+)-, (−)- and (rac)-camphoric acid (cam), C10H16O4, have been synthesized. Two different stoichiometries of the API and co-former are obtained, namely 1:1 and 3:2. Crystallization experiments suggest that the 3:2 co-crystal is kinetically favoured over the 1:1 co-crystal. Single-crystal X-ray diffraction analysis of the co-crystals reveals N—H...O hydrogen bonding as the primary driving force for crystallization of the supramolecular structures. The 1:1 co-crystal contains undulating hydrogen-bonded ribbons, in which the chiral cam molecules impart a helical twist. The 3:2 co-crystal contains discrete Z-shaped motifs comprising three molecules of the API and two molecules of cam. The 3:2 co-crystals with (+)-cam, (−)-cam (space groupP21) and (rac)-cam (space groupP21/n) are isostructural. The enantiomeric co-crystals contain pseudo-symmetry consistent with space groupP21/n, and the co-crystal with (rac)-cam represents a solid solution between the co-crystals containing (+)-cam and (−)-cam.
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Kumar, Rahul, Amit K. Thakur, Nilanjana Banerjee, and Pranava Chaudhari. "Investigation on crystallization phenomena with supercritical carbon dioxide (CO2) as the antisolvent." International Journal of Chemical Reactor Engineering 19, no. 8 (July 14, 2021): 861–71. http://dx.doi.org/10.1515/ijcre-2020-0189.
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Abstract The supercritical antisolvent (SAS) recrystallization process is one of the most promising recrystallization techniques for the particle formation of pharmaceutical compounds. In this process, a solution of active pharmaceutical ingredient (API) is sprayed into the supercritical carbon dioxide (SC CO2) environment. The mass transport of both the solvent and the antisolvent results in supersaturation followed by the crystallization of the API. In this work, a model is developed to estimate the supersaturation profile of solute in a droplet falling in the SC CO2 environment. The droplet consists of paracetamol as a solute and ethanol as a solvent. It moves down in the antisolvent (supercritical CO2) environment. Interestingly, the present model predicts a rise in supersaturation followed by a fall for a while and then a sharp increase. The competing phenomena of nucleation and growth mechanisms are used to justify this variation in the supersaturation.
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Raheem Thayyil, Abdul, Thimmasetty Juturu, Shashank Nayak, and Shwetha Kamath. "Pharmaceutical Co-Crystallization: Regulatory Aspects, Design, Characterization, and Applications." Advanced Pharmaceutical Bulletin 10, no. 2 (February 18, 2020): 203–12. http://dx.doi.org/10.34172/apb.2020.024.
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Pharmaceutical co-crystals are novel class of pharmaceutical substances, which possess an apparent probability of advancement of polished physical properties offering stable and patentable solid forms. These multi-component crystalline forms influence pertinent physicochemical parameters like solubility, dissolution rate, chemical stability, physical stability, etc. which in turn result in the materials with superior properties to those of the free drug. Co-crystallization is a process by which the molecular interactions can be altered to optimize the drug properties. Co-crystals comprise a multicomponent system of active pharmaceutical ingredient (API) with a stoichiometric amount of a pharmaceutically acceptable coformer incorporated in the crystal lattice. By manufacturing pharmaceutical co-crystals, the physicochemical properties of a drug can be improved thus multicomponent crystalline materials have received renewed interest in the current scenario due to the easy administration in the pharmaceutical industry. There is an immense amount of literature available on co-crystals. However, there is a lack of an exhaustive review on a selection of coformers and regulations on co-crystals. The review has made an attempt to bridge this gap. The review also describes the methods used to prepare co-crystals with their characterization. Brief description on the pharmaceutical applications of co-crystals has also been incorporated here. Efforts are made to include reported works on co-crystals, which further help to understand the concept of co-crystals in depth.
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Paolello, Mitchell, Ilyes Bichari, Davinia Brouckaert, Mirvatte Francis, Dawn Yang, and Gerard Capellades. "Kinetic Optimization of the Batch Crystallization of an Active Pharmaceutical Ingredient in the Presence of a Low-Solubility, Precipitating Impurity." Crystals 13, no. 11 (November 3, 2023): 1569. http://dx.doi.org/10.3390/cryst13111569.
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The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the crystallization solvent and simultaneously precipitate with the product. This publication reports the development of a population balance model to investigate if the impurity crystallization kinetics can be selectively inhibited in a seeded batch crystallization system containing acetaminophen (ACM), a commonly used small-molecule active pharmaceutical ingredient (API), and curcumin (CUR), a simulated low-solubility/co-precipitating impurity. Raman spectroscopy was used in combination with a partial least squares (PLS) model for in situ monitoring of the crystallization process. The Raman data were integrated to calibrate a population balance model in gPROMS FormulatedProducts, to predict the evolution of the product’s purity throughout the process. Process optimization demonstrated that a high purity close to equilibrium is feasible within the first 2 h of crystallization, with ACM seed purity being the primary factor controlling this phenomenon. The optimal approach for kinetically rejecting impurities requires a low nucleation rate for the impurity, high product seed purities, and an adjustable crystallization time so the process can be stopped before equilibrium without allowing the impurity to nucleate. Overall, an improvement in product purity before equilibrium is attainable if there is enough difference in growth kinetics between the product and impurity, and if one can generate relatively pure seed crystals.
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Kiss, Tamás, Gábor Katona, and Rita Ambrus. "Crystallization and physicochemical investigation of melevodopa hydrochloride, a commercially available antiparkinsonian active substance." Acta Pharmaceutica Hungarica 91, no. 2 (November 11, 2021): 45–52. http://dx.doi.org/10.33892/aph.2021.91.45-52.
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In this work, the levodopa methyl ester was crystallized from different solvents and its physicochemical proper- ties were explored. This active pharmaceutical ingredient (API) is commercially available as an effervescent tablet in Italy. The crystallization methods were solvent evaporation from different solvents (water, ethanol, methanol) and crystalliza- tion by adding an antisolvent. These methods led to the same product which had the same different Xray powder dif-fractogram that was different from the diffractogram of raw LDME. According to the hotstage microscopy and differential scanning calorimetry (DSC), the melting point was remarkably decreased, however, above the melting point, the melt tended to recrystallize to the raw LDME which was shown by an exothermic peak on the DSC curve. This was verified by an additional test during which the API was heated to 145 °C, thereafter the diffractogram matched perfectly with theraw LDME. These results indicate the presumable formation of a new polymorph. During the crystallization, the LDME did not degrade according to the high-performance liquid chromatography. Besides the recrystallization kinetics of the amorphous form was also followed, the activation energy of recrystallization was 85.3 kJ/mol, the diffractogram of recrys- tallization was the same as in the case of the crystallized products.
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Krummnow, Adrian, Andreas Danzer, Kristin Voges, Samuel O. Kyeremateng, Matthias Degenhardt, and Gabriele Sadowski. "Kinetics of Water-Induced Amorphous Phase Separation in Amorphous Solid Dispersions via Raman Mapping." Pharmaceutics 15, no. 5 (May 2, 2023): 1395. http://dx.doi.org/10.3390/pharmaceutics15051395.
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The poor bioavailability of an active pharmaceutical ingredient (API) can be enhanced by dissolving it in a polymeric matrix. This formulation strategy is commonly known as amorphous solid dispersion (ASD). API crystallization and/or amorphous phase separation can be detrimental to the bioavailability. Our previous work (Pharmaceutics 2022, 14(9), 1904) provided analysis of the thermodynamics underpinning the collapse of ritonavir (RIT) release from RIT/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) ASDs due to water-induced amorphous phase separation. This work aimed for the first time to quantify the kinetics of water-induced amorphous phase separation in ASDs and the compositions of the two evolving amorphous phases. Investigations were performed via confocal Raman spectroscopy, and spectra were evaluated using so-called Indirect Hard Modeling. The kinetics of amorphous phase separation were quantified for 20 wt% and 25 wt% drug load (DL) RIT/PVPVA ASDs at 25 °C and 94% relative humidity (RH). The in situ measured compositions of the evolving phases showed excellent agreement with the ternary phase diagram of the RIT/PVPVA/water system predicted by PC-SAFT in our previous study (Pharmaceutics 2022, 14(9), 1904).
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Inam, Muhammad, Jiajia Wu, Jie Shen, Chi Phan, Guping Tang, and Xiurong Hu. "Preparation and Characterization of Novel Pharmaceutical Co-Crystals: Ticagrelor with Nicotinamide." Crystals 8, no. 9 (August 21, 2018): 336. http://dx.doi.org/10.3390/cryst8090336.
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Two new co-crystals, Ticagrelor with Nicotinamide, have been prepared with improved solubility. Because Ticalegor has a poor solubility and dissolution rate, a novel co-crystallization method with structurally homogenous crystalline material, an active pharmaceutical ingredient (API), and co-former indefinite stoichiometric amount has been made to improve Ticagrelor’s solubility. The co-crystal of Ticagrelor (TICA) with Nicotinamide (NCA) was prepared in ratio (1:1) and confirmed by FTIR, DSC, and XRD characterization. Furthermore, the single crystal structure of TICA-NCA hydrate was analyzed. The solubility of co-crystals was investigated in pH 2 acidic medium, which was a significant improvement as compared to the solubility of a free drug. The in vitro dissolution rate of co-crystal was larger than that of the commercial product.
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Banerjee, Manali, and Blair Brettmann. "Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization." Pharmaceutics 12, no. 10 (October 20, 2020): 995. http://dx.doi.org/10.3390/pharmaceutics12100995.
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Poor water solubility is one of the major challenges to the development of oral dosage forms containing active pharmaceutical ingredients (APIs). Polymorphism in APIs leads to crystals with different surface wettabilities and free energies, which can lead to different dissolution properties. Crystal size and habit further contribute to this variability. An important focus in pharmaceutical research has been on controlling the drug form to improve the solubility and thus bioavailability of APIs. In this regard, heterogeneous crystallization on surfaces and crystallization under confinement have become prominent forms of controlling polymorphism and drug crystal size and habits; however there has not been a thorough review into the emerging field of combining these approaches to control crystallization. This tutorial-style review addresses the major advances that have been made in controlling API forms using combined crystallization methods. By designing templates that not only control the surface functionality but also enable confinement of particles within a porous structure, these combined systems have the potential to provide better control over drug polymorph formation and crystal size and habit. This review further provides a perspective on the future of using a combined crystallization approach and suggests that combining surface templating with confinement provides the advantage of both techniques to rationally design systems for API nucleation.
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Pedro, Sónia N., Carmen S. R. Freire, Armando J. D. Silvestre, and Mara G. Freire. "The Role of Ionic Liquids in the Pharmaceutical Field: An Overview of Relevant Applications." International Journal of Molecular Sciences 21, no. 21 (November 5, 2020): 8298. http://dx.doi.org/10.3390/ijms21218298.
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Solubility, bioavailability, permeation, polymorphism, and stability concerns associated to solid-state pharmaceuticals demand for effective solutions. To overcome some of these drawbacks, ionic liquids (ILs) have been investigated as solvents, reagents, and anti-solvents in the synthesis and crystallization of active pharmaceutical ingredients (APIs), as solvents, co-solvents and emulsifiers in drug formulations, as pharmaceuticals (API-ILs) aiming liquid therapeutics, and in the development and/or improvement of drug-delivery-based systems. The present review focuses on the use of ILs in the pharmaceutical field, covering their multiple applications from pharmaceutical synthesis to drug delivery. The most relevant research conducted up to date is presented and discussed, together with a critical analysis of the most significant IL-based strategies in order to improve the performance of therapeutics and drug delivery systems.
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Tian, Beiqian, Zhiyong Ding, Shuyi Zong, Jinyue Yang, Na Wang, Ting Wang, Xin Huang, and Hongxun Hao. "Manipulation of Pharmaceutical Polymorphic Transformation Process Using Excipients." Current Pharmaceutical Design 26, no. 21 (June 24, 2020): 2553–63. http://dx.doi.org/10.2174/1381612826666200213122302.
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Background: In the pharmaceutical field, it is vital to ensure a consistent product containing a single solid-state form of the active pharmaceutical ingredient (API) in the drug product. However, some APIs are suffering from the risk of transformation of their target forms during processing, formulation and storage. Methods: The purpose of this review is to summarize the relevant category of excipients and demonstrate the availability and importance of using excipients as a key strategy to manipulate pharmaceutical polymorphic transformation. Results: The excipient effects on solvent-mediated phase transformations, solid-state transitions and amorphous crystallization are significant. Common pharmaceutical excipients including amino acids and derivatives, surfactants, and various polymers and their different manipulation effects were summarized and discussed. Conclusion: Appropriate use of excipients plays a role in manipulating polymorphic transformation process of corresponding APIs, with a promising application of guaranteeing the stability and effectiveness of drug dosage forms.
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Lahoti, Anand M., Narendra B. Ambhaikar, D. M. Rajagopal Reddy, Arnab Roy, Kallam V. S. R. Krishna Reddy, and S. Mahender Rao. "Investigation of Alcaftadine using a Double Oxidation Process by Eliminating Column Chromatography." Asian Journal of Chemistry 34, no. 6 (2022): 1431–38. http://dx.doi.org/10.14233/ajchem.2022.23672.
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Alcaftadine is an active pharmaceutical ingredient (API) used as an ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. The originally reported synthesis uses a time-consuming column chromatography technique for the isolation of hydroxymethylated product alcohol (10). A simple yet effective double oxidation strategy is developed using oxidation grade manganese dioxide to avoid tedious chromatographic purification. Firstly, a partial oxidation of hydroxymethylated crude mass (mixture of compounds 9, 10 and 16) was carried out using a limited amount of MnO2 to get rid of critical diol impurity (16) and to allow crystallization of alcohol (10) crude, followed by its second oxidation using additional MnO2 to provide alcaftadine via a scale-up friendly process. This synthetic approach has been proven to be cost effective and commercially viable. Various impurities formed during the process were also identified and eliminated to obtain ICH guideline purity of alcaftadine API. The process was validated in plant scale and US DMF was filed to manufacture alcaftadine API.
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Chewle, Surahit, Franziska Emmerling, and Marcus Weber. "Effect of Choice of Solvent on Crystallization Pathway of Paracetamol: An Experimental and Theoretical Case Study." Crystals 10, no. 12 (December 4, 2020): 1107. http://dx.doi.org/10.3390/cryst10121107.
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The choice of solvents influences crystalline solid formed during the crystallization of active pharmaceutical ingredients (API). The underlying effects are not always well understood because of the complexity of the systems. Theoretical models are often insufficient to describe this phenomenon. In this study, the crystallization behavior of the model drug paracetamol in different solvents was studied based on experimental and molecular dynamics data. The crystallization process was followed in situ using time-resolved Raman spectroscopy. Molecular dynamics with simulated annealing algorithm was used for an atomistic understanding of the underlying processes. The experimental and theoretical data indicate that paracetamol molecules adopt a particular geometry in a given solvent predefining the crystallization of certain polymorphs.
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Dohrn, Stefanie, Samuel O. Kyeremateng, Esther Bochmann, Ekaterina Sobich, Andrea Wahl, Bernd Liepold, Gabriele Sadowski, and Matthias Degenhardt. "Thermodynamic Modeling of the Amorphous Solid Dispersion-Water Interfacial Layer and Its Impact on the Release Mechanism." Pharmaceutics 15, no. 5 (May 19, 2023): 1539. http://dx.doi.org/10.3390/pharmaceutics15051539.
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During the dissolution of amorphous solid dispersion (ASD) formulations, the gel layer that forms at the ASD/water interface strongly dictates the release of the active pharmaceutical ingredient (API) and, hence, the dissolution performance. Several studies have demonstrated that the switch of the gel layer from eroding to non-eroding behavior is API-specific and drug-load (DL)-dependent. This study systematically classifies the ASD release mechanisms and relates them to the phenomenon of the loss of release (LoR). The latter is thermodynamically explained and predicted via a modeled ternary phase diagram of API, polymer, and water, and is then used to describe the ASD/water interfacial layers (below and above the glass transition). To this end, the ternary phase behavior of the APIs, naproxen, and venetoclax with the polymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) and water was modeled using the perturbed-chain statistical associating fluid theory (PC-SAFT). The glass transition was modeled using the Gordon–Taylor equation. The DL-dependent LoR was found to be caused by API crystallization or liquid-liquid phase separation (LLPS) at the ASD/water interface. If crystallization occurs, it was found that API and polymer release was impeded above a threshold DL at which the APIs crystallized directly at the ASD interface. If LLPS occurs, an API-rich phase and a polymer-rich phase are formed. Above a threshold DL, the less mobile and hydrophobic API-rich phase accumulates at the interface which prevents API release. LLPS is further influenced by the composition and glass transition temperature of the evolving phases and was investigated at 37 °C and 50 °C regarding impact of temperature of. The modeling results and LoR predictions were experimentally validated by means of dissolution experiments, microscopy, Raman spectroscopy, and size exclusion chromatography. The experimental results were found to be in very good agreement with the predicted release mechanisms deduced from the phase diagrams. Thus, this thermodynamic modeling approach represents a powerful mechanistic tool that can be applied to classify and quantitatively predict the DL-dependent LoR release mechanism of PVPVA64-based ASDs in water.
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Patyk-Kaźmierczak, Ewa, and Michał Kaźmierczak. "A new high-pressure benzocaine polymorph — towards understanding the molecular aggregation in crystals of an important active pharmaceutical ingredient (API)." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 76, no. 1 (January 16, 2020): 56–64. http://dx.doi.org/10.1107/s2052520619016548.
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Benzocaine (BZC), an efficient and highly permeable anaesthetic and an active pharmaceutical ingredient of many commercially available drugs, was studied under high pressure up to 0.78 GPa. As a result, new BZC polymorph (IV) was discovered. The crystallization of polymorph (IV) can be initiated by heating crystals of polymorph (I) at a pressure of at least 0.45 GPa or by their compression to 0.60 GPa. However, no phase transition from polymorph (I) to (IV) was observed. Although polymorph (IV) exhibits the same main aggregation motif as in previously reported BZC polymorphs (I)–(III), i.e. a hydrogen-bonded ribbon, its molecular packing and hydrogen-bonding pattern differ considerably. The N—H...N hydrogen bonds joining parallel BZC ribbons in crystals at ambient pressure are eliminated in polymorph (IV), and BZC ribbons become positioned at an angle of about 80°. Unfortunately, crystals of polymorph (IV) were not preserved on pressure release, and depending on the decompression protocol they transformed into polymorph (II) or (I).
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Dhondale, Madhukiran R., Pradip Thakor, Amritha G. Nambiar, Maan Singh, Ashish K. Agrawal, Nalini R. Shastri, and Dinesh Kumar. "Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs." Pharmaceutics 15, no. 1 (January 5, 2023): 189. http://dx.doi.org/10.3390/pharmaceutics15010189.
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Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient’s perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the medicine ineffective and toxic. Moisture content is known to be the leading cause of the degradation of nearly 50% of medicinal products, leading to impurities in solid dose formulations. The polarity of the atoms in an API and the surface chemistry of API particles majorly influence the affinity towards water molecules. Moisture induces chemical reactions, including free water that has also been identified as an important factor in determining drug product stability. Among the various approaches, crystal engineering and specifically co-crystals, have a proven ability to increase the stability of moisture-sensitive APIs. Other approaches, such as changing the salt form, can lead to solubility issues, thus making the co-crystal approach more suited to enhancing hygroscopic stability. There are many reported studies where co-crystals have exhibited reduced hygroscopicity compared to pure API, thereby improving the product’s stability. In this review, the authors focus on recent updates and trends in these studies related to improving the hygroscopic stability of compounds, discuss the reasons behind the enhanced stability, and briefly discuss the screening of co-formers for moisture-sensitive drugs.
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Sala, Andrea, Zakiena Hoossen, Alessia Bacchi, and Mino R. Caira. "Two Crystal Forms of a Hydrated 2:1 β-Cyclodextrin Fluconazole Complex: Single Crystal X-ray Structures, Dehydration Profiles, and Conditions for Their Individual Isolation." Molecules 26, no. 15 (July 22, 2021): 4427. http://dx.doi.org/10.3390/molecules26154427.
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Inclusion complexes between cyclodextrins (CDs) and active pharmaceutical ingredients (APIs) have potential for pharmaceutical formulation. Since crystallization of a given complex may result in the isolation of multiple crystal forms, it is essential to characterize these forms with respect to their structures and physicochemical properties to optimize pharmaceutical candidate selection. Here, we report the preparation and characterization of two crystallographically distinct hydrated forms of an inclusion complex between β-cyclodextrin (β-CD) and the antifungal API fluconazole (FLU) as well as temperature–concentration conditions required for their individual isolation. Determination of crystal water contents was achieved using thermoanalytical methods. X-ray analyses revealed distinct structural differences between the triclinic (TBCDFLU, space group P1) and monoclinic (MBCDFLU, space group C2) crystal forms. Removal of the crystals from their mother liquors led to rapid dehydration of the MBCDFLU crystal, while the TBCDFLU crystal was stable, a result that could be reconciled with the distinct packing arrangements in the respective crystals. This study highlights (a) the importance of identifying possible multiple forms of a cyclodextrin API complex and controlling the crystallization conditions, and (b) the need to characterize such crystal forms to determine the extent to which their physicochemical properties may differ.
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Wu, Wei-Yi, and Chie-Shaan Su. "Recrystallization and Production of Spherical Submicron Particles of Sulfasalazine Using a Supercritical Antisolvent Process." Crystals 8, no. 7 (July 18, 2018): 295. http://dx.doi.org/10.3390/cryst8070295.
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In this study, the recrystallization and production of spherical submicron particles of sulfasalazine, an active pharmaceutical ingredient (API), were performed using the supercritical antisolvent (SAS) process, a nonconventional crystallization technique. Sulfasalazine was dissolved in tetrahydrofuran (THF), and supercritical carbon dioxide (CO2) served as the antisolvent. The effects of operating parameters on the SAS process, including the operating pressure, solution concentration, solution flowrate, CO2 flowrate, and spraying nozzle diameter, at two operating temperatures were examined. The solid-state characteristics of sulfasalazine before and after the SAS process, including particle size, crystal habit, and crystal form, were analyzed using a scanning electron microscope (SEM), powder X-ray diffractometer (PXRD), and differential scanning calorimeter (DSC). A higher operating temperature, intermediate operating pressure, higher CO2 flowrate, and lower solution flowrate are recommended to obtain spherical particles of sulfasalazine. The effects of the solution concentration and spraying nozzle diameter on the SAS process were negligible. Under optimal conditions, spherical sulfasalazine crystals with a mean size of 0.91 μm were generated, and this study demonstrated the feasibility for tuning the solid-state characteristics of API through the SAS process.
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Trampuž, Marko, Dušan Teslić, and Blaž Likozar. "Process analytical technology-based (PAT) model simulations of a combined cooling, seeded and antisolvent crystallization of an active pharmaceutical ingredient (API)." Powder Technology 366 (April 2020): 873–90. http://dx.doi.org/10.1016/j.powtec.2020.03.027.
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Wolbert, Friederike, Ineke-Katharina Fahrig, Tobias Gottschalk, Christian Luebbert, Markus Thommes, and Gabriele Sadowski. "Factors Influencing the Crystallization-Onset Time of Metastable ASDs." Pharmaceutics 14, no. 2 (January 23, 2022): 269. http://dx.doi.org/10.3390/pharmaceutics14020269.
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In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon–Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as “larger particles always crystallize later than smaller particles” are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.
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Kartika, Bayu Mahdi, Lely Khojayanti, Nuha, Shelvi Listiana, Susi Kusumaningrum, and Ayustiyan Futu Wijaya. "DEKSTROSA MONOHIDRAT KUALITAS FARMASI DARI PATI Manihot ecsulenta, Metroxylon sagu, Zea mays, Oryza sativa, dan Triticum." Jurnal Bioteknologi & Biosains Indonesia (JBBI) 6, no. 2 (December 3, 2019): 184. http://dx.doi.org/10.29122/jbbi.v6i2.3208.
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Pharmaceutical Grade Dextrose Monohydrate from Manihot ecsulenta, Metroxylon sagu, Zea mays, Oryza sativa, dan Triticum Starch ABSTRACT Pharmaceutical-grade dextrose monohydrate, one of raw materials used as active pharmaceutical ingredients (API) and additives, can be made from starch. There are five types of local Indonesian commercial starch that are potentially used, namely tapioca (Manihot esculenta), sago (Metroxylon sagu), corn (Zea mays), rice (Oryza sativa), and wheat (Triticum) starch. This study aimed to compare these five starches as raw materials for preparing pharmaceutical-grade dextrose monohydrate which was expected to meet the requirements of the Indonesian Pharmacopoeia (5th Edition) and the United States Pharmacopeia (USP). The starch was converted into dextrose monohydrate through liquefaction hydrolysis, saccharification hydrolysis, activated carbon purification and filtration, ion exchange purification, evaporation, crystallization and drying. High Performance Liquid Chromatogram (HPLC) and the Luff-Schoorl methods were used for dextrose equivalent value (DE) analysis. The results showed that only three of the starch types produced pharmaceutical-grade dextrose monohydrate, namely (DE) sago starch (107.23% and 100.77%), corn starch (97.86% and 96.19%), and tapioca starch (85.18% and 99.20%).Keywords: dextrose equivalent, dextrose monohydrate, hydrolysis, pharmaceutical grade, starchABSTRAKDekstrosa monohidrat kualitas farmasi, salah satu bahan baku yang digunakan sebagai active pharmaceutical ingredient (API) dan bahan tambahan, dapat dibuat dari bahan pati-patian. Terdapat lima jenis pati komersial lokal Indonesia yang berpotensi digunakan yakni pati tapioka (Manihot esculenta), pati sagu (Metroxylon sagu), pati jagung (Zea mays), pati beras (Oryza sativa), dan pati gandum (Triticum). Penelitian ini bertujuan membandingkan lima jenis pati tersebut sebagai bahan baku pembuatan dekstrosa monohidrat kualitas farmasi yang diharapkan mampu memenuhi standar persyaratan dari Farmakope Indonesia Edisi V dan United States Pharmacopeia (USP). Pati diubah menjadi dekstrosa monohidrat melalui hidrolisis likuifikasi, hidrolisis sakarifikasi, pemurnian karbon aktif dan filtrasi, pemurnian ion exchange, evaporasi, kristalisasi dan pengeringan. Metode High Performance Liquid Chromatogram (HPLC) dan Luff-Schoorl digunakan untuk analisis dextrose equivalent (DE). Hasil penelitian menunjukkan hanya tiga jenis pati yang menghasilkan dekstrosa monohidrat kualitas farmasi, yakni (DE) pati sagu (107,23% dan 100,77%), pati jagung (97,86% dan 96,19%), dan pati tapioka (85,18% dan 99,20%).Kata kunci: dekstrosa monohidrat, dextrose ekuivalen, hidrolisis, kualitas farmasi, pati
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Machado Cruz, Ricardo, Tereza Boleslavská, Josef Beránek, Eszter Tieger, Brendan Twamley, Maria Jose Santos-Martinez, Ondřej Dammer, and Lidia Tajber. "Identification and Pharmaceutical Characterization of a New Itraconazole Terephthalic Acid Cocrystal." Pharmaceutics 12, no. 8 (August 6, 2020): 741. http://dx.doi.org/10.3390/pharmaceutics12080741.
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The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.
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O'Mahony, Marcus, Anthony Maher, Denise Croker, Ake Rasmuson, and Benjamin Hodnett. "Redefining Solution-Mediated Transformations: Pharmaceutical Systems." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1571. http://dx.doi.org/10.1107/s2053273314084289.
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Engineering the isolation of a metastable or stable crystalline phase of an active pharmaceutical ingredient (API) is of critical importance when crystallizing from solution as an uncontrolled outcome can directly affect API manufacture and performance. The theoretical framework for understanding solution-mediated crystal phase or polymorphic transformation (SMPT) was first established by Cardew & Davey.[1] The process is defined to consist of a metastable phase that dissolves and a stable phase that nucleates and grows independently from the solution. That paper also identified that in terms of a reaction pathway, SMPT could be controlled in either of two ways: by growth of the stable phase or dissolution the metastable phase. Studies concerning SMPT since then have brought the definition and those conclusions into question. Firstly, the recent case of the SMPT from FI to FIII carbamazepine and FII to FIII piractem were studied separately where data on both the solid state composition and solution concentration were collected during the transformation using powder X-ray diffraction and in situ infra-red spectroscopy, respectively. These studies, in combination with a brief review of the literature, reveal that SMPT can be controlled not only in the two ways described by Cardew & Davey but rather in 4 principal ways (Figure 1).[2] Secondly, many studies now identify that nucleation of the stable phase often occurs on the surface of the metastable phase during SMPT [3] and not independently from solution. Again when the literature is examined, this surface supported nucleation event is identified as being either epitaxial in nature or having no or inconclusive evidence of epitaxy. It is concluded that the term "independently" in the definition by Cardew & Davey be redefined to recognize that the crystallization of the stable phase during SMPT is often dependent on the surface of the metastable phase in solution.
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Dimitrokalli, Evangelia, Stefani Fertaki, Michail Lykouras, Petros Kokkinos, Malvina Orkoula, and Christos Kontoyannis. "Warfarin Sodium Stability in Oral Formulations." Molecules 26, no. 21 (November 1, 2021): 6631. http://dx.doi.org/10.3390/molecules26216631.
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Warfarin sodium is a low-dose pharmaceutical blood thinner that exists in two forms: the clathrate form and the amorphous form. In commercially available warfarin sodium oral suspension, the active pharmaceutical ingredient (API) is added in the amorphous state. This study investigates the apparent instability of the commercially available warfarin liquid oral formulation using Raman and IR spectroscopy, X-ray diffraction, differential scanning calorimetry, UV spectroscopy, and optical microscopy. Warfarin, not its sodium salt, was identified as the undissolved solid existing in the suspension. This was found to be due to the dissociation of sodium salt and the protonation of the warfarin ion in the liquid phase, which triggered the crystallization of the sparingly soluble unsalted form. The coexistence of protonated and unprotonated warfarin ions in the supernatant, as detected by Raman and UV spectroscopy, confirmed this assumption. Study of the dissolution of warfarin sodium amorphous salt and crystalline sodium clathrate in the placebo and pure water verified the results. The effect of pH and temperature on warfarin precipitation was also explored.
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Liu, Jiaxu, and Brahim Benyahia. "Systematic Model-Based Steady State and Dynamic Optimization of Combined Cooling and Antisolvent Multistage Continuous Crystallization Processes." Proceedings 62, no. 1 (December 31, 2020): 7. http://dx.doi.org/10.3390/proceedings2020062007.
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Currently, one of the key challenges in the pharmaceutical industry is the transformation of traditional batch production methods into robust continuous processes with the intention of reducing manufacturing costs and time and improving product quality. Crystallization is by far the most important purification technology in Pharma, as more than 80% of the active pharmaceutical ingredients (API) require at least one crystallization step. A successful crystallization process requires tight control over crystal size, shape and polymorphic purity. A rigorous and systematic methodology is presented to design and optimize multistage combined cooling and antisolvent continuous (mixed-suspension, mixed-product removal- MSMPR) crystallizers. The crystallization of acetylsalicylic acid (API) in ethanol (solvent) and water (anti-solvent) is used as a case study. A predictable and validated mathematical model of the system, which consists of a one-dimensional population balance model, was used to develop several optimizations strategies. Firstly, the attainable region of the mean particle size was determined for both minimum and maximum attainable crystal size. The method helped identify the most suitable number of stages and total residence time or volume for a cascade of continuous crystallizers. This was followed by a steady state optimization which helped determine the optimal operating temperatures and antisolvent flowrates. To minimize the startup time, a series of dynamic optimization strategies were implemented, assuming starting from empty vessels. The optimal dynamic profiles of the temperature and antisolvent flow rate, at different crystallization steps, were identified using a systematic and rigorous approach allowing a reduction in the startup time by 31%.
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Steenweg, Claas, Anne Cathrine Kufner, Jonas Habicht, and Kerstin Wohlgemuth. "Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation." Processes 9, no. 12 (December 3, 2021): 2187. http://dx.doi.org/10.3390/pr9122187.
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Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.
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Garbacz, Patrycja, and Marek Wesolowski. "DSC, FTIR and Raman Spectroscopy Coupled with Multivariate Analysis in a Study of Co-Crystals of Pharmaceutical Interest." Molecules 23, no. 9 (August 24, 2018): 2136. http://dx.doi.org/10.3390/molecules23092136.
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Co-crystals have garnered increasing interest in recent years as a beneficial approach to improving the solubility of poorly water soluble active pharmaceutical ingredients (APIs). However, their preparation is a challenge that requires a simple approach towards co-crystal detection. The objective of this work was, therefore, to verify to what extent a multivariate statistical approach such as principal component analysis (PCA) and cluster analysis (CA) can be used as a supporting tool for detecting co-crystal formation. As model samples, physical mixtures and co-crystals of indomethacin with saccharin and furosemide with p-aminobenzoic acid were prepared at API/co-former molar ratios 1:1, 2:1 and 1:2. Data acquired from DSC curves and FTIR and Raman spectroscopies were used for CA and PCA calculations. The results obtained revealed that the application of physical mixtures as reference samples allows a deeper insight into co-crystallization than is possible with the use of API and co-former or API and co-former with physical mixtures. Thus, multivariate matrix for PCA and CA calculations consisting of physical mixtures and potential co-crystals could be considered as the most profitable and reliable way to reflect changes in samples after co-crystallization. Moreover, complementary interpretation of results obtained using DSC, FTIR and Raman techniques is most beneficial.
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Varshosaz, Jaleh, Erfaneh Ghassami, and Saeedeh Ahmadipour. "Crystal Engineering for Enhanced Solubility and Bioavailability of Poorly Soluble Drugs." Current Pharmaceutical Design 24, no. 21 (October 15, 2018): 2473–96. http://dx.doi.org/10.2174/1381612824666180712104447.
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Background: Crystal engineering is dealing with the creation of new structures and new properties in drug molecules through inter-molecular interactions. Researchers of pharmaceutical sciences have used this knowledge to alter the structure of crystalline medications in order to remedy the problems of more than 40% of the new designed drugs which suffer from low solubility and consequently, low bioavailability which have limited their clinical application. Methods: This review covers a broad spectrum of aspects of the application of crystal engineering in pharmaceutics and includes a comprehensive wide range of different techniques used in crystal engineering of active pharmaceutical ingredients (API) to compensate the low water solubility and bioavailability of drugs related specially to class II of biopharmaceutical classification system (BCS). Results: These techniques include; crystalline habit modification, polymorphism, solvates and hydrates, cocrystals, surface modification, crystallization, spherical agglomeration, liquisolid crystals and solid dispersions which are introduced and discussed in this review article. Conclusion: Each of these techniques has advantages and limitations which are emphasized on them.
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Sandhu, Bhupinder, Sergiu Draguta, Tiffany L. Kinnibrugh, Victor N. Khrustalev, and Tatiana V. Timofeeva. "Supramolecular synthesis based on piperidone derivatives and pharmaceutically acceptable co-formers." Acta Crystallographica Section C Crystal Structure Communications 69, no. 4 (March 12, 2013): 421–27. http://dx.doi.org/10.1107/s0108270113006185.
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The target complexes, bis{(E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-oxopiperidinium} butanedioate, 2C27H36N3O+·C4H4O42−, (II), and bis{(E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-oxopiperidinium} decanedioate, 2C27H36N3O+·C10H16O42−, (III), were obtained by solvent-mediated crystallization of the active pharmaceutical ingredient (API) (E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-piperidone and pharmaceutically acceptable dicarboxylic (succinic and sebacic) acids from ethanol solution. They have been characterized by melting point, IR spectroscopy and single-crystal X-ray diffraction. For the sake of comparison, the structure of the starting API, (E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-piperidone methanol monosolvate, C27H35N3O·CH4O, (I), has also been studied. Compounds (II) and (III) represent salts containing H-shaped centrosymmetric hydrogen-bonded synthons, which are built from two parallel piperidinium cations and a bridging dicarboxylate dianion. In both (II) and (III), the dicarboxylate dianion resides on an inversion centre. The two cations and dianion within the H-shaped synthon are linked by two strong intermolecular N+—H...−OOC hydrogen bonds. The crystal structure of (II) includes two crystallographically independent formula units,AandB. The cation geometries of unitsAandBare different. The main N—C6H4—C=C—C(=O)—C=C—C6H4—N backbone of cationAhas a C-shaped conformation, while that of cationBadopts an S-shaped conformation. The same main backbone of the cation in (III) is practically planar. In the crystal structures of both (II) and (III), intermolecular N+—H...O=C hydrogen bonds between different H-shaped synthons further consolidate the crystal packing, forming columns in the [100] and [10\overline 1] directions, respectively. Salts (II) and (III) possess increased aqueous solubility compared with the original API and thus enhance the bioavailability of the API.
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Saumya Das, Aukunuru Jithan, and Raghunadha Gupta. "To study the efficacy of co-crystallization technique in enhancing the bioavailability of oral hypoglycemic agents." International Journal of Research in Pharmaceutical Sciences 11, no. 3 (July 25, 2020): 4201–7. http://dx.doi.org/10.26452/ijrps.v11i3.2628.
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The bioavailability of the drug is mainly governed by factors like partition coefficient, solubility Pka, etc. The modification of these physicochemical properties can be done to enhance the bioavailability and thus effective therapy can be achieved. This research deals with the advantages of co-crystals over salts, solvates (hydrates), solid dispersions and polymorphs. A pharmaceutical co-crystal is a single crystalline solid that incorporates two neutral molecules, one being an active pharmaceutical ingredient (API) and the other a co-crystal former. In the present study co-crystals of Metformin Hydrochloride and Glimepiride were prepared using different co-formers. Different ratio of urea, succinic acid and tartaric acid were used to design the co-crystals. They were formulated by two different methods- cooling crystallization and solvent evaporation. The prepared co-crystals were evaluated for microscopic characters, product yield, Fourier Transform Infrared Spectroscopy, Micromeretic properties, drug content, dissolution study of co-crystals, stability studies. The results indicated that co-crystals prepared by using a suitable co-former can definitely enhance the dissolution rate ultimately leading to enhanced bioavailability. Out of three co-formers used to design the co-crystals, succinic acid is found to be more effective. Moreover the bioavailability of Glimepiride is more enhanced as compared to Metformin Hydrochloride as it belongs to BCS class II.
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An, Hyunseon, Insil Choi, and Il Kim. "Melting Diagrams of Adefovir Dipivoxil and Dicarboxylic Acids: An Approach to Assess Cocrystal Compositions." Crystals 9, no. 2 (January 30, 2019): 70. http://dx.doi.org/10.3390/cryst9020070.
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Pharmaceutical cocrystallization is a useful method to regulate the physical properties of active pharmaceutical ingredients (APIs). Since the cocrystals may form in various API/coformer ratios, identification of the cocrystal composition is the critical first step of any further analysis. However, the composition identification is not always unambiguous if cocrystallization is performed in solid state with unsuccessful solution crystallization. Single melting point and some new X-ray diffraction peaks are necessary but not sufficient conditions. In the present study, the use of melting diagrams coupled with the X-ray diffraction data was tested to identify cocrystal compositions. Adefovir dipivoxil (AD) was used as a model API, and succinic acid (SUC), suberic acid (SUB), and glutaric acid (GLU) were coformers. Compositions of AD/SUC and AD/SUB had been previously identified as 2:1 and 1:1, but that of AD/GLU was not unambiguously identified because of the difficulty of solution crystallization. Melting diagrams were constructed with differential scanning calorimetry, and their interpretation was assisted by powder X-ray diffraction. The cocrystal formation was exhibited as new compositions with congruent melting in the phase diagrams. This method correctly indicated the previously known cocrystal compositions of AD/SUC and AD/SUB, and it successfully identified the AD/GLU cocrystal composition as 1:1. The current approach is a simple and useful method to assess the cocrystal compositions when the crystallization is only possible in solid state.
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Kufner, Anne Cathrine, Adrian Krummnow, Andreas Danzer, and Kerstin Wohlgemuth. "Strategy for Fast Decision on Material System Suitability for Continuous Crystallization Inside a Slug Flow Crystallizer." Micromachines 13, no. 10 (October 21, 2022): 1795. http://dx.doi.org/10.3390/mi13101795.
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There is an increasing focus on two-phase flow in micro- or mini-structured apparatuses for various manufacturing and measurement instrumentation applications, including the field of crystallization as a separation technique. The slug flow pattern offers salient features for producing high-quality products, since narrow residence time distribution of liquid and solid phases, intensified mixing and heat exchange, and an enhanced particle suspension are achieved despite laminar flow conditions. Due to its unique features, the slug flow crystallizer (SFC) represents a promising concept for small-scale continuous crystallization achieving high-quality active pharmaceutical ingredients (API). Therefore, a time-efficient strategy is presented in this study to enable crystallization of a desired solid product in the SFC as quickly as possible and without much experimental effort. This strategy includes pre-selection of the solvent/solvent mixture using heuristics, verifying the slug flow stability in the apparatus by considering the static contact angle and dynamic flow behavior, and modeling the temperature-dependent solubility in the supposed material system using perturbed-chain statistical associating fluid theory (PC-SAFT). This strategy was successfully verified for the amino acids l-alanine and l-arginine and the API paracetamol for binary and ternary systems and, thus, represents a general approach for using different material systems in the SFC.
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Mueller, Lena Karin, Laura Halstenberg, Nicole Di Gallo, and Thomas Kipping. "Evaluation of a Three-Fluid Nozzle Spraying Process for Facilitating Spray Drying of Hydrophilic Polymers for the Creation of Amorphous Solid Dispersions." Pharmaceutics 15, no. 11 (October 27, 2023): 2542. http://dx.doi.org/10.3390/pharmaceutics15112542.
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Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications.
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Jin, Xuping, Seyed Ebrahim Alavi, Abbas Shafiee, Vania Rodrigues Leite-Silva, Kiarash Khosrotehrani, and Yousuf Mohammed. "Metamorphosis of Topical Semisolid Products—Understanding the Role of Rheological Properties in Drug Permeation under the “in Use” Condition." Pharmaceutics 15, no. 6 (June 11, 2023): 1707. http://dx.doi.org/10.3390/pharmaceutics15061707.
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When developing topical semisolid products, it is crucial to consider the metamorphosis of the formulation under the “in use” condition. Numerous critical quality characteristics, including rheological properties, thermodynamic activity, particle size, globule size, and the rate/extent of drug release/permeation, can be altered during this process. This study aimed to use lidocaine as a model drug to establish a connection between the evaporation and change of rheological properties and the permeation of active pharmaceutical ingredients (APIs) in topical semisolid products under the “in use” condition. The evaporation rate of the lidocaine cream formulation was calculated by measuring the weight loss and heat flow of the sample using DSC/TGA. Changes in rheological properties due to metamorphosis were assessed and predicted using the Carreau–Yasuda model. The impact of solvent evaporation on a drug’s permeability was studied by in vitro permeation testing (IVPT) using occluded and unconcluded cells. Overall, it was found that the viscosity and elastic modulus of prepared lidocaine cream gradually increased with the time of evaporation as a result of the aggregation of carbopol micelles and the crystallization of API after application. Compared to occluded cells, the permeability of lidocaine for formulation F1 (2.5% lidocaine) in unoccluded cells decreased by 32.4%. This was believed to be the result of increasing viscosity and crystallization of lidocaine instead of depletion of API from the applied dose, which was confirmed by formulation F2 with a higher content of API (5% lidocaine) showing a similar pattern, i.e., a 49.7% reduction of permeability after 4 h of study. To the best of our knowledge, this is the first study to simultaneously demonstrate the rheological change of a topical semisolid formulation during volatile solvent evaporation, resulting in a concurrent decrease in the permeability of API, which provides mathematical modelers with the necessary background to build complex models that incorporate evaporation, viscosity, and drug permeation in the simulation once at a time.
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Trampuž, Marko, Dušan Teslić, and Blaž Likozar. "Crystal-size distribution-based dynamic process modelling, optimization, and scaling for seeded batch cooling crystallization of Active Pharmaceutical Ingredients (API)." Chemical Engineering Research and Design 165 (January 2021): 254–69. http://dx.doi.org/10.1016/j.cherd.2020.10.029.
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Sanphui, Palash, Lalit Rajput, Shanmukha Prasad Gopi, and Gautam R. Desiraju. "New multi-component solid forms of anti-cancer drug Erlotinib: role of auxiliary interactions in determining a preferred conformation." Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 72, no. 3 (May 13, 2016): 291–300. http://dx.doi.org/10.1107/s2052520616003607.
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Erlotinib is a BCS (biopharmaceutical classification system) class II drug used for the treatment of non-small cell lung cancer. There is an urgent need to obtain new solid forms of higher solubility to improve the bioavailability of the API (active pharmaceutical ingredient). In this context, cocrystals with urea, succinic acid, and glutaric acid and salts with maleic acid, adipic acid, and saccharin were preparedviawet granulation and solution crystallizations. Crystal structures of the free base (Z′ = 2), cocrystals of erlotinib–urea (1:1), erlotinib–succinic acid monohydrate (1:1:1), erlotinib–glutaric acid monohydrate (1:1:1) and salts of erlotinib–adipic acid adipate (1:0.5:0.5) are determined and their hydrogen-bonding patterns are analyzed. Self recognitionviathe (amine) N—H...N (pyridine) hydrogen bond between the API molecules is replaced by several heterosynthons such as acid–pyridine, amide–pyridine and carboxylate–pyridinium in the new binary systems. Auxiliary interactions play an important role in determining the conformation of the API in the crystal. FT–IR spectroscopy is used to distinguish between the salts and cocrystals in the new multi-component systems. The new solid forms are characterized by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) to confirm their unique phase identity.
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Fatima, Syeda Saima, Rajesh Kumar, M. Iqbal Choudhary, and Sammer Yousuf. "Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity." IUCrJ 7, no. 1 (January 1, 2020): 105–12. http://dx.doi.org/10.1107/s2052252519016142.
Full textAbstract:
Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methylideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thiourea by liquid-assisted grinding. The purity and homogeneity of the exemestane–thiourea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N—H...O hydrogen bonding between the amine (NH2) groups of thiourea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml−1) compared with the API (exemestane), which was found to be inactive, and the co-former (thiourea) (IC50 = 21.0 ± 1.25 µg ml−1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.
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Malanovic, Nermina, Giovanni Birarda, Simone Eder, Heidrun Gruber-Woelfler, Franz Reiter, Krunoslav Juraic, and Aden Hodzic. "Small-Angle X-ray Scattering (SAXS) Used for the Identification of Nicomorphine Polymorphic Changes at the Early Stage to Avoid Varied Stability and Possible Side Effects." Pharmaceuticals 17, no. 3 (March 15, 2024): 375. http://dx.doi.org/10.3390/ph17030375.
Full textAbstract:
In this paper, we present the identification of polymorphisms at an early stage, identified by applying non-standard methods such as SAXS. We provide an analytical approach to polymorphism in the quality/purity of an active pharmaceutical ingredient (API), supplied to a generic company by two different suppliers (i.e., manufacturers). Changes in thermodynamic polymorphism firstly become visible in traces in the larger crystal lattices, which are visible on the SAXS spectrum only using the logarithmic scale, as shown in the result figures. Hence, we are here on the trail of the beginning of a new polymorph in nicomorphine, whose crystal waviness at the early stage is visible only in the additional symmetrical peaks identified and calculated using SAXS, while the chemical analyses excluded all kinds of chemical impurities. The chemical and structural properties were studied using the following techniques: SAXS, WAXS, DSC, dissolution, Raman spectroscopy, and FTIR. Only the SAXS technique could identify crucial differences and calculate the additional signals related to giant crystals, whilst a standard method such as WAXS showed none, and nor did the chemical analyses, such as Raman spectroscopy and FT-IR. This means that due to water in crystallization (known in nicomorphine) or thermodynamic waviness, the formation of the new polymorph starts first in traces, which become visible at larger distances from the crystal lattice, detectible only in the SAXS range. This is a very important premise and hypothesis for further research, and we believe that this work lays a new stone in understanding the origin of new unknown polymorphs and their mixtures. Therefore, the aim of this work is to show that the use of non-standard methods (i.e., SAXS) can be of great benefit to API analysis and the identification of polymorphic changes in the early phase, which can cause varied stability, solubility and bioavailability and thus different therapeutic effects or side effects.
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Nugrahani, Ilma, and Maria Anabella Jessica. "Amino Acids as the Potential Co-Former for Co-Crystal Development: A Review." Molecules 26, no. 11 (May 28, 2021): 3279. http://dx.doi.org/10.3390/molecules26113279.
Full textAbstract:
Co-crystals are one of the most popular ways to modify the physicochemical properties of active pharmaceutical ingredients (API) without changing pharmacological activity through non-covalent interactions with one or more co-formers. A “green method” has recently prompted many researchers to develop solvent-free techniques or minimize solvents for arranging the eco-friendlier process of co-crystallization. Researchers have also been looking for less-risk co-formers that produce the desired API’s physicochemical properties. This review purposed to collect the report studies of amino acids as the safe co-former and explored their advantages. Structurally, amino acids are promising co-former candidates as they have functional groups that can form hydrogen bonds and increase stability through zwitterionic moieties, which support strong interactions. The co-crystals and deep eutectic solvent yielded from this natural compound have been proven to improve pharmaceutical performance. For example, l-glutamine could reduce the side effects of mesalamine through an acid-base stabilizing effect in the gastrointestinal fluid. In addition, some amino acids, especially l-proline, enhances API’s solubility and absorption in its natural deep eutectic solvent and co-crystals systems. Moreover, some ionic co-crystals of amino acids have also been designed to increase chiral resolution. Therefore, amino acids are safe potential co-formers, which are suitable for improving the physicochemical properties of API and prospective to be developed further in the dosage formula and solid-state syntheses.
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Martínez-Jiménez, Cecilia, Jorge Cruz-Angeles, Marcelo Videa, and Luz Martínez. "Co-Amorphous Simvastatin-Nifedipine with Enhanced Solubility for Possible Use in Combination Therapy of Hypertension and Hypercholesterolemia." Molecules 23, no. 9 (August 28, 2018): 2161. http://dx.doi.org/10.3390/molecules23092161.
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The high index of simultaneous incidence of hypertension and hypercholesterolemia in the population of many countries demands the preparation of more efficient drugs. Therefore, there is a significant area of opportunity to provide as many alternatives as possible to treat these illnesses. Taking advantage of the solubility enhancement that can be achieved when an active pharmaceutical ingredient (API) is obtained and stabilized in its amorphous state, in the present work, new drug-drug co-amorphous formulations (Simvastatin SIM- Nifedipine NIF) with enhanced solubility and stability were prepared and characterized. Results show that the co-amorphous system (molar ratio 1:1) is more soluble than the pure commercial APIs studied separately. Aqueous dissolution profiles showed increments of solubility of 3.7 and 1.7 times for SIM and NIF, correspondingly, in the co-amorphous system. The new co-amorphous formulations, monitored in time, (molar fractions 0.3, 0.5 and 0.7 of SIM) remained stable in the amorphous state for more than one year when stored at room temperature and did not show any signs of crystallization when re-heating. Inspection on the remainder of a sample after six hours of dissolution showed no recrystallization, confirming the stability of co-amorphous system. The enhanced solubility of the co-amorphous formulations makes them promising for simultaneously targeting of hypertension and hypercholesterolemia through combination therapy.
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Comito, Marziale, Riccardo Monguzzi, Silvia Tagliapietra, Giovanni Palmisano, and Giancarlo Cravotto. "Efficient pilot-scale synthesis of the key cefonicid intermediate at room temperature." Green Processing and Synthesis 11, no. 1 (January 1, 2022): 96–105. http://dx.doi.org/10.1515/gps-2022-0007.
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Abstract Cefonicid is a common second-generation cephalosporin, and the 7-amino-3-[sulphomethyl-1-H-tetrazol-5-yl-thiomethyl]-3-cephem-4-carboxylate monosodium salt is a key synthetic intermediate in its preparation. Despite the considerable international demand for this antibiotic, its preparation is hampered by low synthetic yield, long reaction time, and time-consuming industrial filtration over charcoal after the purification step. In the context of the industrial production of pharmaceutical intermediates, in which the balance between streamlining and enhancing productivity is necessary in order to compete in the global active pharmaceutical ingredients (API) market, we have investigated an efficient and practical procedure for the synthesis of a key cefonicid intermediate that features a telescopic route whose synthetic steps are all performed at room temperature; from the displacement of the acetoxy group with boron trifluoride to crystallization without treatment with charcoal. In other words, a simpler, scalable, cost-effective and energy-saving protocol is herein reported as a means of moving towards commercial manufacturing. The optimization of the process parameters and the industrial-scale impact assessment should pave the way for industrialization.
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Hean, Duane, Andreas Lemmerer, and Joseph Michael. "Rampant Polymorphism in Pharmaceuticals: An Isoniazid Derivative." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C653. http://dx.doi.org/10.1107/s2053273314093462.
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Investigations into the polymorphic forms of Active Pharmaceutical Ingredients (APIs) are of vital importance to drug formulations and are often kept a closely guarded secret by pharmaceutical companies. This secrecy is maintained as the nature of the polymorph could either make or break a drug formulation. Polymorphism is the ability of a solid crystalline form to exist in more than one structural arrangement. The variation in the crystalline forms often displays different mechanical, thermal, and chemical properties. These changes can remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the API [1]. Isoniazid, a well-known pharmaceutical, is used as a first-line treatment against Mycobacterium tuberculosis (TB) which is known to possess multiple polymorphs. Derivatives of isoniazid were developed in response to TB drug resistance. One such derivative, isonicotinic acid-(1-phenyl-ethylidenehydrazide) (IPH) [2] was found to exhibit an array of polymorphic behaviour as a result of its hydrogen bond acceptors, donors and conformational freedom along its backbone. To date only one crystal structure of IPH has been reported in the literature [3]. We have discovered and isolated an additional five novel polymorphs of IPH from various crystallization techniques, namely slow cooling, rapid evaporation, sublimation, as well as from hot-stage experiments. All of the polymorphs display hydrogen bonding through the carbonyl acceptor and hydrazide donor. However the torsion of these hydrogen bond acceptors and donors, relative to the molecular backbone, deviate due to the conformational flexibility of the molecule. Structural information of the polymorphs was obtained by SCXRD, PXRD, IR and Raman. The thermal phase relationships of these polymorphs were also investigated using DSC and HSM. Elucidating these novel polymorphs and establishing phase relationships are a key step in the design of isoniazid based pharmaceuticals.
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Lukman, Zulfahmi, Nornizar Anuar, Noor Fitrah Abu Bakar, and Norazah Abdul Rahman. "Characterization and Prediction of the Non-Bonded Molecular Interactions between Racemic Ibuprofen and α-Lactose Monohydrate Crystals Produced from Melt Granulation and Slow Evaporation Crystallization." Indonesian Journal of Chemistry 20, no. 6 (July 13, 2020): 1255. http://dx.doi.org/10.22146/ijc.48912.
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Granulation of racemic ibuprofen (±IBP) and α-lactose monohydrate (ALM) at a slightly lower (±IBP) melting point is an efficient method of binding the active pharmaceutical ingredients (API) and excipient in a binderless condition. However, the co-crystals may be formed from recrystallization of ±IBP on ALM. The objective of this study is to evaluate the tendency of co-crystal formation of granules (3:7 w/w ratio of ±IBP:ALM) by melt granulation process. Second, investigate the recovery of crystals from polyethylene glycol (PEG) 300 solutions containing ±IBP-ALM mixtures. Characterizations of the samples were performed using Fourier Transform Infrared (FTIR) spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-Ray Diffraction (PXRD) system of the ±IBP-ALM granules produced from melt crystallization and harvested crystals from PEG 300 solution which is produced using slow evaporation crystallization. Crystal analysis of solution containing ±IBP-ALM mixtures revealed that the crystals formed were not co-crystals. Molecular interactions assessment through binding prediction between ±IBP and ALM terminating surfaces was conducted using molecular modelling technique. The result showed that the favorable binding sites of ±IBP molecules were on the surfaces of (0-20), (1-10), (001) and (011) ALM crystals. Successful binding prediction by the attachment energy method has proven that the co-crystal formation between these molecules is theoretically possible.
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Toth, Scott, Justin Newman, Paul Schmitt, Christopher Dettmar, Shijie Zhang, Lynne Taylor, and Garth Simpson. "PPM Detection Limits in PXRD by Integrating Nonlinear Optics and Synchrotron XRD." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1082. http://dx.doi.org/10.1107/s2053273314089177.
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SHG microscopy allows rapid and selective identification of trace chiral crystals within amorphous media, enabling targeted XRD using a 5-10 micrometer diameter "minibeam". The sensitivity of PXRD is increased substantially by reducing the background scattering contributions of amorphous material otherwise encountered with a larger beam. In addition, performing diffraction only at the locations most likely to produce diffraction greatly reduced the overall beam-time required to perform the PXRD analyses. Integration of the SHG microscope directly into a synchrotron X-ray beamline at Argonne National Laboratory recovered high spatial registry between the regions of interest identified by SHG for positioning within the X-ray beam. Using this approach, diffraction was performed on individual griseofulvin nanocrystals suspended within an amorphous polymer, corresponding to a total of ~20 fg of total crystalline material. Additional measurements for ritonavir in hydroxypropylmethylcellulose (HPMC) were also performed, in which a bulk API concentration of 100 ppm produced diffraction peaks with a signal to noise ratio of >3000. Among other applications, sensitive detection of trace crystallinity can inform the design of amorphous formulations, in which the bioavailability of active pharmaceutical ingredients (APIs) is enhanced by maintaining them in an amorphous state. However, the long-term stability of a final dosage form can be negatively impacted by spontaneous transitioning to the typically more stable crystalline forms of the APIs, such that extensive quantitative characterization of the crystallization behaviors of amorphous formulations is routinely performed.