Continuous Manufacturing of High Quality Pharmaceutical Cocrystals Integrated with Process Analytical Tools for In-Line Process Control

Moradiya, Hiren G.; Islam, Muhammad T.; Scoutaris, Nikolaos; Halsey, Sheelagh A.; Chowdhry, Babur Z.; Douroumis, Dennis

doi:10.1021/acs.cgd.6b00402

Cited by 46 publications

(35 citation statements)

References 36 publications

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“…In addition to the characterization techniques discussed above, some of the well-advanced techniques such as pair-distribution function PXRD [ 224 ], Terahertz (THz) spectroscopic imaging [ 225 ], Probe-Type Low-Frequency Raman Spectroscopy [ 226 ], combined near IR and Raman spectroscopies [ 227 ], in situ Raman spectroscopy, in situthermomicroscopy [ 192 ], calorimetric analysis [ 192 ] and PAT [ 75 ] are being used widely by many researchers nowadays in order to understand the phase transition events that possibly occur during a cocrystallization process.…”

Section: Characterization Of Cocrystalsmentioning

confidence: 99%

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

2018

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Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

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Section: Characterization Of Cocrystalsmentioning

confidence: 99%

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

2018

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“…Only limited studies have been published concerning the issues of large-scale production of cocrystals. Spray drying, 34 screw extrusion, 43 and supercritical fluid technology 44 have been reported as scalable cocrystallization techniques to produce multi-kilogram batches of cocrystals.…”

Section: Synthesis and Characterization Of Cocrystalsmentioning

confidence: 99%

Recent advances in improving oral drug bioavailability by cocrystals

et al. 2018

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Introduction: Oral drug delivery is the most favored route of drug administration. However, poor oral bioavailability is one of the leading reasons for insufficient clinical efficacy. Improving oral absorption of drugs with low water solubility and/or low intestinal membrane permeability is an active field of research. Cocrystallization of drugs with appropriate coformers is a promising approach for enhancing oral bioavailability. Methods: In the present review, we have focused on recent advances that have been made in improving oral absorption through cocrystallization. The covered areas include supersaturation and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes, drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology with supramolecular design. Marketed cocrystal products and PK studies in human subjects are also reported. Results: Considering supersaturation and consequent precipitation properties is necessary when evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find applications in improving oral bioavailability of poorly permeable drugs. It has been shown that cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns. Some of coformers may interact with intestinal absorption of drugs through changing intestinal blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential towards improving absorption of poorly soluble drugs. Conclusions: Cocrystals have found their way from the proof-of-principle stage to the clinic. Up to now, at least two cocrystal products have gained approval from regulatory bodies. However, there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of cocrystals in the human.

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“…There are several novel methods to achieve cocrystallization including mechanochemical and liquid assisted grinding, freeze-drying, through slow evaporation of the two components, melt-assisted grinding, slurry methods and a number of emerging approaches using supercritical fluids, microfluids and ultrasound [ 24 ]. Despite the growing number of approaches for cocrystal synthesis, full industrial exploitation of cocrystals has thus far been limited in part due to two limiting factors, one or both of which applies to the aforementioned methods: that they are batch controlled and that it is difficult to scale-up production [ 23 , 25 ]. These are challenges that can be overcome through hot-melt extrusion.…”

Section: Introductionmentioning

confidence: 99%

“…Immense friction takes place between the screw and barrel at high temperatures which provides good mixing of the raw materials, reducing particle size, and breaking down the hydrogen bonds linking the raw materials. New hydrogen bonds will form between complementary pairs during the conveying stage of the HME process and during cooling, forming cocrystals [ 6 , 25 , 27 ]. Over the last decade, HME has received renewed attention in the pharmaceutical industry as it offers distinct advantages over other commercially available pharmaceutical processing technique [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals

et al. 2021

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The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

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Continuous Manufacturing of High Quality Pharmaceutical Cocrystals Integrated with Process Analytical Tools for In-Line Process Control

Cited by 46 publications

References 36 publications

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

Recent advances in improving oral drug bioavailability by cocrystals

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals

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