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P g pert plus case study and solution

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Abstract The application of twin screw extrusion TSE as a scalable and green process for the manufacture of cocrystals was investigated.

Four model cocrystal forming systems, Caffeine-Oxalic acid, Nicotinamide-trans cinnamic acid, Carbamazepine-Saccharin, and Theophylline-Citric acid, were selected for the study. The parameters of the extrusion process that influenced cocrystal formation were examined.

TSE was found to be an effective method to make cocrystals for all four systems studied. It was demonstrated that temperature and extent of mixing in the extruder were the primary process parameters that influenced extent of conversion to the cocrystal in neat TSE experiments.

In addition to neat extrusion, liquid-assisted TSE was also demonstrated for the first time as a viable process for making cocrystals. Notably, the use of catalytic amount of benign solvents led to a lowering of processing temperatures required to form the cocrystal in the extruder. TSE should be considered as an efficient, scalable, and environmentally friendly process for the manufacture of cocrystals with little to no solvent requirements.

Introduction Pharmaceutical scientists are currently facing an increasing number of drug molecules with less than ideal properties such as poor solubility and a lack of acceptable physical and chemical stability [ 1 ]. As part of these efforts, cocrystals have been identified as viable solid forms that may improve the pharmaceutical properties of a development candidate in some instances. Cocrystals have been defined as crystalline materials that are comprised of two or more components that are solids at room temperature in order to distinguish them from hydrates and solvates held together by non-covalent forces [ 2 - 4 ].

The distinction between a salt and a cocrystal lies in the fact that there is no proton transfer occurring between the constituents of a cocrystal. There has been an increased interest in cocrystals in the last few years and a number of publications have highlighted the beneficial properties offered by cocrystals.

Due to these reported advantages that cocrystals provide, there has been a lot of effort invested in the pharmaceutical industry in identifying, synthesizing, and manufacturing these materials.

Application of Twin Screw Extrusion in the Manufacture of Cocrystals, Part I: Four Case Studies

To this end, there are many reports that detail how to identify and make cocrystals at a small scale [ 17 - 22 ]. However in order to be considered viable candidates for development, a scalable method to produce cocrystals must be established.

Traditionally cocrystals have been prepared by slow evaporation or by neat-grinding of the constituents [ 2324 ].

  • Liquid-assisted extrusion was performed with appropriate amounts of benign liquids added to the powder blends prior to extrusion;
  • However in order to be considered viable candidates for development, a scalable method to produce cocrystals must be established;
  • It was demonstrated that temperature and extent of mixing in the extruder were the primary process parameters that influenced extent of conversion to the cocrystal in neat TSE experiments.

Recently, liquid-assisted grinding has been developed as a more effective method to make cocrystals [ 2526 ]. In addition cocrystals have also been prepared by melt crystallization, sublimation, and solution crystallization.

Of these techniques only solution crystallization has proven to be a practical scalable process, due to the ease in reproducibility, phase control, and particle size control.

However, the use of solution crystallization for cocrystal scale up does present challenges as knowledge of the ternary phase diagram between the cocrystal constituents and the solvent is necessary and the measurement of such phase diagrams involves a large number of experiments which may be cumbersome to perform [ 27 - 29 ].

In recent years significant progress has been made towards designing simple procedures for using solution crystallization to scale-up the production of cocrystals [ 3031 ].

P g pert plus case study and solution

Nevertheless, use of solution crystallization requires drying of solvent from the final product to acceptable levels and also introduces the risk of forming solvates. We had recently introduced twin-screw extrusion TSE of cocrystal components as a scalable and solvent-less process that provides a viable alternative to solution crystallization [ 32 ].

Using this process we demonstrated continuous production of cocrystals of Caffeine-Oxalic acid and AMG 517-Sorbic acid. A detailed study of the effect of temperature and processing conditions on Ibuprofen-Nicotinamide cocrystal formation was reported.

They confirmed that extrusion was an excellent method of producing cocrystals while at the same time being easily amenable to a quality-by-design QbD approach which is emerging as a new paradigm in manufacture of pharmaceutical materials. In this paper, we add to understanding and use of TSE in the production of cocrystals.

In Part I of this paper we discuss the use of this technique to produce cocrystals of the following systems: All these systems have been extensively studied in literature enabling a comparative analysis between TSE and other methods of forming cocrystals. All solvents used were of analytical grade.

  1. Zone B is composed of four distributive elements that are 4 mm in length each for a total of 16 mm. The vibration frequency of the mill was set at 15 Hz for all experiments.
  2. The extruder has four controllable temperature zones including the die zone.
  3. In this paper, we add to understanding and use of TSE in the production of cocrystals. Zone B is a highly mixing zone with neutral conveying capacity.

Where applicable, literature procedures were followed to generate the cocrystals. In general, the samples to be milled were placed in a 25-mL chamber with metal grinding balls at room temperature. The vibration frequency of the mill was set at 15 Hz for all experiments.

P g pert plus case study and solution

The samples were milled for varying lengths of time between 0 and 90 minutes. Cocrystals formed after milling were assessed using X-ray powder diffraction and 13C solid state NMR to determine the extent of cocrystallization.

  • Abstract The application of twin screw extrusion TSE as a scalable and green process for the manufacture of cocrystals was investigated;
  • Integrated scheduling of tasks and gynecologists to improve patient appointment scheduling a case study in this paper we focus on a case study plus the two;
  • TSE should be considered as an efficient, scalable, and environmentally friendly process for the manufacture of cocrystals with little to no solvent requirements;
  • Problem solving nine case studies and lessons learned case study number 1 2 3 4 5 6 7 8 9 lox solutions to the problems stemming from the bar;
  • This article has been cited by other articles in PMC.

Milling samples were used as reference material against which cocrystals generated by TSE were compared. A Prism PharmaLab 16mm twin screw extruder 25: The extruder has four controllable temperature zones including the die zone.

For these experiments the die zone was not used. Temperature of the extruder barrel was changed according to the model system studied.

The screw was designed for high mixing capacity and long residence time to enhance conversion to cocrystal cf. The screw design was setup with alternating 16-mm segments of Zone A and Zone B throughout the barrel. Zone A is a purely conveying zone with minimal mixing capacity.

Zone A is a single element, 16 mm in length with a pitch of 7. Zone B is a highly mixing zone with neutral conveying capacity. Zone B is composed of four distributive elements that are 4 mm in length each for a total of 16 mm.

  • All these systems have been extensively studied in literature enabling a comparative analysis between TSE and other methods of forming cocrystals;
  • To this end, there are many reports that detail how to identify and make cocrystals at a small scale [ 17 - 22 ].

Liquid-assisted extrusion was performed with appropriate amounts of benign liquids added to the powder blends prior to extrusion. All remaining details of the extrusion experiments are provided in the discussion section for each of the systems studied.

Each experiment processed anywhere between 20—100 grams of material.