Purification distillation, filtration, drying

The hydration state of risedronate sodium was monitored continuously in a fluidized bed dryer and correlated to data on the physical stability of tablets made from the monitored material [275]. The final granulation moisture was found to affect the solid-state form, which in turn dictated the drug s physical stability over time. The process of freeze-drying mannitol was monitored continuously with in-line Raman and at-line NIR spectroscopies [276]. The thin polymer solvent coatings, such as poly(vinyl acetate) with toluene, methanol, benzene, and combinations of the solvents, were monitored as they dried to generate concentra-tion/time profiles [277]. 

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There is a great number of separation and purification processes to choose from in process development, but classical separations such as crystallization, filtration, drying, liquid-liquid extraction and distillation are still predominantly used. For solid products crystallization, filtration, and drying are the first options although vacuum distillation and extraction combined with the other techniques are also possible. For liquid products, liquid-liquid... 

The aldehyde is separated from the lower aqueous layer as a colorless liquid and dried over 10 g. of anhydrous sodium sulfate. The drying agent is removed by filtration, and the product is distilled under reduced pressure using a Claisen distillation apparatus to give 92-94 g. (82-84%) of cyclohexanecarboxaldehyde, b.p. 52-63° (18 mm.), 1.4484 (Notes 10, 11). A purity of about 98% was established by gas chromatographic analysis (Note 12) the product is suitable for synthetic use without further purification (Note 13). 

B. 2-Methylcyclopenlane-l,3,5-trione hydrate. A mixture of 200 g. (0.89 mole) of the keto ester prepared above, 910 ml. of water, and 100 ml. of 85% phosphoric acid is healed under reflux for 4 hours and then cooled in an ice-salt bath to —5°. The trione mixed with oxalic acid separates and is collected by filtration and dried under reduced pressure. The dried material is extracted with boiling ether (250-300 ml.) under reflux, and the ethereal extract is separated from the undissolved oxalic acid. The original aqueous filtrate is also extracted with ether in a continuous extractor. The two extracts are combined, and ether is removed by distillation. The crude trione separates as a dark brown solid and is crystallized from ca. 250 ml. of hot water. The once-crystallized, faintly yellow product weighs 95-105 g. (74-82%), m.p. 70-74°. This product is used in the next step without further purification. A better specimen, m.p. 77-78°, which is almost colorless, can be obtained by recrystallization from hot water after treatment with Norit activated carbon. 

Practical-grade 4-cthoxy-3-methoxybenzaldehyde (4-ethoxy-m-anisaldehyde) was obtained by the submitters from MC and B Manufacturing Chemists and by the checkers from Aldrich Chemical Company, Inc. This material was purified by distillation (b.p. 125-135°/0.1 mm.), followed by one recrystallization from cyclohexane (100 ml./lO g. crude solid). Colorless crystals, m.p. 60-62°, wrere obtained after filtration and vacuum drying. Purification of 20 g. of the commercial material gave about 15 g. of recrystallized product. 

Vacuum-dried KF (8.7g. 150mmol) and an unsaturated aldehyde (50mmol) were placed in a 200-mL stainless steel autoclave, the autoclave was cooled to —196 C, evacuated and SF4 (16.2 g, 150 mmol) condensed in it. The filled autoclave was allowed to warm slowly to rt then agitated for 48-72 h. The volatile products were removed at — 35 C under reduced pressure and C HCI, was added to the residue. A suspension of KF was filtered off, the filtrate was washed with 10% aq NaFlC03, dried (MgS()4) and the solvent removed under vacuum. The crude product was subjected to distillation or GC purification. 

Adsorbents. The macroreticular resins XAD-2 and XAD-4 were separately suspended in distilled water, and the suspensions were stirred to leave the fine particulates floating. These fines were removed by decantation of the supernatant layer. This operation was repeated until no opalescence was noticeable in the supernatant layer. After filtration through Whatman no. 1 filter paper and washing with methanol, the resins were dried at 70 °C in a convection oven prior to further purification. The average weight per milliliter of the resin was found to be 0.40 0.02 g. 

In a 500-cc. round-bottomed, three-necked flask fitted with a reflux condenser, dropping funnel, and a mercury-sealed stirrer (Note 1) is placed a solution of 46 g. (0.5 mole) of dry aniline in 125 cc. of pure dry benzene. Stirring is started, and a solution of 42 g. (0.5 mole) of ketene dimer (p. 64) in 75 cc. of pure dry benzene is added dropwise over a period of half an hour. The reaction mixture is then heated under reflux on the steam bath for one hbur. After the major portion of the benzene has been removed by distillation from the steam bath, the remainder is removed under reduced pressure. The residue is dissolved in 500 cc. of hot 50 per cent aqueous alcohol from which the aceto-acetanilide separates on cooling. The mixture is cooled to 0° before filtration. A second crop of crystals can be obtained by adding 250 cc. of water to the mother liquor and cooling again (Note 2). The total yield of product, m.p. 82-83.5°, is 65 g. (74 per cent of the theoretical amount). Further purification by recrystallization from 300 cc. of 50 per cent alcohol yields 55 g. of a product which melts at 84-85°. 

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