Labile pharmaceuticals

The advantages over conventional crystallization of crystallization under supercritical conditions are particularly clear, when non-volatile, thermally labile pharmaceutical substances are to be crystallized. As non-contaminating solvents at close-to-ambient temperatures, supercritical fluids might be an attractive alternative to conventional organic solvents. 

OMD offers major advantages in comparison with the conventional thermal concentration techniques. The low temperature employed can help avoid chemical or enzymatic reactions associated with heat treatment [85] and prevent degradation of flavor, color, and loss of volatile aroma [38]. The low-operating pressure (atmospheric pressure) results in low investment costs, low risks of fouling, and low limits on compactive strength of the membrane. Since the separation is based on vapor-liquid equilibrium, only volatile compounds which can permeate the membrane and the nonvolatile solutes such as ions, sugars, macromolecules, cells, and colloids are totally retained in the feed. These factors make OMD an attractive alternative to traditional thermal routes currently used for concentration of liquid foods or aqueous solutions of thermally labile pharmaceutical products and biologicals [86]. 

According to perceived wisdom, the solid, dry state of otherwise labile pharmaceutical materials can be equated with stability , dehned by an extended shelf life, with reference to specihed storage conditions. Let us consider the exact meaning of stability , although even the more basic word dry , as used, often somewhat carelessly, in freeze-drying... 

Figure 15.5 shows an ion mobility spectrum of irinotecan, athermally labile pharmaceutical with a molecular weight of 586.7 Da a thermal desorption IMS instrument was used for detection. A complex spectrum was obtained containing multiple thermal decomposition products of various mobilities. 

The micellar environment is sufficiently different from the simple aqueous environment that reaction rates may sometimes be dramatically changed because of this there has built up a school of chemistry in which micellar systems are used deliberately to alter the rates and directions of chemical reactions. In pharmaceutical formulations the influence of surfactant on the stability of the pharmaceutical is generally secondary to its main purpose, but surfactants may be used to stabilize labile pharmaceuticals, and an understanding of the mode of action and interactions can avoid the problem of destabilization which might unwittingly occur. 

You have to sterilize an aqueous solution of a heat-labile pharmaceutical compound by a membrane process. Pseudomonas diminuta (0.3 pm in diameter for our purpose) is conveniently used as a bacterial model to test the membrane for its integrity. However, you have an opportunity to test and determine only the bubble-point pressure of the membrane with water. Such a test yielded a value of 55 psia. What is the value of the largest pore... 

Sugar is destroyed by pH extremes, and inadequate pH control can cause significant sucrose losses in sugar mills. Sucrose is one of the most acid-labile disaccharides known (27), and its hydrolysis to invert is readily catalyzed by heat and low pH prolonged exposure converts the monosaccharides to hydroxymethyl furfural, which has appHcations for synthesis of glycols, ethers, polymers, and pharmaceuticals (16,30). The molecular mechanism that occurs during acid hydrolysis operates, albeit slowly, as high as pH 8.5 (18). 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

How do we decide whether to separate a mixture by gc or hplc In gc, mixtures are examined in the vapour phase, so that we have to be able to form a stable vapour from our mixture, or convert the substances in it to derivatives that are thermally stable. Only about 20% of chemical compounds are suitable for gc without some form of sample modification the remainder are thermally unstable or involatile. In addition, substances with highly polar or ionisable functional groups often show poor chromatographic behaviour by gc, being very prone to tailing. Thus hplc is the better technique for macromolecules, inorganic or other ionic species, labile natural products, pharmaceutical compounds and biochemicals. 

The most important advantages of the supercritical fluid technique in the application to pharmaceuticals is the high quality of the products in terms of purity, their unique morphology, and the wide range of materials that can be processed. Furthermore, the mild operating conditions can be especially favourable to bio-labile molecules, such as protein- or genetic material involved in pharmaceutical applications. 

Charton, M. 1977.The prediction of chemical lability through substituent effecBefeign of Biopharmaceut-ical Properties through Prodrugs and Analggpdited by E. B. Roche, 22280. V foshington, D.C. American Pharmaceutical Association. 

Diagrams provide another form of visualization that rapidly communicates pharmaceutical properties of a drug candidate. For example, the labile sites of a molecule can be diagrammed in simple format superimposed on the structure (Figure 5.6) to rapidly communicate the labile sites or soft spots of the candidate structure (Lee... 

Tray dryers, the simplest type of dryer, are commonly used for batch drying of biological materials, where the wet solids are placed on trays which are then transferred into a chamber. The chamber may have a heating jacket, heated tray supports, or a hot air supply. Vacuum may be applied to reduce the temperature at which the liquid evaporates, preserving heat labile products. These are well suited to low-volume products or flexible plants where a number of different products with different characteristics must be dried. They are relatively inefficient to operate, difficult to clean, and labor intensive to operate. The product is exposed when being loaded and unloaded, so the dryer may need to be located in a clean room or area for pharmaceutical products. 

Since the 1, 3,4-oxadiazoles have recently achieved an increased significance pharmaceutically, the metabolism of 2-m- and 2-p-hydroxyphenyl-l,3,4-oxadiazole has also been investigated.131 They are however, completely stable in vivo, in contrast to the relatively labile 1,3,4-oxadiazolinones,132 and are incorporated into the organism as esters of sulfuric acid or of glucuronic acid. 

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