Formulation injectable products

Reacting the drug with succinic anhydride results in the hemisuccinate derivative, obviously now a large 25-carbon carboxylic acid. Its solubility is less than 1 mg/ml. However, by the simple expedient of neutralizing the acidic function and forming the ionic sodium salt the solubility is increased to over 200 mg/ml. This is more than adequate to formulate injectable products of considerable concentrations. 

One of the most difficult parenteral dosage forms to formulate is a suspension. It requires a delicate balance of variables to formulate a product that is easily resuspended and can be ejected through an 18-to 21-gauge needle through its shelf life. To achieve these properties it is necessary to select and carefully maintain particle size distribution, zeta potential, and rheological properties, as well as the manufacturing steps that control wettability and surface tension. The requirements for, limitations in, and differences between the design of injectable suspensions and other suspensions have been previously summarized [17b, 18,19]. 

Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable in order to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formulation at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 2 to about pH 11. 

Dilute solutions in aqueous buffers exposed to diffused or direct sunlight gave dimethylamine and 5-diazoimidazole-4-carboxamide (215). At pH 1.0 or pH 7.4 and above, this cyclized to 2-azahypoxanthine (216). In the intermediate pH range, a different product was obtained (217) which happens to be the aglycone of the antibiotic bredinin. Compound (217) was not formed by irradiation of (216). It was suggested that the betaine arose from a carbene (218) which had been quenched by water. However, (217) is colourless. Formulated injection solutions which had been found to lose activity contained 10 mg/ml... 

Cefuroxime is only poorly absorbed from the gastrointestinal tract and so was originally only an injectable product, but a commercially successful new orally-administered cerufoxime ester product has been developed which has created a new surge in sales. This acetoxyethyl pro-drag form of cefuroxime is rapidly hydrolysed in the brash-border mucosal epithehal cells of the duodenum and small intestine, but requires special formulation so as to ensure efficient dissolution following investigation. 

As discussed above, cosolvents can be an effective way to alter the solubility and stability of compounds. In formulating a parenteral product, often these two parameters can be exploited to produce a commercially acceptable, elegant product. Often cosolvents can be used to concentrate a formulation to allow production of a dosage form for presentation as an ampule or vial. The concentrated ampule or vial is then diluted before administration to the patient. Nema et al. [107] has reviewed excipient use, including cosolvents, in commercially available injectable products. 

Several other events occur simultaneously with these activities. Some events focus on extending therapeutic applications and formulations. Clinical studies are conducted to extend the diseases (indications) for which the drug is proven efficacious and safe. For example, TAXOL was initially approved for the treatment of ovarian cancer, and was later extended for the treatment of breast cancer after follow-on clinical studies demonstrated efficacy for the new indication. In addition, new product formulations are investigated to extend the routes of administration for patient convenience, increased bioavailability, and new disease therapies. For example, a drug initially developed as an injectable product may be formulated as a tablet for oral administration. 

Worldwide sales of insulin are currently in the region of 2 billion. It is estimated that if an effective pulmonary formulation is developed and receives approval, there would be a 20% switch from the injectable products within a year. The same would apply in the case of an effective oral product. Assuming an initial high price (perhaps 30% above that of injectable insulin), this represents potential sales of 400 million for the new product a year after launch. 

This chapter introduces the basic aspects of small-volume injectable products—their use, types and primary characteristics of dosage forms, formulation ingredients, and packaging systems. Additional information is available in a variety of reference texts and book chapters. Only conventional SVI... 

Several sources of information were used to summarize the information compiled in this chapter. ° Formulation information on the commercially available injectable products was entered in a worksheet. Tables presented in this chapter are condensed from this worksheet. Each table is categorized based on the... 

Simply because an excipient is listed as Generally Recognized As Safe (GRAS) does not mean that it can be used in parenteral dosage form. The GRAS list may include materials that have been proven safe for food (oral administration) but have not been deemed safe for use in an injectable product. This makes it difficult for the formulation development scientist to choose additives during the dosage form development. 

In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid. Injectable products containing phenytoin, digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water-miscible solvent (such as an alcohol-water mixture) or as a solubilised (e.g. micellar) preparation. Addition of the formulation to water may result in precipitation of the dmg, depending on the final concentration of the dmg and solvent. It has been suggested that precipitation of the relatively insoluble diazepam may account for the high (3.5%) incidence of thrombophlebitis which occurs when diazepam is given intravenously. 

During the discovery phase, when availability of compound is at a premium, the formulation of a simple injectable product for use in animal studies can be problematical. If a drug candidate required for formulation as a parenteral product is non-ionizable, lipophihc or does not form a water-soluble salt with acceptable properties, solubilization by use of cosolvents should be considered as the next option. In cases... 

Homogeneous solutions are the preferred formulation systems for parenteral administration because they can be easily visually inspected for the absence of particulate matter. For this reason, cosolvent solubilization is the first choice for parenteral products once purely aqueous systems provide insufficient solvency. The compositions of three commercial, injectable products are given in Table 39.5. The first product (1) has a low percentage of cosolvent in the separate solvent ampoule. The drug substance is provided as a dry powder because of its limited stability in solution. The second one (2) is solubiUzed with two cosolvents amounting to 50% of the total volume, whereas in the third product the drug dose is dissolved in a water-free mixture of cosolvents. This draws the attention to a further point to consider when cosolvents are employed in formulations. The formulation has to be devised such that the effect of dilution of... 

At this stage, clinical formulations are simple, such as drug-filled capsules or injectable products. As such, specifications will be largely based on the drug substance, because the study objectives are to examine drug tolerability, safety, and pharmacokinetics in small numbers of human subjects. 

The protocol is a written document (see Section II.C.I) that describes the necessary parts of a stability study. It details the basic plan that will be executed, and its two major components include the tests to be performed and the schedule of testing that is planned. The types of batches that require a protocol are clinical, formulation development, registration, and marketed product. In addition, compatibility of a product with a vehicle (e.g., an injectable product in an intra venous saline solution) is often studied to support the use of injectable products for hospital use. Probe stability studies are generally more experimental in nature and may not be suitable for a formal written protocol. 

Preservatives should not usually be included in parenteral formulations except where a multidose product is being developed. The Committee for Proprietary Medicinal Products (CPMP) Notes for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products states that the physical and chemical compatibility of the preservative (or antioxidant) with the other constituents of the formulation, the container and closure must be demonstrated during the development process. The minimum concentration of preservative should be used, which gives the required level of efficacy, as tested using pharmacopoeial methods. Certain preservatives should be avoided under certain circumstances, and preservatives should be avoided entirely for some specialised routes. The guidelines also require that both the concentration and efficacy of the preservative are monitored over the shelf life of the product. In multidose injectable products, the efficacy of the preservative must be established under simulated in-use conditions. Table 9.2 shows some of the most commonly encountered preservatives in licensed products and their typical concentrations. 

In addition, with colored glass or plastic, it is virtually impossible to observe a color change in a drug formulation, and it is difficult to examine an injectable drug solution for particulate matter. Therefore, injectable products raise the most difficult... 

The choice of elastomer has the greatest effect on a formulation. The most common elastomers that can be used for closures for injectable products are given in Table 12.5. Of these elastomers, natural rubber, synthetic polyisoprene, butyl, chlorobutyl and bromobutyl rubber are typically used for the manufacture of rubber closures and stoppers used in the packaging and administration of parenterals. 

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