Excipients formulation development

A variety of approaches exist for stabilizing proteins, for example, chemical modification, immobilization, and site-directed mutagenesis [95,96], but these techniques are not within the scope of this chapter. The focus here will be on stabilization of proteins via formulation development. The principal formulation strategy is to stabilize the protein using clinically acceptable additives (excipients) or through the use of suitable pharmaceutical-processing technologies. 

Formulation Development. The formulation of the new drug product will be designed in conjunction with medical and marketing input. Excipients to be used will be tested for chemical and physical compatibility with the drug substance. The preliminary formulation design will be optimized at this stage. 

Excipients are thus one of the three components that in combination produce the medicine that the patient will take. In therapeutic terms, the API is of primary importance because without it there is no treatment and no product. However, in terms of the development and manufacture of the product, all three components are equally important, and we neglect any one of them at our peril. The annals of formulation development in most companies, both large and small, are probably littered with examples where some aspect of one of these three components has been neglected in some way, with unfortunate consequences for the project. The interactions between excipients and the other two components (the API and the manufacturing process), and/or between two or more excipients, are fundamental to the transformation of an API into a medicinal product. 

Because particle size is so intimately intertwined with powder performance, it is one of the prime considerations in selecting excipients to develop or improve a formulation. This is particularly important with direct compression formulations where excipient flowability and compaction performance are critical. Typically, excipients for these applications exhibit narrow size distributions with moderate-to-coarse particle size, having a mean size from 100 to 200 pm. 

IMPORTANCE OF EXCIPIENT SELECTION IN THE PROCESS OF ORAL LIQUID FORMULATION DEVELOPMENT... 

In fact, it is a regulatory expectation that an appropriate excipient be chosen and its level (amount) in a formulation be demonstrated and justified through formulation screening and development studies (29,30). The science of protein formulation development has become increasingly sophisticated over the past 20 years and its discussion is beyond the scope of this chapter. The interested reader is referred to excellent reviews on this subject for further study (31-34). 

In the race to be the first to market a drug product, or in the midst of quality or supply issues, it is not uncommon for a distributor to receive phone calls on a Friday afternoon asking for a Monday delivery of excipients, because many excipient users do not necessarily follow a Monday through Friday, 9 00 a.m. to 5 00 p.m. schedule. This is especially true of product development groups in small, privately owned companies. It is not uncommon for formulation development to continue into the weekend. It has already been noted that small volume shipments are more difficult than large volume ones, and, further, arranging for these materials to be available on short notice can certainly compound the challenge. 

Gad and Cassidy (2006) summarized the comprehensive information of maximum tolerabilities for 65 single component vehicles used in 368 studies across multiple species (e.g., dog, primate, rat, mouse, rabbit, guinea pig, minipig, chick embryo, and cat) by multiple routes. The paper serves as a good reference for excipient selection in the toxicology formulation development. 

Several good surfactants in terms of solubility, compatibility, and toxicity can be selected for prototype formulation development. In general, one surfactant can be used as the primary solubilizer in a prototype formulation. Functional excipients, such as antioxidants, tonicity agents for parenteral products and sweeteners, and taste masking agents for oral products, may be added to the prototyp formulation. 

Formulation development provides the basic information on the active chemical, the formula, and the impact of raw materials or excipients on the product. Typical supportive data generated during these activities may include the following ... 

Senderoff RI, Mahjour M, Radebaugh, GW. 1992. Characterization of adsorption behaviour by solid dosage form excipients in formulation development. Int. J. Pharm. 83 65-72. 

Mohan G. 2005. Functionality testing of excipients and their impact on formulation development. Am. Pharm. Rev. 8(6) 64-67. 

Great effort should be taken to stabilize a formulation in such a way that the shelf life becomes independent of the storage conditions. The photostability of drugs and excipients should be evaluated at the formulation development stage in order to assess the effects of packaging on the stability of the final product. Molsidomine tablet preparations in inadequate primary containers (blister) without secondary containers when exposed to irradiation may produce morpholine. These results illustrate the importance of packaging for the stability of molsidomine [19]. 

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