Formulation development

The interface of formulation development, dosage forms, and polymorphism is extremely important in the pharmaceutical industry. A tablet can turn into either a powder or a rock, due to polymorphic instability triggered by either interconversion of polymorphs or by 

1 Physical Property Design of the Active Pharmaceutical Ingredient 

In general, the selection of a suitable salt10 or co-crystal11 is mainly driven by biophar-maceutical and stability considerations. Where several modifications exist, the selection of the most suitable for formulation purposes is a general formulation issue as well.12 

Emphasis has also been placed on the particle size distribution and the uniform size distribution of the API rather than on the mean particle size alone by other authors.1416 Rohrs et al.16 give a nomograph for identifying the maximum median particle diameter to pass USP 28 stage I content uniformity criteria with 99% confidence as a function of dose as well as width of particle size distribution (geometrical standard deviation). 

In addition to the particle size of the API, the genesis of the material is of importance. Typically, the final step of the API preparation is a milling or micronization process, which determines physical properties like cohesiveness and the tendency 

One other drawback of the utilization of micronized API in the context of fluidized bed granulation is the potential to lose a material fraction into the filters of the equipment due to the fact that smaller particles demand lower suspension velocities than large ones. More specifically, the potential loss of dmg substance via the air current according to Eq. (4.1) is determined by the fact that the air current which is applied to suspend a particle is proportional to the square root of its diameter 21 

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Sihcone polymer plasticizers have historically been used in many formulations. These plasticizers (qv) are of the same Si—O backbone as the functional polymers but generally are terrninated with trimethyl groups which are unreactive to the cure system. This nonreactivity means that, if improperly used, the plasticizer can migrate from the sealant and stain certain substrates. Staining has been a widely pubHcized flaw of sihcone sealants, but the potential of a formulation to stain a substrate can be minimized or eliminated with proper formulation work. In general, this is accompHshed by not using plasticizers for formulations developed for stain-sensitive substrates. 

Most of these procedures are proprietary. Formulation development is also becoming more complex for preparation and deHvery of new vaccines. The classical vaccines are mostly prepared as injectable solutions. Aseptic techniques are required in the design and operation of the faciHties. 

Nitropolystyrene has been suggested for use in mining. Of the more than several expl formulations developed for such a purpose one is presented here as an example Nitropolystyrene 7.2, DNT 10.8 and Penthrite 82.0%. With a d of 1.58g/cc the deton vel of this expl compn is 752Qm/sec... 

Phosphate-cycle programs, which first became available at the turn of the twentieth century and were researched and formalized in the 1920s, have gradually replaced the carbonate-cycle programs. Formulation developments include combined phosphate-carbonate cycle programs, which incorporate the best of both basic programs while minimizing the problems associated with carbonate breakdown. 

Drug substance/drug product purity, potency, and other testing Drug substance/drug product stability testing Method development, validation, and transfer Drug product formulation development... 

PP Constantinides, KJ Lambert, AK Tustian, B Schneider, S Lalji, W Ma, B Wentzel, D Kessler, D Worah, SC Quay. Formulation development and... 

E. Instrumentation of Capsule-Filling Machines and Their Role in Formulation Development... 

A major development in pharmaceutical technology has been the application of instrumentation techniques to tablet presses. The ability to monitor the forces that develop during the compaction, ejection, and detachment of tablets has brought about new insights into the physics of compaction, facilitated formulation development, and provided a means for the in-process control of tablet weight in manufacturing [62,63], In... 

H. Systematic Formulation Development and Analysis of Critical Variables... 

Because membrane filtration is the only currently acceptable method of sterilizing protein pharmaceuticals, the adsorption and inactivation of proteins on membranes is of particular concern during formulation development. Pitt [56] examined nonspecific protein binding of polymeric microporous membranes typically used in sterilization by membrane filtration. Nitrocellulose and nylon membranes had extremely high protein adsorption, followed by polysulfone, cellulose diacetate, and hydrophilic polyvinylidene fluoride membranes. In a subsequent study by Truskey et al. [46], protein conformational changes after filtration were observed by CD spectroscopy, particularly with nylon and polysulfone membrane filters. The conformational changes were related to the tendency of the membrane to adsorb the protein, although the precise mechanism was unclear. 

The formulation development process used for traditional low molecular weight drugs is well understood. The same principles that are applied to this process may be applied to the formulation development of... 

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, production, and stability testing of clinical dosage form... 

Powder flow is most frequently thought of as relevant to formulation development, and there are numerous references attempting to correlate any one of a number of measures of powder flow to the manufacturing properties of a formulation [34—40]. In particular, the importance of physical properties in affecting powder flow has been well documented. Research into the effect of the mechanical properties on powder flow has, however, been very limited. It is, of course, important to be able to determine and quantitate the powder flow properties of formulations. It is of equal importance, however, to determine the powder flow characteristics of bulk drug early in the development process (preformulation phase). Often, the preformulation or formulation scientist is constrained by time, materials, and manpower. Yet certainly the preformulation studies carried out should be meaningful. Well-defined experimental methods and procedures should be used the information generated should be reproducible and permit useful predictions to be made. 

Table 6 shows the usefulness of shear cell data in formulation development. Variations in relative humidity can profoundly influence flow this is a valuable piece of information for formulation development. Shear cell methodology thus provides useful data for optimizing the flow of formulations as well. 

Although various polysorbates are used, the experience with an EPO-based product (trade-name Eprex) sounds a potential cautionary note in terms of formulation development, as outlined in Box 4.1. 

Frokjaer, S. 2000. Pharmaceutical Formulation Development of Peptides and Proteins. Taylor and Francis. Grindley, J. and Ogden, J. 2000. Understanding Biopharmaceuticals. Manufacturing and Regulatory Issues. Interpharm Press. 

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