Formulation process solid forms

All of our observations lead us to believe that the crystallization of VPI-5 involves a solid phase reordering process. This solid phase transformation does not involve TBA as either a template or a space-filler. TBA may be present in the solid phase in very low concentrations that are below detection limits by IR and NMR and may still play some role in the crystallization mechanism. Also, it may serve to moderate the pH of the reaction mixture during its formulation and heating such that certain aluminophosphate precursor species are present in the solid phase. Here we will explore these two possibilities in order to further understand the crystallization process for forming VPI-5. 

Regardless of the stage of formulation/process development being considered, a detailed identification of variables and responses is necessary for early program planning. Typical variables and responses that could be expected in a granulated solid dosage form are listed in Table 1. This list is by no means complete and is intended only as an example. 

The concentration and the solidification of ammonium nitrate and urea solutions to form solid fertilizers require considerable expenditure of eneq>y and processing expense so it is attractive to use the solutions in the formulation of liquid fertilizers, without processing them into solid form. However, neither ammonium... 

Companies will custom formulate colorant and additive products designed to be used by plastic molders, who will, in turn, produce the final consumer products. The raw materials for colorant and additive products may be in powder, liquid, or solid form. The products formulated from them may also be in powder, liquid, or solid form. Dry color formulations (powder form) currently comprise less than 5% of the total colorant and additive products being produced today. Liquid formulations account for another 5% however, this form of product is increasing in popularity and is expected to capture a larger share of the colorant and additives market in the near future. The solid form, known as concentrates or masterbatch products, are concentrated ingredients encapsulated in a carrier resin that is usually in pellet form. This type of product comprises the overwhelming majority of the formulated products used by molders and compounders today. A discussion of the basic production processes associated with the production of the various colorant and additive product types is presented below. 

When processing auxiliaries such as copovidone in formulations for solid dosage forms, the particle size distribution can be of considerable importance. This particularly applies to the manufacture of tablets. However, it can also be important in solutions, e.g. film-coating solutions for tablets, as the dissolution rate and the dusting properties depend on the proportions of coarse and fine particles respectively. 

The physicochemical properties of the drug both in solution and in the solid state play a critical role in drug formulation. The solid-state form of the drug is often preferred, because it is often more chemically stable, easier to process, and more convenient to administer than liquid formulations. However, if the drug is in the solid state, it must dissolve before it can be therapeutically active, and once it is in solution, it must be both sufficiently soluble and chemically stable. For these reasons, it is critical to determine the physicochemical properties of the drug both in solution and in the solid state. 

In the solid state proteins are frequently more stable, so formulations of solid dosage forms are often used to increase the stability. However, the process of making solids is still quite challenging. 

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

As with many activities associated with physicochemical property analysis, solubility measurements can follow a tiered workflow. For example, all lead optimization compounds can be assayed at pH 7.4, 6.5, 4.0, and 1.5 using DMSO solutions. Lead compounds that progress onward through the discovery process can be examined in solid form at pH 7.4 and 4.0 to facilitate downstream formulation activities [25],... 

Solid form selection involves the preparation and property evaluation of many derivatives of an active molecule. Drug substance properties of importance in the drug development process may be categorized as shown in Table 1. These properties depend on the nature of the drug substance and the final formulation. Many bioactive organic molecules contain ionizable groups such as carboxylic... 

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