Solid form selection

For drugs with low solubility, special efforts must be made to bring the concentration into the therapeutically active range. In this section, some of the common methods to increase solubility will be discussed salt versus free form, inclusion compounds, prodrugs, solid form selection, and dissolution rate. It should be noted that efforts to increase solubility also have an influence (often negative) on the stability of a compound. For this reason, the most soluble form is often not the first choice when formulating the drug. 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

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... 

In this chapter we describe the form selection process. A short review of the analytical techniques commonly employed is followed by sections covering salt and solid form selection. Form selection should be approached in a planned, rational manner, but it is important to realize that not all compounds will allow adherence to a single experimental plan. The exercise is a scientific one, and it will yield the best results only if carried out with judgment and flexibility. 

It is obvious from the preceding discussion that salt and solid form selection are intertwined. The propensity of a compound, either neutral or a salt, to exist in different crystal forms is considered as part of the salt selection process. However, once selected for inclusion in drug product, the solid-state properties of a given compound must be evaluated in detail. The following section describes the solid-form selection process as it is carried out with a single chemical entity. 

Given all the possible structures available to an organic solid, form selection can be a daunting task. The process typically begins once the molecular structure of the active has been selected, but can also accompany salt selection (see above). The first step in solid form selection is to determine if polymorphic and/or amorphous forms of the molecule of interest (drug substance) exist. This process is called polymorph screening (46). Once forms are identified, they must be characterized and their important properties determined. Only with such data in hand can a rational selection of final solid form be made. 

Drug substance solid form selection can be approached in a rational manner. The process consists primarily of salt selection and polymorph screening, both of which involve preparation and property evaluation of many samples. It is critical that multiple analytical techniques be employed during this work. The amount of information that needs to be collected is large, and evaluation of it requires experience and flexibility. 

Challenges of Pharmaceutical Industry Related to Solid Form Selection... 

Though the CPSSC is an emerging field, many of the approaches have proved their importance for the industry and are already embedded in the workflows of various pharmaceutical companies. Moreover, though it is currently impossible to build a reliable statistics regarding the use of CPSSC over the whole industry, it is known that some of the methods (like computational support of solid form selection) have already been successfully used to support New Drug Applications (NBAs) of some of the recently approved drugs. 

This chapter reviewed only H-bond propensity analysis approaches to complement polymorph screening by facilitating the risk assessment of a missed more stable form. A focus was given to different theoretical approaches of H-bonding ranking, which were developed to accurately reproduce experimental observations as well as high-level theoretical calculations. Successful applications of COSMO-RS and QTAIM-based methods to support the pharmaceutical solid form selection were demonstrated. 

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