Salt Selection in Drug Development - Pharmaceutical Technology

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Salt Selection in Drug Development
The selection of an appropriate salt form for a potential drug candidate is an opportunity to modulate its characteristics to improve bioavailability, stability, manufacturability, and patient compliance.

Pharmaceutical Technology
Volume 3, Issue 32

Table IV: Techniques for the characterization of salt forms.
Techniques for the characterization of salts. After synthesis, the formation of the salt forms must be confirmed. Next, their pharmaceutical properties must be assessed. Several characterization techniques provide valuable information for salt screening (see Table IV).

Salt-selection studies. Morris et al. adopted a multitiered approach to screen salts for their optimal physical forms (39). In this approach, physicochemical tests are conducted in several tiers, and a go–no-go decision is made after each tier. Only appropriate salts, free acids, or bases are tested further, thus avoiding the generation of extensive data about each salt form generated. The studies can be planned so that the least time-consuming experiments that could still prompt a go–no-go decision are conducted in the first tier. Experiments that are more time consuming and labor intensive can be conducted at later tiers. In this way, many salt forms can be screened with a minimum of experimental effort. If the tiered approach eliminates all the candidates, additional salts must be considered before reevaluating any salt rejected in an earlier tier.

Figure 3: Flow diagram for selecting the optimal salt form of a drug.
For a rational approach to salt screening, the tiered approach should be combined with a goal-oriented approach in which the main problems associated with the free acid or base are handled first, followed by secondary problems. For example, ranitidine hydrochloride is hygroscopic with a critical relative humidity of approximately 67% (40). However, the hydrochloride salt of ranitidine has better absorption properties compared with the free base and is one of the most successful drugs ever marketed. In a multitiered approach, the hydrochloride salt would have been rejected after hygroscopicity testing, in spite of its better absorption profile (41). High hygroscopicity could be mitigated by developing proper packaging. Similarly, the hydrochloride form of sertaline (i.e., Pfizer's Zoloft) might have been rejected because of its reported 28 polymorphic forms (42). This fact underlines the importance of a goal-oriented approach that addresses the most critical problems first. Less critical problems could be overcome by a proper development strategy. The final salt form selected should have a fine balance of the optimal physicochemical and biopharmaceutical properties. Each stage of salt selection (see Figure 3) is relevant and contributes to the selection of the optimal salt form. However, salt selection can be a difficult task because each salt imparts unique properties to the parent compound.

Stages of salt selection. Salt screening starts with the characterization of free acid or base, followed by the identification of possible counterions. The acid or base characterization provides information for potential counterion selection and for planning relevant crystallization experiments. This stage is followed by a screening of crystallization conditions for the desired salts, salt formation and its confirmation, and finally the preformulation characterization of generated salts (20).

During salt-form selection, the determination of pK a and corresponding ionizable groups gives an idea of the feasibility of salt formation. This information is the basis for selecting suitable counterions and a preliminary synthesis of salt forms, preferably at the microlevel, coupled with characterization for salt formation. After the confirmation of salt formation, the prepared salts are screened for various biopharmaceutical properties with a view to selecting the optimal salt form.

Assessment of crystallinity is the first stage of salt selection. The salt form should preferably be crystalline so that its properties remain constant during pharmaceutical handling, transportation, and use. However, the amorphous form may have advantages (e.g., solubility) that can be harnessed by proper formulation development. On the other hand, stabilizing the amorphous form for devitrification to crystalline form may lead to the loss of these advantages. Atorvastatin calcium was originally developed in an amorphous form. During Phase III clinical trials, it reverted to crystalline form, and the final product was developed using a crystalline form (43).


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