The Selection of a Pharmaceutical Salt-The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance.

A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product.

Measurement and Accurate Interpretation of the Solubility of Pharmaceutical Salts.

Salt formation is one of the primary approaches to improve the developability of ionizable poorly water-soluble compounds. Solubility determination of the salt candidates in aqueous media or biorelevant fluids is a critical step in salt screening. Salt solubility measurements can be complicated due to dynamic changes in both solution and solid phases. Because of the early implementation of salt screening in research, solubility measurements often are performed using minimal amount of material. Some salts have transient high solubility on dissolution. Recognition of these transients can be critical in developing these salts into drug products. This minireview focuses on challenges in salt solubility measurements due to the changes in solution caused by self-buffering effects of dissolved species and the changes in solid phase due to solid-state phase transformations. Solubility measurements and their accurate interpretation are assessed in the context of dissolution monitoring and solid-phase analysis technologies. A harmonized method for reporting salt solubility measurements is recommended to reduce errors and to align with the U.S. Pharmacopeial policy and Food and Drug Administration recommendations for drug products containing pharmaceutical salts.

Salvinorin A: A Mini Review of Physical and Chemical Properties Affecting Its Translation from Research to Clinical Applications in Humans.

Salvinorin A is a potent and selective agonist of kappa opioid receptors in the brain. Recent studies in several animal models have revealed that Salvinorin A has anti-addiction, anti-depression properties and exhibits pronounced neuroprotective effects against hypoxia/ischemia induced brain damage, and have raised interest in potential clinical applications in several acute pathologies involving oxygen deficiency in the brain. This review focuses on the chemical and physical properties of Salvinorin A and their impact on development of a rational formulation to enable its translation from a research compound to a novel therapeutic agent.

Predicting solubility in multiple nonpolar drugs-cyclodextrin system.

This study presents a model to predict the solubility of a nonpolar drug D(A) in the presence of other nonpolar drugs D(1) em leader D(n) in a complexing ligand L system such as hydroxypropyl-beta-cyclodextrin (HPbetaCD). Using an equilibrium approach, the model describes the molecular interactions among these drug species and the ligand. The model indicates that the solubility of D(A) invariably decreases as a result of the presence of D(1) em leader D(n). Furthermore, the decrease in D(A) solubility is related to the sum of the products of the intrinsic solubilities of the other drugs and drug-ligand complexation constants. To test the model, three steroids (prednisolone, 17alpha-hydroxyprogesterone, and progesterone) were used as model compounds in HPbetaCD solutions. The experimental data showed that the solubility of any particular drug decreased in the presence of other drugs. At all tested HPbetaCD concentrations, these experimental solubility data were in good agreement with the predicted solubility data. This result lends strong support to the reliability and effectiveness of the proposed model.