Porosity. The porosity of dry powder may have a significant effect on its reconstitution. Haeger et al. showed that an increase in porosity of the lyophilized cake by decreasing the concentration of the fill solution before lyophilization yielded a fluffy, low-bulk density lyophilized parenteral formulation with the desired characteristic of rapid reconstitution time (10). Several methods for determining the porosity of powder by means of mercury intrusion porosimetry (11–14), nitrogen gas adsorption (14, 15), and X-ray tomography (16) have been reported.

Solid-state form. A drug can exist in crystalline, solvate, or amorphous form. Polymorphism, the existence of several crystalline forms of a single compound, affects dissolution properties of the drug (17). Different pseudopolymorphic forms also have different dissolution rates. For example, acyclovir exists as a hydrate and as an anhydrate, with each form having significantly different dissolution rates (18).

The amorphous form of a drug has higher kinetic solubility compared with the crystalline form as a result of its inherent high-energy state. Amorphization is, therefore, used to enhance a drug's dissolution properties in PI formulations. Bornstein et al. reported that the reconstitution time of the freeze-dried amorphous form of cefazolin sodium was decreased by 50% when compared with its crystalline form (19).

Powder wettability. Wetting is the primary step in the reconstitution process that is followed by the submergence, dispersion, and dissolution of the particle (31). Wettability, is a measure of the ability of a bulk powder to imbibe the liquid under the influence of capillary forces, and it depends on variables such as particle size, density, porosity, surface charge, surface area, and surface activity (32). Although, several techniques are available to determine the wettability of a powder, it is difficult to accurately assess powder wettability because of the complexity of this phenomenon in powder systems.

Wettability is largely reflected by the contact angle between the powder surface and the penetrating diluent (32). The commonly used contact angle measurement on solid surfaces is influenced not only by the physicochemical properties of the powder, but also by factors such as surface roughness, chemical heterogeneity, sorption layers, molecular orientation, swelling, and partial dissolution of the solid in the liquid (33). Consequently, there is no universal test to measure the wettability of powders and each powder–liquid pair must be examined on a case-by-case basis to select the most appropriate method (33).

Figure 2

Formulation factors. The inherently low aqueous solubility of an API in formulation may contribute to incomplete reconstitution. Several formulation interventions are used in such instances, including the use of cosolvents, cyclodextrin complexation, lipidic systems, and amorphization by freeze drying. A rapid dissolution of anidulafungin, an antifungal compound, was observed with 5–30% w/v ethanolic solution used as a diluent (46). The reconstitution behavior of melphalan, an anticancer drug, was improved by using cyclodextrins ((SBE)7m-β-CD or HP-β-CD) solution as the reconstitution diluent (47).