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.
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).
Degree of crystallinity.
The degree of crystallinity, which is the percentage of crystalline form of any compound in the amorphous matrix, can markedly
affect dissolution properties. Analytical techniques used to determine the degree of crystallinity include powder X ray diffractometry
(20), near infrared spectroscopy (21), Raman spectrometry (22), solid-state nuclear magnetic resonance (23), dynamic vapor
sorption (24), and thermoanalytical techniques such as isothermal microcalorimetry (24–26), differential scanning calorimetry
(27), modulated temperature differential scanning calorimetry (28), and solution calorimetry (29). Reliability of the results
may improve if several techniques are used in parallel (30).
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).
Methods to determine wettability of powders have been classified according to the size of the sample and the mechanism of
wetting as shown in Figure 2 (33). Details of each method can be found in the cited literature (9, 34–45).
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).