A molecular descriptor known as R3m
(the R-GETAWAY third-order
autocorrelation index weighted by the atomic mass) was previously
identified as capable of grouping members of an 18-compound library
of organic molecules that successfully formed amorphous solid dispersions
(ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone
vinyl acetate (PVPva) at two concentrations using two preparation
methods. To clarify the physical meaning of this descriptor, the R3m
calculation is examined in the context of the physicochemical mechanisms
of dispersion formation. The R3m equation explicitly captures information
about molecular topology, atomic leverage, and molecular geometry,
features which might be expected to affect the formation of stabilizing
non-covalent interactions with a carrier polymer, as well as the molecular
mobility of the active pharmaceutical ingredient (API) molecule. Molecules
with larger R3m values tend to have more atoms, especially the heavier
ones that form stronger non-covalent interactions, generally, more
irregular shapes, and more complicated topology. Accordingly, these
molecules are more likely to remain dispersed within PVPva. Furthermore,
multiple linear regression modeling of R3m and more interpretable
descriptors supported these conclusions. Finally, the utility of the
R3m descriptor for predicting the formation of ASDs in PVPva was tested
by analyzing the commercially available products that contain amorphous
APIs dispersed in the same polymer. All of these analyses support
the conclusion that the information about the API geometry, size,
shape, and topological connectivity captured by R3m relates to the
ability of a molecule to interact with and remain dispersed within
an amorphous PVPva matrix.
Although salt formation is the most ubiquitous and effective method of increasing the solubility and dissolution rates of acidic and basic drugs, it consumes large quantities of organic solvents and is a batch process. Herein, we show that the dissolution rate of indomethacin (a poorly water-soluble drug) can be increased by using hot melt extrusion of a 1:1 (mol/mol) indomethacin:tromethamine mixture to form a highly crystalline salt, the physicochemical properties of which are investigated in detail. Specifically, pH-solubility studies demonstrated that this salt exhibited a maximal solubility of 19.34 mg/mL (>1000 times that of pure indomethacin) at pH 8.19. A solvent evaporation technique was also used for salt formation. Spectroscopic analyses (infrared, nuclear magnetic resonance) of both; demonstrated, in situ salt formation with proton transfer. Powder X-ray diffraction and differential scanning calorimetry confirmed the crystalline nature of salts formed by both methods. Even though a number of amorphous salts of acidic drugs have been reported, the formation of a crystalline salt of an acidic drug by hot melt extrusion is completely unprecedented, which makes this study an important benchmark for the pharmaceutical production industry.
Organoleptic agents constitute an important niche in the field of pharmaceutical excipients. These agents encompass a range of additives responsible for coloring, flavoring, sweetening, and texturing formulations. All these agents have come to play a significant role in pharmaceuticals and cosmetics due to their ability to increase patient compliance by elevating a formulation's elegance and esthetics. However, it is essential to review their physical and chemical attributes before use, as organoleptic agents, similar to active pharmaceutical ingredients (APIs), are susceptible to physical and chemical instability leading to degradation. These instabilities can be triggered by API-organoleptic agent interaction, exposure to light, air and oxygen, and changes in pH and temperature. These organoleptic agent instabilities are of serious concern as they affect API and formulation stability, leading to API degradation or the potential for manifestation of toxicity. Hence, it is extremely critical to evaluate and review the physicochemical properties of organoleptic agents before their use in pharmaceuticals and cosmetics. This literature review discusses commonly used organoleptic agents in pharmaceutical and cosmeceutical formulations, their associated instabilities, and probable approaches to overcoming them.
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