skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.


Title: Impurity retention and pharmaceutical solid solutions: visualizing the effect of impurities on dissolution and growth using dyed crystals
Pharmaceutical solid solutions are gaining increased interest as alternatives to salts and co-crystals for the enhancement of drug solubility and dissolution kinetics. Industrially, they are also responsible for the entrapment of potentially toxic impurities in drug substances. The accidental incorporation of process impurities into the lattice of a growing crystal, or the intentional incorporation of an additive, can vastly alter the product's properties. Reported effects include solubility enhancements, changes in melting point, shifting polymorph stabilities, growth inhibition, and change in crystal habit, among others. This work combines the fields of impurity rejection, solid solutions, and dyeing crystals, to provide visual evidence of those effects, and to further demonstrate how impure regions in a single crystal can present vastly different behaviors to the purified regions of the same crystal. The work revolves around four model host–guest pairs, two of them previously unreported. These include mixed crystals of acetaminophen with curcumin, sulforhodamine B, and acid fuchsin, as well as potassium sulfate dyed with acid fuchsin. Results challenge common assumptions in the study of multicomponent crystals, demonstrating how neglecting composition anisotropy may lead to misdiagnosing solid solutions as surface adsorbed impurities in impurity retention diagnostics, and how neglecting the habit-modifying effects of dissolved impurities may lead to the use of erroneous models for growth inhibition. At the same time, we present opportunities for the development of novel impurity rejection and crystal engineering strategies, aiding the growth of anisotropic crystals with properties that can be fine-tuned in continuum.  more » « less
Award ID(s):
2301629 2339644
PAR ID:
10567651
Author(s) / Creator(s):
; ; ; ; ;
Publisher / Repository:
Royal Society of Chemistry
Date Published:
Journal Name:
CrystEngComm
Volume:
26
Issue:
38
ISSN:
1466-8033
Page Range / eLocation ID:
5337 to 5350
Subject(s) / Keyword(s):
crystallization solid solutions impurities pharmaceutical solubility
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract Arctic single‐layer mixed‐phase clouds were studied using a one‐dimensional model that incorporated the adaptive habit growth model for ice microphysics. The base case was from the Indirect and Semidirect Aerosol Campaign, and it was perturbed over a range of cloud‐average temperatures, maximum (per model run) ice nuclei (IN) concentrations, and large‐scale subsidence velocities. For each parameter combination, the model was iterated out to 48 hr, and the time, called the glaciation time, to complete disappearance of liquid recorded if this occurred within the 48 hr. Dependence of glaciation times on cloud‐average temperatures from −30°C to −5°C, maximum IN concentrations from 0.10 to 30 L−1, and strong–no subsidence, with both isometric and habit‐dependent ice crystal growth, were investigated. For isometric crystal growth, the relationship between the critical maximum IN concentration (INcrit), the maximum (per model run) IN concentration above which a mixed‐phase cloud glaciated within a fixed model runtime, and cloud‐average temperature was monotonic. INcritdecreased with decreasing cloud‐average temperature. Strengthening of subsidence led to a further decrease in INcritfor every cloud‐average temperature. For habit‐dependent ice crystal growth, the relationship between INcritand cloud‐average temperature was nonmonotonic. Ice crystals develop dendritic and columnar habits near −15°C and −7°C, respectively, and at these two temperatures, ice crystals grew and depleted supercooled liquid water faster than the case when ice crystals grew isometrically. This led to deep local minima in INcritaround these two temperatures in the model runs. Habit‐dependent ice crystal growth, coupled with changes in cloud‐average temperature, INcrit, and subsidence strength, led to significant changes in Arctic single‐layer mixed‐phase cloud lifetimes. 
    more » « less
  2. Abstract Hematin crystallization is an essential element of heme detoxification of malaria parasites and its inhibition by antimalarial drugs is a common treatment avenue. We demonstrate at biomimetic conditions in vitro irreversible inhibition of hematin crystal growth due to distinct cooperative mechanisms that activate at high crystallization driving forces. The evolution of crystal shape after limited-time exposure to both artemisinin metabolites and quinoline-class antimalarials indicates that crystal growth remains suppressed after the artemisinin metabolites and the drugs are purged from the solution. Treating malaria parasites with the same agents reveals that three- and six-hour inhibitor pulses inhibit parasite growth with efficacy comparable to that of inhibitor exposure during the entire parasite lifetime. Time-resolved in situ atomic force microscopy (AFM), complemented by light scattering, reveals two molecular-level mechanisms of inhibitor action that prevent β-hematin growth recovery. Hematin adducts of artemisinins incite copious nucleation of nonextendable nanocrystals, which incorporate into larger growing crystals, whereas pyronaridine, a quinoline-class drug, promotes step bunches, which evolve to engender abundant dislocations. Both incorporated crystals and dislocations are known to induce lattice strain, which persists and permanently impedes crystal growth. Nucleation, step bunching, and other cooperative behaviors can be amplified or curtailed as means to control crystal sizes, size distributions, aspect ratios, and other properties essential for numerous fields that rely on crystalline materials. 
    more » « less
  3. Abstract Despite their highly anisotropic complex-oxidic nature, certain delafossite compounds (e.g., PdCoO2, PtCoO2) are the most conductive oxides known, for reasons that remain poorly understood. Their room-temperature conductivity can exceed that of Au, while their low-temperature electronic mean-free-paths reach an astonishing 20 μm. It is widely accepted that these materials must be ultrapure to achieve this, although the methods for their growth (which produce only small crystals) are not typically capable of such. Here, we report a different approach to PdCoO2crystal growth, using chemical vapor transport methods to achieve order-of-magnitude gains in size, the highest structural qualities yet reported, and record residual resistivity ratios ( > 440). Nevertheless, detailed mass spectrometry measurements on these materials reveal that they are not ultrapure in a general sense, typically harboring 100s-of-parts-per-million impurity levels. Through quantitative crystal-chemical analyses, we resolve this apparent dichotomy, showing that the vast majority of impurities are forced to reside in the Co-O octahedral layers, leaving the conductive Pd sheets highly pure (∼1 ppm impurity concentrations). These purities are shown to be in quantitative agreement with measured residual resistivities. We thus conclude that a sublattice purification mechanism is essential to the ultrahigh low-temperature conductivity and mean-free-path of metallic delafossites. 
    more » « less
  4. Abstract The structure and composition of the crystal growth unit are of huge fundamental and practical consequence. We propose a method to identify the solute species that incorporates into the growth site on crystal surfaces, the kinks, which rests on the kinetics of the elementary reaction at the kinks. We use as model crystals olanzapine, an antipsychotic medication, and etioporphyrin I, a field‐effect transistor. We combine time‐resolvedin situatomic force microscopy with Raman and absorption spectroscopies, complemented by density functional theory and all‐atom molecular dynamics modeling of the solutions. We show that the structure of the growth unit cannot be deduced neither from the solute oligomers nor from the crystal structure. Chemical kinetics analyses reveal that if the dominant solute species is the one that incorporates into the crystal growth sites, then the kinetics of layer growth complies with a monomolecular rate law. By contrast, if the crystal growth unit assembles from two units of the dominant solute form, a bimolecular rate law ensues. Solutions of both olanzapine and etioporphyrin I are dominated by solute monomers, which exist in equilibrium with a minority of dimers. Whereas numerous olanzapine crystal structures incorporate dimer motifs, etioporphyrin I crystals organize as stacks of monomers. Olanzapine crystal grow by incorporation of dimers. One of the studied face of etioporphyrin I grows by incorporation of the majority monomers, whereas the other one selects the minority dimers as a growth unit. The results highlight the power of the crystallization kinetics analyses to identify the growth unit and illuminate one of the most challenging issues of crystal growth. 
    more » « less
  5. Background/Objectives: The co-formulation of active pharmaceutical ingredients (APIs) is a growing strategy in biopharmaceutical development, particularly when it comes to improving solubility and bioavailability. This study explores a co-precipitation method to prepare co-formulated crystals of griseofulvin (GF) and dexamethasone (DXM), utilizing nanostructured, functionalized polylactic glycolic acid (nfPLGA) as a solubility enhancer. Methods: An antisolvent precipitation technique was employed to incorporate nfPLGA at a 3% concentration into the co-formulated GF and DXM, referred to as DXM-GF-nfPLGA. The dissolution performance of this formulation was compared to that of the pure drugs and the co-precipitated DXM-GF without nfPLGA. Results: Several characterization techniques, including electron microscopy (SEM), RAMAN, FTIR, TGA, and XRD, were used to analyze the nfPLGA incorporation and the co-precipitated co-formulations. The inclusion of nfPLGA significantly enhanced the dissolution and initial dissolution rate of both GF and DXM in the DXM-GF-nfPLGA formulation, achieving a maximum dissolution of 100%, which was not attained by the pure drugs or the DXM-GF formulation. The incorporation of nfPLGA also reduced the amount of time taken to reach 50% (T50) and 80% (T80) dissolution. T50 values decreased from 52 and 82 min (for pure DXM and GF) to 23 min for DXM-GF-nfPLGA, and the T80 improved to 50 min for DXM-GF-nfPLGA, significantly outpacing the pure compounds. Furthermore, incorporating nfPLGA into the crystal structures greatly accelerated the dissolution rates, with initial rates reaching 650.92 µg/min for DXM-GF-nfPLGA compared to 540.60 µg/min for DXM-GF, while pure GF and DXM showed lower rates. Conclusions: This work demonstrates that nfPLGA incorporation enhances dissolution performance by forming water channels within the API crystal via hydrogen-bonding interactions. This innovative nfPLGA incorporation method holds promise for developing hydrophobic co-formulations with faster solubility and dissolution rates. 
    more » « less