Inclusion Complex Crystals Research Articles

Drug-Loaded Nanocarriers Composed of Cholesteryl Oleate Crystal Cores and Multiple-Nanosheet Shells of γ-Cyclodextrin Inclusion Complex Crystals.

In this study, we prepared drug-loaded nanocarriers made of cholesteryl oleate (ChO) and γ-cyclodextrin (γ-CD). A nanosuspension (nanosuspension-I, NS-I) containing nanoparticles with a mean size of approximately 170 nm was obtained through the solvent-diffusion method using ethanol. A second nanosuspension (nanosuspension-II, NS-II), which was prepared by freeze-drying and redispersion of NS-I, exhibited an increased particle size of approximately 210 nm. Cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM) force-distance curves indicated that the nanoparticles in NS-I were oblong and soft. However, those in NS-II were angular and stiff, and, interestingly, multiple nanosheets covered the solid-liquid interface. Synchrotron wide-angle X-ray diffraction (WAXD) analysis of NS-II indicated that the nanoparticles in it had a core-shell structure, where the ChO crystal in the inner core was covered by multiple nanosheets of ChO/γ-CD inclusion complex crystals. The X-ray peak analysis suggested that the γ-CD columns of the nanosheets were vertically stacked onto the ChO crystal interface. It was found that the nanosheets on the nanoparticle interface were formed during the freezing process. A model drug carbamazepine (CBZ) was loaded into the ChO/γ-CD nanoparticles by pre-dissolving CBZ in ethanol during the solvent-diffusion process. Cryo-TEM, 1H NMR, ζ-potentials, and synchrotron WAXD indicated that CBZ was unexpectedly loaded into the shell as a CBZ/γ-CD inclusion complex crystalline nanosheet. The specific nanosheet structure, where ChO and CBZ coexisted in the same crystal of γ-CD, could achieve CBZ loading in the nanoparticles. ChO/γ-CD nanoparticles with the unique core-shell structure are expected to perform as practical carriers for drug delivery.

The guest polymer effect on the dissolution of drug-polymer crystalline inclusion complexes.

A drug–polymer crystalline inclusion complex (IC) is a novel solid form of drug, in which drug molecules form parallel channels, and linear polymer chains reside in these channels. In this study, we used carbamazepine (CBZ) as a model drug, and directly studied the effect of different types of guest polymers on the dissolution properties of drug–polymer ICs. We successfully prepared ICs formed from CBZ with hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(ε-caprolactone) (PCL), respectively, and confirmed that these two drug–polymer ICs both had the same channel-type crystal structure as CBZ form II. During the dissolution test, CBZ–PEG IC showed a faster dissolution rate compared to CBZ form II under both sink and non-sink conditions. CBZ–PCL IC was confirmed to be more stable in aqueous medium, as the guest polymer PCL delayed its transformation to less-soluble crystals during dissolution.

Development and evaluation of crystalline inclusion complex of finasteride using electrospraying as a novel approach

Solid form of drug plays the central role in optimizing its physicochemical properties, thus discovery of new solid forms always provides more options to achieve the desirable pharmaceutical profiles of drugs. Recently, certain drugs have been found to form crystalline inclusion complexes (ICs) with multiple types of linear polymers, representing a new sub-category of pharmaceutical solids. In this study, Finasteride (FNS) was used as the model host and poly (ethylene glycol) (PEG) as the guest, to form ICs of drug with the purpose of offering solubility advantage. Electrospraying as a novel approach was used for production of micro-particles of crystalline ICs of FNS, as it gave narrow particle size distribution and dry powder as end product. The obtained dry powder was characterized using powder X-ray diffraction, NMR spectroscopy and other characterization methods. The results revealed that FNS formed ICs with the biodegradable hydrophilic polymer (PEG), thus offering a FNS-PEG ICs as a potential new solid form. Compared with pure FNS crystals the FNS-PEG ICs crystals showed significantly higher solubility and faster dissolution rates; making it more suitable to achieve higher drug release profiles. Results demonstrated the possibility of using drug-polymer ICs microparticles as solid forms, providing a new approach to design formulations with enhanced drug release. In a nutshell developed formulation was found to be suitable for enhancing water solubility of poorly soluble actives.

Supramolecular hydrogels based on poly (ethylene glycol)-poly (lactic acid) block copolymer micelles and α-cyclodextrin for potential injectable drug delivery system

A supramolecular hydrogel system was prepared by the host-guest interaction between the α-cyclodextrin (α-CD) and poly (ethylene glycol) (PEG) chains of the poly (ethylene glycol)-block-poly (lactic acid) (PEG-b-PLA) micelles. The formation of inclusion complex (IC) crystals between α-CD and the PEG chains of the micelles was verified by different techniques. Rheological studies indicated that the gelation kinetics and the mechanical strength of the hydrogels could be modulated by the α-CD concentration. Also, the shear-thinning and self-healing properties of the hydrogels were confirmed. Doxorubicin (DOX) could be encapsulated into the hydrogels via the micelles and be released from the hydrogels sustainably, with the release rate dependent on the α-CD concentration. The released DOX showed higher inhibition efficacy against HeLa cells compared with the free drug. These attractive features, together with the superior biocompatibility, make the present hydrogels an potential injectable drug delivery system for tumour treatment.

Nevirapine-polycaprolactone crystalline inclusion complex as a potential long-acting injectable solid form

Nevirapine (NVP) is recommended by WHO as the antiretroviral treatment to prevent HIV passing from mother to child. However, the once-daily oral administration results in poor patient compliance, and a long-acting injectable form of NVP is desirable. Using single-crystal X-ray diffraction and other characterization methods, we demonstrated NVP can form crystalline inclusion complex (IC) with the biodegradable hydrophobic poly(ε-caprolactone) (PCL), and investigated the potential of the NVP-PCL IC microparticles as a long-acting injectable solid form. Compared with pure NVP crystals and NVP/polylactide microparticles, the NVP-PCL IC crystals showed significantly decreased solubility and slower dissolution rate, making it more suitable to be developed to achieve sustained-release profiles. In addition, the NVP-PCL IC microparticles with an average diameter below 10 μm can be conveniently prepared by spray drying and are found to be easily injectable through a 25G needle. These results demonstrated the possibility of using drug-polymer IC microparticles as long-acting injectable forms, providing a new approach to design sustained-release drug products.

Reorganizing Polymer Chains with Cyclodextrins.

During the past several years, we have been utilizing cyclodextrins (CDs) to nanostructure polymers into bulk samples whose chain organizations, properties, and behaviors are quite distinct from neat bulk samples obtained from their solutions and melts. We first form non-covalently bonded inclusion complexes (ICs) between CD hosts and guest polymers, where the guest chains are highly extended and separately occupy the narrow channels (~0.5–1.0 nm in diameter) formed by the columnar arrangement of CDs in the IC crystals. Careful removal of the host crystalline CD lattice from the polymer-CD-IC crystals leads to coalescence of the guest polymer chains into bulk samples, which we have repeatedly observed to behave distinctly from those produced from their solutions or melts. While amorphous polymers coalesced from their CD-ICs evidence significantly higher glass-transition temperatures, Tgs, polymers that crystallize generally show higher melting and crystallization temperatures (Tms, Tcs), and some-times different crystalline polymorphs, when they are coalesced from their CD-ICs. Formation of CD-ICs containing two or more guest homopolymers or with block copolymers can result in coalesced samples which exhibit intimate mixing between their common homopolymer chains or between the blocks of the copolymer. On a more practically relevant level, the distinct organizations and behaviors observed for polymer samples coalesced from their CD-ICs are found to be stable to extended annealing at temperatures above their Tgs and Tms. We believe this is a consequence of the structural organization of the crystalline polymer-CD-ICs, where the guest polymer chains included in host-IC crystals are separated and confined to occupy the narrow channels formed by the host CDs during IC crystallization. Substantial degrees of the extended and un-entangled natures of the IC-included chains are apparently retained upon coalescence, and are resistant to high temperature annealing. Following the careful removal of the host CD lattice from each randomly oriented IC crystal, the guest polymer chains now occupying a much-reduced volume may be somewhat “nematically” oriented, resulting in a collection of randomly oriented “nematic” regions of largely extended and un-entangled coalesced guest chains. The suggested randomly oriented nematic domain organization of guest polymers might explain why even at high temperatures their transformation to randomly-coiling, interpenetrated, and entangled melts might be difficult. In addition, the behaviors and uses of polymers coalesced from their CD-ICs are briefly described and summarized here, and we attempted to draw conclusions from and relationships between their behaviors and the unique chain organizations and conformations achieved upon coalescence.

Crystalline inclusion complexes formed between the drug diflunisal and block copolymers

The solid form of drugs plays a central role in optimizing the physicochemical properties of drugs, and new solid forms will provide more options to achieve the desirable pharmaceutical profiles of drugs. Recently, certain drugs have been found to form crystalline inclusion complexes (ICs) with multiple types of linear polymers, representing a new subcategory of pharmaceutical solids. In this study, we used diflunisal (DIF) as the model drug host and extended the guest of drug/polymer ICs from homopolymers to block copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL). The block length in the guest copolymers showed a significant influence on the formation, thermal stability and dissolution behavior of the DIF ICs. Though the PEG block could hardly be included alone, it could indeed be included in the DIF ICs when the PCL block was long enough. The increase of the PCL block length produced IC crystals with improved thermal stability. The dissolution profiles of DIF/block copolymer ICs exhibited gradually decreased aqueous solubility and dissolution rate with the increasing PCL block length. These results demonstrate the possibility of using drug/polymer ICs to modulate the desired pharmaceutical profiles of drugs in a predictable and controllable manner.

The effect of PEG molecular weights on the thermal stability and dissolution behaviors of griseofulvin-PEG crystalline inclusion complexes

Co-crystals formed between small molecular drugs and hydrophilic co-formers have shown great potential to optimize the dissolution profiles of drug substances. So far most of the co-formers used are small molecules. However, linear polymers are also able to form drug-polymer crystalline inclusion complexes (ICs). In contrast to the small molecular co-formers, molecular weight of the polymer co-formers can be easily changed without disrupting the IC crystal structure, and hence represents an interesting approach to tune the IC properties. In this study, we investigated the effect of PEG molecular weights on the thermal stability and dissolution behavior of Gris-PEG ICs. It was found that the thermal stability of Gris-PEG IC crystals first increased with PEG molecular weight, and then reached a plateau value, while an optimized PEG molecular weight existed for the dissolution profile. The experimental results were explained by the formation of two types of crystal defects during the IC growth in PEG melt: the void defects and the grain boundary defects. This is the first study on the pharmaceutical profiles of drug-polymer crystalline inclusion complexes.

Coalesced poly(ε-caprolactone) fibers are stronger.

Melt-spun fibers were made from poly(ε-caprolactone) (PCL) coalesced from stoichiometric inclusion complex crystals formed with host urea. Melting and crystallization behaviors, mechanical properties, and the birefringence of undrawn and cold-drawn fibers were investigated. Undrawn coalesced PCL fibers were observed to have 500-600% higher moduli than undrawn as-received (asr) PCL fibers and a modulus comparable to drawn asr PCL fibers. Drawn coalesced PCL fibers have the highest crystallinity, orientation, and 65% higher moduli than drawn asr PCL fibers. Drawn coalesced PCL fibers have only a 5% higher crystallinity than drawn asr PCL fibers, yet they have 65% higher moduli and lower elongation at break values. Clearly, the intrinsic alignment of the coalesced polymers is the reason for their higher moduli and lower elongation, as confirmed by the birefringence observed in drawn coalesced and asr-PCL fibers. The improved mechanical properties of coalesced PCL fibers make them a better candidate for use in tissue engineering as scaffolds.

Formation of a Polymer-Coated Inclusion Complex of D-Limonene and β-Cyclodextrin by Spray Drying

The polymer-coated inclusion complex powder formation of D-limonene and β-cyclodextrin obtained by spray drying was investigated with respect to the effects of various types of polymer coating agents on the powder particle size and morphology. The addition of the polymer coating agent affected the average particle size, morphology, and internal structures of the spray-dried powders. The average particle diameter of the uncoated spray-dried powders was approximately 5 µm. The powder particle size increased upon the addition of a polymer coating reagent. With the addition of 9 wt% of the polymer coating agent, an average diameter of approximately 80 µm was obtained for the spray-dried powder particles. However, further addition showed a negligible effect on the particle size. Inclusion complex crystals were observed on the surface and inside of the powder particles.

Nonoxynol‐9‐α‐cyclodextrin inclusion compound and its application for the controlled release of nonoxynol‐9 spermicide

AbstractNonoxynol‐9 (N‐9) is the most active ingredient in commercially available spermicidal products in the United States. There are many applications of cyclodextrin inclusion complexes (CD‐ICs), but there are no reported studies investigating the formation of and controlled release from a N‐9 spermicide‐CD‐IC. We have successfully formed the inclusion compound between N‐9 and α‐CD using a solution‐heating technique. The N‐9‐α‐CD‐IC was characterized by Fourier Transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and wide angle X‐ray diffraction observations. Silicone elastomer (SILASTIC MDX4‐4210) film embedded with crystalline N‐9‐α‐CD‐IC was prepared and evaluated for its efficacy in the controlled release of N‐9 spermicide against bovine sperm. Silicone elastomer with N‐9‐α‐CD‐IC was as successful in reducing the motility and viability of bovine spermtazoa as silicone elastomer swollen with an equivalent amount of neat N‐9. The permeability of the flexible silicone elastomer apparently enables the N‐9 spermicide to diffuse from its embedded inclusion complex crystals to contact, immobilize, and kill bovine sperm cells. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007

Curing Behavior of Epoxy Resin Initiated by Amine-Containing Inclusion Complexes

Imidazole derivatives and alkylamines are very useful as hardeners of epoxy resins. These amine compounds form inclusion complexes with 1,1,2,2-tetrakis(4-hydroxyphenyl) ethane (TEP). When these amine-containing inclusion complexes are reacted with epoxy resins, curing acceleration, pot life extension, and higher curing temperatures are observed.An explanation for this curing behavior is that guest molecule “amine compounds” are trapped in inclusion complex crystals. X-Ray crystal structure data shows the existence of O-H–N hydrogen bonding between host and guest molecules. With the imidazole molecule in the inclusion complex, hydrogen bonding prevents easy attack of the epoxy ring. Amine-TEP inclusion complexes show these enhanced curing behaviors when reacted with epoxy resins.

Crystalline Cyclodextrin Inclusion Compounds Formed with Aromatic Guests: Guest-Dependent Stoichiometries and Hydration-Sensitive Crystal Structures

A series of solid inclusion complexes (ICs) containing the aromatic guests aniline, benzene, ethylbenzene, phenol, p-xylene, styrene, and toluene were formed with host γ-cyclodextrin (γ-CD). IC stoichiometry was observed to depend on the nature of the included aromatic guest. The molar ratio of styrene, aniline, and phenol guests to γ-CD host was ∼2:1 in their individual IC crystals, whereas ethylbenzene, p-xylene, and toluene guests formed ∼1:1 inclusion complexes with γ-CD. Thermogravimetric analysis showed that the thermal stabilities of these volatile aromatic guest molecules increased due to guest−host interactions once they were included in their γ-CD-ICs. X-ray diffraction (WAXD) observations performed on the aromatic guest−CD-IC crystals showed that all of them have channel-type crystalline structures. Moreover, it was observed that the presence of guest molecules inside the γ-CD cavities stabilized the channel structure of stacked γ-CDs. However, a solid-phase transition from tetragonal to hexago...

Two-phase channel structures based on alpha-cyclodextrin-polyethylene glycol inclusion complexes.

Wide-angle X-ray scattering observations of alpha-cyclodextrin (CD)-poly(ethylene glycol) (PEG) inclusion complexes (ICs) have shown for the first time that two crystalline columnar modifications (forms I and II) are produced in the process of their formation. This was made possible by precise azimuthal X-ray diffraction scanning of oriented IC samples. Form I is characterized by CDs threaded onto PEG chains and arranged along channels in the order head-to-head/tail-to-tail, while form II is formed by unbound CDs also arranged into columns in a head-to-tail and also possibly a head-to-head/tail-to-tail manner, probably as a result of template crystallization on the form I IC crystals. It was shown that similar structural peculiarities are inherent for channel structures based on ICs obtained with PEG with a wide range of molecular weights (MWs). The characteristic feature of ICs based on PEG, especially with MW > 8000, is the presence of unbound polymer in the composition of the complex. The amount of unbound PEG was shown to rise with increasing MW of PEG, resulting in greater imperfections in the IC crystalline structure. The polyblock structure of ICs based on alpha-CD and PEG was therefore proposed.

Unidirectional cis–trans photoisomerization of cis‐3,3′‐bis(diphenylhydroxymethyl)stilbene in inclusion complex crystals

AbstractWhen a 1:1 complex of cis‐3,3′‐bis(diphenylhydroxymethyl)stilbene (1) with acetone was irradiated in the solid state at room temperature using a high‐pressure mercury lamp with a Pyrex filter for 6 h, a 1:1 complex of the trans‐isomer (2) with acetone was obtained without losing the guest acetone molecules. Similar results were obtained without a guest or in the presence of other guests. Internal rotation around the double bond bearing the very large triphenylhydroxymethyl substituent is hardly imaginable in the confinement of the crystal. Therefore, the geometrically easier ‘hula‐twist’ (HT) mechanism with its movements primarily in the molecular plane provides a viable mechanistic alternative for the cis–trans isomerization. The solid‐state mechanism of the reaction was studied by x‐ray and atomic force microscopy (AFM) analyses. Face‐selective efflorescence formed a protective cover on (100) and can be related to the crystal structure. Further molecular migration was not detected with the sensitivity of AFM and the crystal of 1ċacetone did not lose its clarity and microscopic shape. The cis–trans conversion profits from cages that are present in the crystal lattice. X‐ray structural analysis confirmed a strong loss of crystallinity upon the photochemical conversion of 1ċacetone which precludes a definitive conformational proof of HT by x‐ray diffraction. The formation of the amorphous phase excludes a topotactic reaction. Copyright © 2003 John Wiley & Sons, Ltd.

Novel Bisurea Host Compounds

New host molecules, 4,4′-bis(dimethylamino-urea)diphenylmethane (1) and its derivatives (2 and 3), are reported. These hosts are shown to give inclusion complex crystals with a wide variety of organic guest molecules with high selectivity. The crystal structure of 1:2 inclusion complex of 1 with THF has been determined from X-ray crystal structure analysis. The cyclic N–H...O intermolecular hydrogen bonds between host molecules were found to form columns for accommodation of the guest molecules.

Manipulation of Nylon-6 Crystal Structures with Its α-Cyclodextrin Inclusion Complex

We successfully formed an inclusion complex between nylon-6 and α-cyclodextrin and attempted to use the formation and subsequent disassociation of the nylon-6/α-cyclodextrin inclusion complex to manipulate the polymorphic crystal structures, crystallinity, and orientation of nylon-6. Formation of the inclusion complex was verified by Fourier transform infrared (FTIR) spectroscopy, wide-angle X-ray diffraction (WAXD), differential scanning calorimetry (DSC), and CP/MAS 13C NMR. After obtaining the inclusion complex of nylon-6 and α-cyclodextrin, the sample was treated in an acid environment to remove the host α-cyclodextrin and coalesce the nylon-6 guest polymer. Examination of as-received and IC coalesced nylon-6 samples showed that the α-form crystalline phase of nylon-6 is the dominant component in the coalesced sample. X-ray diffraction patterns demonstrate that the γ-form is significantly suppressed in the coalesced sample. Along with the change in crystal form, an increase in crystallinity of ∼80% was revealed by DSC, and elevated melting and crystallization temperatures were also observed for the coalesced nylon-6 sample. FTIR spectroscopy revealed a significant degree of orientaion for the nylon-6 chains coalesced from their α-cyclodextrin inclusion complex crystals. Thermogravimetric analysis indicated that nylon-6 has an ∼30 °C higher thermal degradation temperature after modification by threading into and being extracted from its α-cyclodextrin inclusion complex.

Inclusion Complex Formation between α,γ-Cyclodextrins and a Triblock Copolymer and the Cyclodextrin-Type-Dependent Microphase Structures of Their Coalesced Samples

A triblock copolymer (PCL−PPG−PCL, Mn = 1.38 × 104) of poly(e-caprolactone) (PCL) and poly(propylene glycol) (PPG) was synthesized by ring-opening polymerization of e-caprolactone. Cyclodextrin (CD)-type-dependent formation of inclusion complexes (ICs) between cyclodextrins and this triblock copolymer was studied. Only PCL blocks were included as guests in the IC formed with α-cyclodextrin (α-CD), while both PCL and PPG blocks were included in the IC formed with γ-cyclodextrin (γ-CD). As a result, the copolymer coalesced from its IC crystals with α-CD showed an increased crystallinity, while to the contrary, the copolymer coalesced from its IC crystals with γ-CD exhibited a decreased crystallinity, when both were compared to the as-synthesized triblock copolymer. Fourier transform infrared (FTIR) spectra, 13C CP/MAS solid-state NMR, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and wide-angle X-ray diffraction (WAXD) measurements were employed to study the formation of ICs as ...

Crystal engineering for molecular dynamics

Molecules of some achiral compounds are arranged in a chiral form in their own crystals. When achiral molecules cannot be arranged in a chiral form in the crystal, they can be arranged in a chiral form in inclusion complex crystals with a chiral host compound. Reaction of the inclusion complex in the solid state gives the optically active compound. Some new examples of these enantioselective reactions will be discussed. By inclusion complexation with a host compound, molecules can be accommodated in one form in inclusion crystals. By this method, tautomerism and equilibrium can be frozen and one tautomer and configurational or conformational isomer may be isolated in a pure state. X-Ray analytical and CD spectral studies of these isolated isomers will also be discussed.

First isolation of tautomeric isomers of 4-isopropyltropolone as inclusion complex crystals

Tautomeric isomers of 4-isopropyltropolone have been isolated as inclusion complex crystals and their crystal structures have been elucidated by X-ray analyses.