Introduction
Over the last decade, highly non-polar drugs have emerged from discovery groups as a consequence of the drive to improve specificity at novel target sites that are hard to access with traditional compounds with lesser lipophilicities. Inherently poorly-water soluble, these potent compounds present considerable difficulties for enteral delivery and absorption. Indeed, it has been recognized for many years that Biopharmaceutical Classification System (BCS) class II compounds (i.e. those with low aqueous solubility but high permeability 1 ) can present absorption rate-limiting dissolution in the gastric media, impacting significantly on bioavailability.
Introduction
An increasingly valuable strategy for improving the bioavailability of this class of active pharmaceutical ingredients is to use an amorphous drug species [2] [3] . The glassy amorphous state theoretically has a higher apparent solubility than the crystalline counterpart 4 because these two morphologies differ in the thermodynamic processes of breaking intermolecular associations during dissolution, i.e. enthalpy, entropy, and free energy 5 . This solid state manipulation can therefore be exploited as a means to achieve significant apparent dissolution rate enhancement. However, due to the inherent instability of the amorphous state, a viable dosage form requires a method of stabilizing this meta-stable state to prevent recrystallization to the more stable, less soluble crystalline form 2 . To this end, one strategy is to disperse amorphous drug in a polymeric matrix or gel. Ideally, the polymer will be robust in order to withstand manufacture processes, will be pharmacologically inert and biocompatible with no appreciable toxicity and will be able to sequester the active pharmaceutical ingredient.
Introduction
Using differential scanning calorimetry to screen compatibility of ketoprofen with excipients, Mura et al. 6 reported the loss of the drug melting peak in a simple physical blend with K30 polyvinylpyrrolidone (PVP). In the same year, solid-state interactions in mixtures between ibuprofen and (PVP) were reported by Sekizaki et al 7 ; the formation of amorphous ibuprofen in the mixtures was enhanced by elevated storage temperatures, a high weight ratio of PVP and by using lower molecular weight PVP.
Introduction
In our earlier work, we employed cross-linked polyvinylpyrrolidone (PVP-CL) as a carrier in physical mixtures with ibuprofen [8] [9] [10] with results suggesting that disruption of drug crystallinity was facilitated primarily through hydrogen bonding with a secondary mechanism involving electrostatic/hydrophobic interactions through the ibuprofen benzene ring. Following grinding and mixing, hydrogen-bonding between ibuprofen dimers and linear PVP (Povidone K25) was reported 11 . In contrast, Di
Introduction
Martino reported no evidence for interaction between ketoprofen and linear PVP K30 after gentle mixing, although powder X-ray diffraction showed that the drug lost crystallinity following 10 months storage 12 . More recent studies using different propionic acids with linear PVP K30 have further confirmed our earlier findings that hydrogen bonding and electrostatic interactions are key determinants in the solid-state interactions between ibuprofen and polyvinylpyrrolidones 13, 14 whilst illustrating the role of relative humidity.
Introduction
Whilst the mechanisms underpinning the thermodynamic drivers remain unclear, our own previous work using cross-linked PVP and the literature employing linear PVP
Introduction
with aryl propionic acids, shows that inter-molecular hydrogen bonding is the driving force for retention and stabilization of the drug as "X-ray amorphous"; here, we define "X-ray amorphous" as meaning the absence of clear Bragg diffraction peaks from the powder X-ray diffraction pattern, whilst recognizing that this does not necessarily mean that the material in question is truly amorphous; it may in fact be nanocrystalline. Thus, through tailoring the molecular composition of cross-linked
Introduction
PVPs by designing functionalized cross-linking agents, the stabilizing properties of the polymer can be optimized. We sought to synthesize novel cross-linking agents where the NVP residues were connected by hydrophilic oligoethers rather than hydrophobic alkane-based residues as in all previous work 15, 16 . PEG polymers have been used for solid dispersions and potential hydrogen bonding mechanisms have previously been reported 17 . We hypothesise that the enhanced hydrogen bonding potential of the oligoethers would further aid disruption of ibuprofen crystallinity when incorporated into pharmaceutical formulations. Herein we report the design, synthesis and pharmaceutical uses of a series of novel polyvinylpyrrolidones built with oligoether cross-linkers of varying polarities at different molar fractions, and demonstrate the ability of these polymers to create stable amorphous delivery systems when simply mixed with the model poorly-water soluble drug ibuprofen.
Experimental Section Materials
Ibuprofen (IB) was obtained from Wessex Fine Chemicals (Horsham, UK) and commercial cross-linked polyvinylpyrrolidone XL-10 (PVP-CL) was from ISP Technologies Inc. All other reagents were purchased from Sigma-Aldrich Chemical
Experimental Section Materials
Company (Poole, UK) and were used as received except for N-vinylpyrrolidone (NVP) which was freshly distilled prior to use and 2,2' azobisisobutyronitrile (AIBN) which was recrystallized from methanol.
Experimental Section Materials
Solvents were also purchased from Sigma-Aldrich Chemical Company (Poole, UK) and were used without purification except; dichloromethane was pre-dried over calcium hydride prior to distillation; tetrahydrofuran (THF) was distilled from sodium and benzophenone prior to use; pyridine was dried over potassium hydroxide prior to distillation; benzene used in polymerization reactions was degassed for 30 minutes prior to use. All glassware was dried overnight in an oven at 120 °C prior to use.
Synthetic methods

Synthesis of cross-linkers
Two novel cross-linking agents were synthesized for subsequent use in polymerization with N-vinylpyrrolidone. The cross-linkers were designed to possess appropriate reactivity ratios with the monomer and hence coupled two NVP units with oilgoether chains of varying lengths, as illustrated in Figure 1 . Once cooled, the tough gel was cut into small pieces and subjected to Soxhlet extraction with chloroform before the polymer was dried in a vacuum oven (50 ºC, 10 mmHg, 48 hours). The polymers were then size reduced (planetary ball mill; 1 hour)
Synthesis of cross-linkers
followed by additional drying in a vacuum oven (50 ºC, 10 mmHg, 18 hours) which provided fine white polymer powders that were sieved (Fritsch Vibratory Sieve Shaker, Germany) to recover particle sizes between 30-50μm for subsequent studies, the same size range as the commercial cross-linked polyvinylpyrrolidone (PVP-CL XL10).
Synthesis of cross-linkers
The two cross-linking agents were used in different proportions to generate varied cross-linking densities in the novel polymers (Table 1 ). For simplicity, polymers using the shorter tetra-oligo linker are given the prefix "5" and those synthesised using the longer hexa-oligo linker are prefixed with "7". To include the varying percentage of cross-linker used in the reactions, the polymers are then designated with either 1, 2.5 or 5%. Thus, 5 PVP 1% is the polymer synthesised using the shorter tetra-oligo cross-linking agent at 1% in the reaction whereas 7 PVP 5% is constructed from the longer hexa-oligo linker included at 5% in the polymerisation reaction. under a purge of dry nitrogen gas. The samples were held at 300°C for 1 minute before cooling at 20°C/min to 0°C and then reheated at 20°C/min to 300°C; glass transition temperatures were determined during the second heating cycle, after controlling the thermal history of the polymers.
Synthesis of cross-linkers
The surface morphologies of the polymer particles (and physical mixtures of drug:polymers during pharmaceutical evaluation) were visualized using a LEO 145
Synthesis of cross-linkers
OVP Scanning Electron Microscope. Samples were mounted onto aluminum stubs using double sided adhesive tape before coating with gold in a high resolution sputter coater (Edwards Sputter Coater S150B).
Synthesis of cross-linkers
Infrared spectra of the polymers were collected using a Perkin Elmer Spectrum 100
Synthesis of cross-linkers
FT-IR spectrometer equipped with a universal ATR sampling accessory. Typically 100 scans collected at 4 cm -1 were averaged for each polymer. The same parameters were used to analyze drug:polymer mixtures.
Pharmaceutical evaluation

Preparations of physical mixtures
Prior to preparing physical mixtures, both ibuprofen and the novel cross-linked PVPs were sieved (Fritsch Vibratory Sieve Shaker, Germany). The same sieve fraction as that of commercial PVP-CL, namely 30-50 μm, was collected for further use, thus reducing potential variations as a result of differences in polymer particle sizes.
Preparations of physical mixtures
In the case of IB, the sieve fraction 75-180 μm was chosen to eliminate both large aggregates and "fine" particles which would be unfavorable in mixing. Physical mixtures of IB and polymers (novel PVPs and PVP-CL) were prepared containing 30% by weight IB to replicate the optimum drug:polymer ratio identified in our previous studies with PVP-CL 6 . The batch size was 4g and all samples were mixed for 15 minutes in a sealed container using a Turbula mixer (Glen Creston Ltd, UK).
Preparations of physical mixtures
Likewise, controls of IB and polymers alone were treated for 15 minutes in the mixer to parallel any effects arising from attrition. All samples were stored in sealed glass vials before analysis.
Preparations of physical mixtures
The homogeneity of each physical mixture was confirmed. Drug contents in three samples (30 mg) taken randomly from each physical mixture were determined by UV spectroscopy at 222 nm (Varian Cary 50 Bio UV-Visible Spectrophotometer, US) against a calibration curve; measured IB contents were between 29.83-30.06%
Preparations of physical mixtures
(theoretical contents 30%), showing that all mixtures were homogeneous.
Dissolution testing
Dissolution testing of the physical mixtures and samples of pure IB (75-180 μm) was 
Dissolution testing
Where ΔH is the melting enthalpy of the physical mixture (J/g), ΔH IB is the melting enthalpy of pure ibuprofen (J/g, and assumed to be 100% crystalline) and W is the weight fraction of ibuprofen in the physical mixture (i.e. W=0.3). All analyses were in triplicate.
Powder X-ray diffraction
Powder X-ray diffraction (PXRD) patterns were recorded using a D8 Advance Diffractometer (Bruker AXS) operating in Bragg-Brentano (flat plate) geometry under the following conditions: target CuKα 1 (λ = 1.54056Å); voltage 40 kV; current 40 mV. The data were collected from 5-602using a step size of 0.010 2. The scanned samples were placed in a standard holder and the surface of the material carefully smoothed in order to minimize and zero point error.
Results and discussion

Monomer design and synthesis
Previous work has shown that there is a large difference in reactivity ratios between the vinyl group in NVP and well-studied monomers such as methacrylate and styrene 18, 19 . Thus, attempts to co-polymerize commercial cross-linkers such as ethylene dimethacrylate and divinylbenzene with NVP do not result in random, homogeneously cross-linked co-polymers that are the target of this work.
Monomer design and synthesis
The problem of the incompatibility of reactivity ratios between NVP and commercial cross-linking monomers has been elegantly overcome by White et al 15, 16 . During fundamental studies into the kinetics of NVP polymerizations they produced a novel cross-linker, synthesized by the addition of two equivalents of NVP to 1,6-dibromohexane under basic conditions. The resulting cross-linker, containing two NVP residues, was found to be readily compatible with NVP under photo-initiated free radical polymerization conditions, producing homogeneously cross-linked materials. This approach to synthesizing cross-linked NVP has recently been exploited by Engström et al. to produce supports for solid phase synthesis and water swellable drug delivery systems [20] [21] [22] .
Monomer design and synthesis
Our targeted diNVP cross-linkers were accessed through the addition of the known hydroxy functionalized NPV derivative 21, 22 to either of the commercially available ditosylates ( Figure 3 ). It should be noted that attempts to form oligoether cross-linkers by direct addition of NVP to the ditosylates under basic conditions failed as a consequence of over alkylation of the NVP ring, which led to a complex mixture of cyclic and oligomeric species. In our cross-linkers, both NVP units and the oligoether chains appear to be hydrogen bond active. It was expected that modulating the oligoether chain and the density of cross-linking might additionally affect the number of hydrogen bonding sites and also their accessibility in the PVP network. As our cross-linkers are NVP derivatives, they were expected to possess similar reactivity ratios as NVP (as a result of structural similarity) and so co-polymerize easily with NVP without compositional drift. Indeed, the syntheses of our novel PVPs via free radical polymerization succeeded, affording the six polymers ( Figure 2) varying in the length of the oligoether chain (PVPs with the shorter and longer oligoether chain were abbreviated as "5 PVP" and "7 PVP", respectively) and in the density of cross-linking (the cross-linker content in the feed polymerisation mixture were 1, 2.5 or 5 wt%).
Analysis of novel polymers
Following polymerization, crude cross-linked PVPs were pale yellow glasslike materials. Soxhlet extraction and grinding in a planetary ball mill followed by drying Scanning electron microscopy showed that the novel polymers presented a very rough "popcorn-like" appearance, a surface morphology that is similar to commercial PVP-CL, as illustrated in Figure 4 . The presence intra-particle pores and expanded surface area make the newly synthesized PVPs interesting materials to investigate in terms of potential application as a drug carrier. FT-IR spectra of all the novel polymers, as well as PVP-CL, were similar.
Analysis of novel polymers
Absorption bands appearing in the region 3000-2800 cm -1 were attributed to the C-H stretching modes, whereas absorption bands at 1420 cm -1 were assigned as the C-H bending modes. All spectra featured a strong absorption band at 1670 cm Table 2 . reduced free volume) which would increase the glass transition temperature.
Analysis of novel polymers
Furthermore, it was observed that novel cross-linked PVP containing longer oligoether chains exhibited slightly lower glass transitions than their counterparts with shorter oligoether chain, e.g. T g of 5 PVP 5% > T g of 7 PVP 5%. This suggests that the length of the oligoether chain can affect the distance between polymer chains and hence the free volume of polymer. Polymers with longer oligoether chains should exhibit higher free volume than their counterparts with shorter oligoether chains which would decrease the glass transition temperature.
Pharmaceutical evaluation
Example images from scanning electron microscopy of physical mixtures of drug and polymer are in Figure 5 . Ibuprofen displays a characteristic 'needle' morphology ( Figure 5A ) and there is clear evidence of these needles in the mixture with PVP-CL
Pharmaceutical evaluation
(5B). This is consistent with the previous finding of Rawlinson et al 10 where, although crystalline to amorphous drug conversion occurred upon mixing and storage with PVP-CL, a significant part of the IB remained in a crystalline form. However for the physical mixtures prepared using the novel polymers, no evidence of ibuprofen crystals could be found when examining the samples over a range of magnifications.
A) B) C) D)

Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
There are two potential explanations for these results. The first is that a 'macro' dispersion of the ibuprofen has occurred on mixing with the cross-linked PVPs, that is the ibuprofen particles are hidden, being reduced in size and fully embedded inside polymer cavities; the dimension of the PVP cavities dictates that any crystalline dispersed drug would be significantly size reduced. The images provide no evidence for this type of interaction between the drug and carrier. The second possibility is that a 'micro' dispersion has occurred; the highly ordered crystal lattice of ibuprofen has been completely disrupted and the "free" ibuprofen molecules are adsorbed on the polymer particle surfaces or embedded within the polymer in an amorphous form.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
The effects of the polymer carriers on the dissolution of IB were investigated for physical mixtures with 30% drug contents. As IB is a weakly acidic drug (pK a =5. The improved dissolution characteristics of physical mixtures, when compared to pure IB, were accompanied by differences in the appearance of the samples in the dissolution medium. Ibuprofen alone floated in an agglomerated form on the surface of the dissolution medium and did not disperse readily throughout the medium even after a few minutes of agitation. However, physical mixtures with all PVP matrices exhibited good dispersion of IB particles (significant deagglomeration) and the physical mixture samples readily "sank" in the dissolution medium and dispersed. These observations provide evidence that the novel cross-linked PVP and commercial cross-linked PVP-CL enhanced the wettability of the IB particles. The mechanism and kinetics of IB release from the polymeric systems was explored.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Despite the swellability of the polymers, the dissolution data fitted a first order release profile, consistent with drug release from a porous insoluble matrix.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Differential scanning calorimetry was used to detect changes in the thermal response of IB in physical mixtures compared with a sample of pure IB, to estimate the level of disruption to IB crystallinity in the physical mixture. It is well known that a decrease in drug melting enthalpy could result from dissolution into the polymer matrix but our previous study demonstrated that the thermal results from physical mixtures correlated well with X-ray diffraction data and so melting enthalpy reductions can be used to quantify crystal disruption 10 The DSC trace of pure IB showed a single relatively sharp endothermic peak with a melting temperature (peak maximum) of 77.9 o C and enthalpy of fusion of 118.8 J/g. Significant changes in the peak shape, height-to-width ratio and temperature of melting transition of IB was observed for the drug in physical mixtures; the DSC curves exhibited relatively broad melting endotherms.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
The widening of the endothermic melting peak and lowering of the onset temperature is indicative of disruption of the IB crystalline structure in the presence of the PVPs.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
This effect is analogous to the polymers behaving as an impurity for the crystalline IB and provides clear evidence that the cross-linked PVP carriers interact with the drug.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Melting points, enthalpies of fusion and estimated drug crystallinity data can be retrieved as Supporting information and are available free of charge via the internet at http://pubs.acs.org
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Reduction in IB crystallinity in the physical mixture with commercial cross-linked PVP was consistent with literature data 9 . As evident from the DSC analysis, the novel cross-linked polymers appeared to be more effective in disrupting IB crystallinity than commercial cross-linked PVP-CL. Furthermore, the data suggests that the oligoether moieties incorporated into the structure of the novel cross-linked PVP affected the level of disruption IB crystallinity. The most disruptive novel PVPs contained the highest level of oligoether moieties and the highest density of crosslinking. For the same density of cross-linking, the novel polymers containing longer oligoether chains (7 PVP) disrupted crystallinity to a greater extent that their counterparts with shorter oligoether chains (5 PVP).
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
The increased ability of the PVPs to disrupt IB crystallinity may arise as a result of the presence of oligoether moieties which could provide additional sites for hydrogen bonding interactions. From this, a hypothesis can be proposed that a greater number of hydrogen bonding sites and/or hydrogen bonding sites that may display stronger bonding potential due to neighbor influences will enable a greater degree of disruption of the IB crystal lattice.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
In probing molecular interactions between IB and PVP, FT-IR spectra of the PVPs and crystalline IB were used as references for comparison with spectra of the physical mixtures. Functional groups with potential to form hydrogen bonding interactions within the physical mixture were the carboxyl group of IB (-C=O(OH)), the carbonyl group of the N-vinylpyrrolidone ring (-C=O) and the ether group in the novel PVP cross-linkers (-C-O) and so these groups were the focus of the FT-IR studies.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Based on the structures of IB and the PVPs (Figure 8 ), it can be seen that the polymers can only act as a proton acceptor (through -C=O and -C-O), while IB can only act as a proton donor (through -OH in the carboxyl group). Thus, hydrogen bonds between IB and PVPs should be detected in the acid carboxyl absorption modes of IB, and PVP carbonyl or C-O absorption modes, depending on the site of interactions. From the above, it might be concluded that the thermodynamic driver for IB disruption remained, and that kinetics of the process, whilst slower, continued for an extended time. It is likely that formation of hydrogen bonds in the IB+PVP systems, which is the main driver for disrupting IB crystallinity (as shown above), occurred not only for the "recently" prepared physical mixtures, but proceeded over the time as
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
well. This conclusion could be supported by FT-IR spectra of the "recently" prepared physical mixtures of IB+PVP. The presence of free non-hydrogen bonded carbonyl groups of PVP in the FT-IR spectra indicated that not all hydrogen bonding sites on the PVP were occupied by IB, hence some "PVP hydrogen bonding potential" remained, i.e. bonding sites were unsaturated. Another conclusion drawn from the stability studies was that IB in the physical mixture did not exhibit a tendency to recrystallize, probably because interactions between IB and PVP restricted mobility of the amorphous IB molecules preventing recrystallization. The stability study may also suggest that complete drug conversion to the amorphous state might be achieved through alternative preparation methods that facilitate molecular mobility and therefore formation of these hydrogen bonds, for example solid dispersions manufactured via solvent or thermal methods.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
In addition to the formation of amorphous drug, the PVPs could improve dissolution of poorly-water soluble drugs by improving wetting or the generation of microcrystalline domains. To explore the mechanisms underpinning the enhanced drug dissolution from mixtures, the percentage of IB released within the first 15 minutes (Table 3) can be used as a marker for enhancement in dissolution and can be related to the percentage of drug remaining in the crystalline state as estimated from thermal analysis. The data ( Figure 11 ) shows a linear relationship between amorphous drug fraction and ibuprofen release at 15 minutes. Such a relationship suggests that the predominant mechanism by which the PVPs improved ibuprofen dissolution was via the generation of amorphous drug rather than by other mechanisms described in the literature for dispersed drug in carrier materials, such as increased wettability or particle size reduction. However, we have previously explored the role that moisture may play in mediating interactions between PVP-CL and ibuprofen. Adding 10% water to a simple physical mixture decreased the extent of crystal disruption, potentially through water competing for hydrogen-bonding sites in the polymer 30 . Further, dried PVP-CL (at 60C, 72h) was mixed with ibuprofen and again extensive crystal disruption was seen by X-ray diffraction 31 . However, the polymer is hygroscopic and had adsorbed 5-6% moisture during the mixing process, a similar moisture content to the starting material. Consequently, experiments were repeated under a vacuum of 700 mmHg and again, ~47% of the ibuprofen crystallinity was lost following simple mixing. The role of external humidity and adsorbed water in facilitating the interactions between PVP-CL and ibuprofen is currently under further investigation.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
Finally, ibuprofen has a relatively low melting point (~78C) which may suggest facile intra-molecular bond breakage to permit hydrogen-bonding with the polymer.
Figure 5. SEM of A) ibuprofen and physical mixtures of ibuprofen with B) PVP-CL, C) 5 PVP 5% and D) 7 PVP 5% (high magnification)
It was suggested that enantioselective interactions occurred between ibuprofen and PVP when crystal disruption was compared between the S(+)-enantiomer (melting point ~ 52C) and the racemate 32 . Counter-intuitively, when a series of propionic acids were evaluated with increasing melting points (ibuprofen < ketoprofen < flurbiprofen < fenbufen), crystal disruption following 60 minutes of mixing increased with increasing melting points 31 . Using a similar series, subsequent work by Gashi et al showed that only ibuprofen spontaneously dispersed in linear PVP, attributed partially to its weak crystalline structure 13 but on storage at 75% RH the rate of crystal disruption of ibuprofen, ketoprofen, fenbufen and naproxen were similar 14 .
Conclusions
Two novel oligoether cross-linking agents were designed, synthesized and characterized. The cross-linkers, tailored to increase the hydrogen bonding capability of polyvinylpyrrolidones, were successfully polymerized with N-vinylpyrrolidone to provide six novel PVPs with varying cross-linking oligo chain lengths and cross-link densities. These polymers swell in a range of solvents and have surface characteristics similar to those of commercially available cross-linked PVP. Mixing ibuprofen with the polymers disrupted drug crystallinity and the degree of amorphous conversion was more efficient with the optimized polymers than with commercial PVP-CL. The disruption of crystallinity was directly related molecular interactions between the drug and polymers, with evidence of ibuprofen dimer disruption and hydrogen bond association between the drug and carriers. Although evidence of disintegrant activity was observed in the swelling studies, the amorphous drug content increased the dissolution rate of ibuprofen from the mixtures, and was the prime mechanism for this enhancement, with no evidence for wetting or microcrystalline drug-based mechanisms operating. The polymers inhibit recrystallization of the drug, even though crystals are present in the initial mixtures, and indeed crystal disruption continued over time.

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