Dissolution and Solubility Enhancement of the Highly Lipophilic Drug

Jun 5, 2015 - Herein, a series of seven excipient models was prepared by both homopolymerization and copolymerization of 1-vinyl-2-pyrrolidone (VP) an...
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Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N‑isopropylacrylamideco-vinylpyrrolidone) Excipients Lakmini Widanapathirana, Swapnil Tale, and Theresa M. Reineke* Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455-0431, United States S Supporting Information *

dispersions (ASDs) of poorly aqueous soluble active ingredients with excipients has emerged as a promising modality to increase the solubility and bioavailability of drug candidates with challenging physical properties toward solubilization.2,3 Excipients are pharmacologically inert materials that can be of natural product or synthetic origin and may make up a substantial portion of a pharmaceutical product. For example, many polysaccharide derivatives have been examined to enhance drug solubility such as cyclodextrin4,5 and various cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC),6−8 hydroxypropylmethylcellulose acetate succinate (HPMCAS),6,9 and ethylcellulose.8,10 In addition, synthetic excipient models have also been examined, e.g., polyethylene glycol,11 polymethacrylates,12 and Soluplus,13 to name a few. Among synthetic excipients, polyvinylpyrrolidone (PVP) is a useful material in the pharmaceutical industry due to its solubility in aqueous and polar organic solvents and biocompatibility. A wide range of vinylpyrrolidone homopolymers with different molecular weights are available from BASF under the name Kollidon. Copolymer-based excipients have been prepared by copolymerization of vinyl acetate (VAc) with VP [poly(VAc-co-VP)] and are available from BASF as Kollidon VA64 (copovidone). Incorporation of the VAc monomer in VP chain results in an excipient that is less hygroscopic than related systems and offers shelf-stable formulations.14 ASDs containing PVP have been repeatedly shown to inhibit crystallization of a variety of drugs such as ketoprofen,15 piroxicam,16 lansoprazole,17 curcumin,18 and probucol19 and thereby improve the solubility, dissolution rates, and bioavailability of these APIs. While PVP is known to improve formulation performance, the solubility enhancement is still not optimal for certain drugs such as carbamazepine,20 itraconazole,21 griseofulvin,22 and phenytoin.14 It was reported that HPMC, which contains numerous hydrogen bond donor sites (i.e., free hydroxyl groups) along the backbone is a better stabilizer for itraconazole (with multiple hydrogen bond acceptor sites) in solution compared to PVP, which has hydrogen bond acceptors in the form of carbonyl groups along the backbone.21 Therefore, this drug-dependent performance of PVP may be attributed to the specific intermolecular interactions of the polymer with the functional groups of the API in solution, which

ABSTRACT: Excipients of natural or synthetic origin play an important role in pharmaceutical performance to enhance the solubility, bioavailability, release, and stability of insoluble drugs. Herein, a series of seven excipient models was prepared by both homopolymerization and copolymerization of 1-vinyl-2pyrrolidone (VP) and N-isopropylacrylamide (NIPAAm) by free radical polymerization yielding two homopolymers poly(VP) and poly(NIPAAm) and five copolymers of poly(NIPAAm-co-VP) at difference compositions. While the VP monomer provided aqueous solubility at a variety of conditions to the excipient, the incorporation of NIPAAm into the copolymer offered additional hydrogen bond donating sites to optimize the drug−polymer interactions in the system. Due to the presence of NIPAAm, the copolymers were sensitive to temperature as well. It was found that as the proportion of VP was increased (from 0 to 100%), the lower critical solution temperature (LCST) and the water solubility of the polymer models increased. To examine the role of specific drug− polymer interactions during dissolution on drug solubility and bioavailability, the polymers were formulated with the anticonvulsant drug phenytoin, which is a poorly water-soluble BCS class II drug where oral absorption is limited by the drug solubility. Amorphous solid dispersions (ASD) were prepared via spray drying of phenytoin with the polymer excipient models to contain 10% and 25% by weight drug loading. Physical characterization of the ASDs by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) revealed that the polymers held the drug in a high-energy amorphous phase in all the formulations prepared. All ASDs exhibited improved in vitro dissolution rates compared to drug only and physical mixtures of the polymers and the drug. Drug solubility was the highest with the ASDs containing poly(NIPAAmco-VP) 60:40 and 50:50, which showed a solubility enhancement of near 14-fold increase compared to pure drug, indicating the significance of copolymer composition to improve drug−polymer interactions toward increasing bioavailability. KEYWORDS: poly(NIPAAm-co-VP), phenytoin, dissolution, crystallization inhibition, supersaturation maintenance

I

t has been estimated that Biopharmaceutics Classification System (BCS) class II drugs make up about 60% of active pharmaceutical ingredients (API) under current development as new pharmaceuticals.1 Formation of amorphous solid © XXXX American Chemical Society

Received: March 11, 2015 Revised: April 23, 2015 Accepted: May 22, 2015

A

DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Communication

Molecular Pharmaceutics

copolymer with phenytoin at different drug loadings were prepared by spray drying. Very similar bulk properties were displayed by all the ASDs prepared as revealed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). However, their dissolution performance exhibited significant dependence on the copolymer composition. We reveal that copolymerization of these monomers can be used to modify the chemical composition of a polymer excipient and thereby tune its physiochemical properties and in vitro dissolution behavior. Thus, understanding the structure−activity relationships of new excipient designs and drug formulations will aid with the rational design of new structures to promote drug solubility for challenging pharmaceutical candidates. Copolymerization of NIPAAm with VP using various monomer feed ratios was carried out by a free radical polymerization technique in DMF at 70 °C using AIBN as the free radical initiator at various monomer feed ratios (Table 1). The

results in variations in nucleation and crystal growth inhibition at supersaturated conditions. To this end, we sought to understand the role of PVPcontaining materials to solubilize phenytoin, a BCS class II drug used primarily in the management of complex partial seizures (see Figure 1 for phenytoin properties). Due to the poor aqueous

Figure 1. Chemical structure of (a) phenytoin (with physical properties) and (b) poly(NIPAAm-co-VP).

solubility (32 μg/mL), the high lipophilicity (indicated by the octanol/water partition coefficient (logP) value of 2.2), and the strong intermolecular interactions indicated by the high melting temperature (286 °C), the oral absorption of phenytoin is severely limited by its dissolution rate and high crystallization propensity, thus requiring significant enhancement in solubility for increasing its oral bioavailability. Improvement of the dissolution rate and bioavailability of phenytoin by ASDs prepared by coprecipitation with PVP have been investigated previously. Sekikawa et al. reported that a phenytoin−PVP coprecipitate (1:3) improved the dissolution of the drug. However, the maximum concentration reached was about 63 μg/mL.23 The coprecipitate of phenytoin with a carrier combination of sodium deoxycholate (DC-Na) and PVP (DC-Na-PVP) at the ratio of 1:1:1 was found to improve the dissolution by nine-fold at 5 min (up to 278 μg/mL). However, the high drug-to-excipient ratio used resulted in a gradual concentration decrease over time due to phenytoin crystallization in the bulk solution.24 Furthermore, the use of DC-Na, which is a surface active carrier, resulted in poor in vivo safety profiles for the above excipient. Given that higher excipient levels in solid dispersions result in higher drug dissolution, Jachowich et al. reported a 30−40% drug dissolution and a solubility enhancement of phenytoin when it was incorporated in a solid dispersion with PVP (10 wt % phenytoin) with varying molecular weights.25 To our knowledge, the best dissolution profile prior to this report for phenytoin with a PVP excipient was achieved by Franco et al. when employing a solid dispersion of phenytoin with PVP K-30 at a 5 wt % drug loading (380 μg/mL).26 The poor dissolution enhancement of phenytoin in the presence of PVP excipients may likely be due to the lack of sufficient hydrogen bonding sites in the polymer. PVP has hydrogen bond acceptor carbonyl groups along the backbone, which can interact with the two amide −NH protons of the phenytoin molecule. To strengthen the noncovalent interactions, we hypothesized that the introduction of structurally similar hydrogen bond donor sites within a PVP-based polymer backbone would be an interesting strategy to enhance the polymer excipient interactions with drugs containing both hydrogen bond donor and acceptor functional groups. Herein, the role of a polymer composition was examined to promote the solubilization and superstaturation maintenance of the model drug phenytoin. NIPAAm comonomers, which have hydrogen bond donor (−NH) and acceptor (−CO) functionalities were introduced to a VP polymer chain at various ratios to modify the hydrogen bonding capacity of the excipient. Introduction of NIPAAm allowed us to create a polymer that is also sensitive to temperature. ASD formulations of each

Table 1. Polymer Characterization Data feed mol %

actual mol %a

NIPAAm

VP

NIPAAm

VP

Mn,SECb (g/mol)

Đc

Tg,DSCd (°C)

100 75 60 50 40 25 0

0 25 40 50 60 75 100

100 74 59 49 42 26 0

0 26 41 51 58 74 100

42800 108000 158000 326000 220000 370000 341000

1.76 1.44 1.34 1 37 1.22 2.44 2.32

96 100 94 96 92 96 104

a

Mol % of NIPAAm and VP in the polymer backbone determined by H NMR spectroscopy in CDCl3. bTotal number-averaged molecular weight. cDispersity as measured on a SEC based on dn/dc values in THF. dReported as the second heating cycle with a 10 °C/min heating rate. 1

detailed procedure is available in the Supporting Information. The polymers were isolated by precipitation with diethyl ether and dried under vacuum, and the final copolymer compositions were obtained by 1H NMR spectroscopy, using integral area of chemical shifts of monomer functional groups. The numberaveraged molecular weight and dispersity were determined by size exclusion chromatography (SEC), and the glass transition temperatures (Tg) were reported using differential scanning calorimetry (DSC) (Table 1). The incorporation of NIPAAm into the VP model polymer excipients offered hydrogen bonding donating sites to the system (for optimizing polymer−drug interactions) and also offers the added advantage of thermoresponsiveness to the excipient for potential future application. The lower critical solution temperature (LCST) of NIPAAm can be modulated around the physiological temperature (37 °C) by copolymerization with suitable hydrophilic monomers such as VP.27,28 Below the LCST of NIPAAm, this polymer displays extensive hydrogen bonding interactions with the surrounding water molecules (and potential drug molecules), which allows NIPAAm containing polymers to be soluble in aqueous media. However, phase separation occurs upon heating above its LCST due to the disruption of the hydrogen bonds with water and formation of inter- and intramolecular hydrogen bonding and hydrophobic interactions among polymer chains.29 Thus, it can be hypothesized that the hydrogen bonding of phenytoin with poly(NIPAAm-co-VP) is optimal at solution temperatures below the phase transition B

DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Figure 2. (a) Copolymer composition−LCST behavior relationship for poly(NIPAAm-co-VP) 100:0 (black), 75:25 (yellow), 60:40 (red), 50:50 (green), 40:60 (blue), and 25:75 (pink). The LCST values were found to be 28, 37, 42, 44, 46, and 51 °C, respectively. (b) Solubility of the polymers at 37 °C in PBS/FaSSIF at pH 6.5. Solubility of a marketed PVP product (Kollidon 25) was used as a control.

compared to that of the crystalline drug (see Supporting Information, Figure S5). The characteristic crystalline peaks of phenytoin were absent in all spray dried dispersions (SDD) and a broad, diffuse diffractogram was observed indicating that at least 95% of the drug in the SDD is transformed to the amorphous state. The main goal of these excipient model formulations was to understand the role of copolymer composition in facilitating solubility and supersaturation maintenance of BCS II drugs, specifically phenytoin. To determine the extent of drug solubility and supersaturation maintenance, in vitro dissolution testing was performed on all SDDs in phosphate buffered saline (pH 6.5) containing 0.5% simulated fasted duodenal solution (FaSSIF) at physiological temperature. Crystalline phenytoin only and a physical mixture of 10 wt % crystalline phenytoin and poly(NIPAAm-co-VP) 60:40 were used as negative controls. To estimate the total amount of phenytoin dissolved in the dissolution media over the course of 6 h, the area under the curve (AUC360) for the dissolved concentration versus time curve was calculated (Table 2). The dissolution performance of SDDs in solution reveals their potential to improve the bioavailability of phenytoin in vivo. During the assay, crystalline phenytoin that was formulated via a physical mixture of the drug with the polymer excipient showed a negligible dissolution profile (less than 10%) compared to the SDD formulations (see Figure 3a inset). The observation can be ascribed to the conversion of the drug from its crystalline state to the high energy amorphous state during the solid dispersion preparation. The concentration−time profiles showed several types of behaviors for the SDDs prepared with 10% drug loading. For poly(NIPAAm-co-VP) 100:0, i.e., the homopolymer of NIPAM, the aqueous concentration of phenytoin gradually increased over the course of 6 h, but the cmax achieved was only 122 μg/mL, which is a three-fold increase in solubility compared to that of crystalline drug (38 μg/mL) in the dissolution media (Figure 3a). The corresponding area under the curve for the concentration−time profile (AUC360) is 4.2 × 104 μg·min/mL, which is a 2.5 times increase compared to the crystalline drug. The AUC360 of NIPAAm homopolymer is comparable to that of marketed product control (Kollidon 25). With an LCST (28 °C) lower than physiological temperature (37 °C), PNIPAAm phase separated in the dissolution media at

temperature of the polymer where extended polymer chains are present. Above this temperature, the NIPAAm moieties are buried in the collapsed polymer structure and cannot interact with the surroundings to a great extent. Herein, we sought to examine the role of hydrogen bonding capacity of the polymer excipient on the dissolution enhancement of phenytoin, a drug that contains both hydrogen bond donating and accepting sites and is a challenging candidate for solubilization due to its high crystallization tendency. The LCST of each polymer composition was measured in PBS buffer containing 0.5 wt % simulated fasted duodenal solution (FaSSIF) as a function of percent transmittance at 450 nm. At low temperatures, the polymer solution was clear, thus the transmittance of light was high. With an increase in the temperature, the polymers phase separated (due to aggregation), which caused the solution to become turbid, and the transmittance decreased rapidly. The solubility of the polymers at physiological temperature was then studied by dissolving the polymer in a known amount of the PBS buffer. According to Figure 2, the LCST profiles of the thermoresponsive, watersoluble copolymers were elevated from 28 to 51 °C with the increasing amount of VP in the polymer composition. With LCST values above 37 °C the NIPAAm segments of all the copolymers exist in its free form in aqueous dissolution media, exposing most of the hydrogen bond donor and acceptor sites to its surroundings. Furthermore, due to the hydrophilicity imparted by the 2-pyrrolidone ring, aqueous solubility of the copolymer at physiological temperature also increased from 0 to 72 mg/mL with increasing amount of VP from 0 to 100%. ASDs are typically obtained by solvent evaporation methods, such as spray drying, which is an extensively studied technique to obtain solid dispersions.3,18,19,30 The relatively short processing time, versatility for a wide range of polymers, and scalability from milligram to kilogram quantities make this technique unique and advantageous over other solvent methods. A typical spray drying process involves dissolving the excipient and drug into a volatile solvent, atomizing the solution into a spray of droplets of micron size in a drying chamber pumped with a hot and dry gas stream, and collecting the dried particles using a filter.30 Formulations of polymer excipients and phenytoin were prepared by spray drying a mixture of each polymer with 10 and 25 wt % drug loadings in tetrahydrofuran at an inlet temperature of 68 °C. To characterize the physical state and stability of the ASDs, PXRD patterns of the spray dried phenytoin−polymer mixtures were obtained and C

DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Table 2. Dissolution Results of SDDs with Poly(NIPAAm-co-VP) Excipients at 10 and 25 wt % Phenytoin Loadings as Compared to the Marketed Product (Kollidon 25) 10 wt % poly(NIPAM-co-VP) composition 100:0 75:25 60:40 50:50 40:60 25:75 0:100 marketed product

cmax (μg/mL)a 122 313 526 489 600 627 384 175

25 wt %

c360 (μg/mL)b

AUC360 (μg·min/mL)c

122 294 526 256 245 273 236 87

4.2 × 10 1.0 × 1005 1.8 × 1005 1.4 × 1005 8.9 × 1004 1.1 × 1005 1.1 × 1005 4.0 × 1004 04

EFd 2.5 6.1 10.6 8.5 5.3 6.7 6.2 2.4

cmax (μg/mL)a 241 309 469 504 612 516 383 134

c360 (μg/mL)b

AUC360 (μg·min/mL)c

EFd

116 275 247 251 162 255 235 63

4.2 × 10 9.9 × 1004 1.4 × 1005 1.5 × 1005 8.6 × 1004 8.8 × 1004 9.9 × 1004 2.5 × 1004

2.5 5.9 8.1 8.6 5.1 5.2 5.9 1.5

04

a

Maximum concentration of phenytoin. bConcentration of phenytoin at 360 min. cTotal area under the curve during the 6 h dissolution test. Enhancement factor defined as the ratio of AUC360 of a SDD to that of crystalline phenytoin. The cmax, c360, and AUC360 of crystalline phenytoin was 38, 48, and 1.7 × 104 μg·min/mL, respectively.

d

Figure 3. Dissolution data of SDDs with 10 wt % phenytoin loading at 37 °C. Polymer compositions used are poly(NIPAAm-co-VP) 100:0 (black), 75:25 (yellow), 60:40 (red), 50:50 (green), 40:60 (blue), 25:75 (pink), and 0:100 (gray). The inset represents the dissolution data for crystalline phenytoin (×) and poly(NIPAAm-co-VP) 60:40 physically mixed with 10 wt % phenytoin (▲) used as a negative control. The target concentration of phenytoin was 1000 μg/mL. Error bars represent the standard deviation where n = 2.

formulations, the PVP homopolymer promoted a considerable amount of phenytoin dissolution. This observation is likely due to the interactions between phenytoin and the hydrogen bond accepting 2-pyrrolidone rings in PVP, which may inhibit the association of drug molecules to form crystal nuclei. Also, significant differences in the dissolution profiles for the synthesized PVP and marketed PVP product (Kollidon 25) were found (AUC360 1.1 × 105 μg·min/mL vs 4.0 × 104 μg·min/mL) and could be due to the differences in dispersity, molecular weight, and aqueous solubility among the two samples. The

the condition tested for solubility. Consequently, PNIPAAm offered only a slight improvement in phenytoin dissolution. The homopolymer of VP [poly(NIPAAm-co-VP) 0:100] and poly(NIPAAm-co-VP) 75:25 showed similar dissolution profiles with a slightly higher cmax of 384 and 313 μg/mL, respectively, which provided about 10-fold solubility enhancement to the crystalline drug (Figure 3a,b). The AUC360 shows a six-fold improvement compared to the crystalline drug for both compositions. Although the dissolution performance of PVP was lower than most of the (NIPAAm-co-VP) copolymer D

DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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NIPAAm was more than the administrated polymer concentration (9 mg/mL for 10 wt % drug loading and 3 mg/mL for 25 wt % drug loading) and thus are completely soluble in the aqueous dissolution media. To this end, it is hypothesized that both the 50:50 and the 60:40 copolymer compositions perform best due to a synergistic combination of including both VP monomers (hydrogen bond accepting and promotes solubility) and NIPAAm monomers (hydrogen bond donating and accepting to the API). It has been reported that phenytoin molecules surface adsorb and interact with other phenytoin molecules in the crystal lattice during crystal growth via π−π interactions between the phenyl rings as well as “ribbon-like” hydrogen bonding chains between amide and carbonyl groups.31 Thus, phenytoin crystal growth at supersaturation conditions occurs mainly along the direction of this hydrogen-bond chain.31 It is reasonable to hypothesize that a disturbance to these uniaxial phenytoin−phenytoin hydrogen bonding chains by competitive hydrogen bonding with a structurally similar moiety would inhibit the nucleation and crystal growth at supersaturation conditions. Thus, it can be hypothesized that the copolymers containing NIPAAm (with hydrogen bond donor −NH and acceptor −CO) moieties in the copolymer inhibits phenytoin crystal growth (due to structural similarity) aiding supersaturation maintenance. Therefore, altering the NIPAAm content in the copolymer was shown to have a direct impact on the solubility and supersaturation maintenance of this API in aqueous dissolution media. Increasing the NIPAAm content can result in polymers with poor solubility in solution at physiological temperature due to the reduction of LCST below physiological temperature as well as the reduction of VP content. However, reduction of the NIPAAm content reduces the number of hydrogen bond donor sites along the polymer backbone, which appear essential for increasing the interaction of phenytoin with the excipient (and influencing crystallization inhibition). The dissolution results indicate that the balance between these two factors govern the performance of poly(NIPAAm-co-VP) as an excipient for improving the drug solubility and bioavailability. Consequently, these chemical moieties are very promising for incorporation into excipient candidates for phenytoin, which possess substandard solubility due to its high crystallization ability. In conclusion, copolymerization was used as a strategy to alter inter- and intramolecular interactions of a polymer with its surroundings (drug and solvent) and thereby tune the physical properties toward better excipient design. Herein, we sought to examine the role of the excipient hydrogen bonding capacity and solubility on the dissolution and supersaturation maintenance of the highly lipophilic API phenytoin. The LCST and the solubility of poly(NIPAAm-co-VP) increased with increasing amount of VP in the copolymer. Two copolymer compositions poly(NIPAAm-co-VP) 50:50 and 60:40 were found to significantly increase API dissolution. This was attributed to the transformation of crystalline phenytoin into its high energy amorphous form upon spray drying from tetrahydrofuran. We propose that it is essential to incorporate similar chemical groups in the polymer backbone that are also present in the drug molecular structure, which can interfere with the drug crystallization mechanism and inhibit crystal nucleation. The specific drug−polymer interactions provided by NIPAAm and VP moieties, along with the enhanced solubility of VP in aqueous conditions collectively assist in inhibiting nucleation and crystal growth of phenytoin, which are essential for the supersaturation maintenance. The balance between the VP and NIPAAm content

number-averaged molecular weight of the marketed product (Kollidon 25) is reported to be 28 000−34 000 g/mol, thus fairly small compared to the PVP polymer synthesized via free radical polymerization (341 000 g/mol). The aqueous solubility of the systems were similar as the synthesized PVP yielded a solubility of 72 mg/mL, while Kollidon 25 yielded a solubility of 66 mg/mL. Miller et al. reported that a high molecular weight PVP grade enhances the supersaturation of itraconazole for a greater extent compared to a smaller analogue.21 The observation was attributed to the stronger interaction of the high molecular weight polymer with the API due to the increased number of functional groups (hydrogen bonding sites in this case) present in the polymer. Furthermore, that study commented that the increased viscosity provided by the high molecular weight polymer could reduce the molecular mobility of the drug, hence higher crystal growth inhibition leading to the above observation.21 Most of the poly(NIPAAm-co-VP) SDDs improved phenytoin dissolution profiles compared to the VP and NIPAAm homopolymer analogues as well as the marketed product. The best dissolution performance for phenytoin was observed by the poly(NIPAAm-co-VP) 60:40 composition in aqueous media (Figure 3c). A high level of supersaturation was achieved at early time points (411 μg/mL at 4 min), and the concentration increased over 6 h to obtain a cmax of 526 μg/mL, which is a 14-fold solubility enhancement compared to crystalline phenytoin. The AUC360 for this composition is 1.8 × 105 μg· min/mL and outperforms crystalline phenytoin by 11 times and Kollidon 25 by 4.5 times. For the poly(NIPAAm-co-VP) 50:50 model, the concentration of phenytoin also achieved rather high levels of supersaturation at early time points, but it stayed constant for a significant amount of time (90 min) before slowly decreasing to a c360 of 256 μg/mL (Figure 3d). The phenytoin solubility showed a 13-fold enhancement; however, the AUC360 started to decrease at this composition compared to the best performer [poly(NIPAAm-co-VP 50:50 and 60:40]. For copolymers poly(NIPAAm-co-VP) 40:60 and 25:75, the concentration of dissolved phenytoin achieved a maximum at the beginning of the experiment. However, these compositions were not very effective at maintaining solubility as the concentration quickly decreased and then plateaued over the rest of the time of the experiment (Figure 3e,f). With cmax values of 600 and 627 μg/mL, the phenytoin solubility enhancement was initially higher for these two compositions compared to the best performers; however, the overall dissolution performance (AUC360) was low. In summary, the dissolution rate of the poly(NIPAAm-co-VP) systems decreased with both higher (100:0, 75:25) and lower (50:50, 25:75, 0:100) NIPAAm compositions along the polymer backbone. Similar trends were observed for the SDDs prepared with 25% drug loading as well (see SI Figure S6 for concentration−time plots). Overall, poly(NIPAAm-co-VP) 60:40 and 50:50 models were found to significantly increase phenytoin dissolution and supersaturation maintenance compared to the other polymer models. It should be noted that the LCST of these copolymers did not change upon SDD preparation (see SI Figure S4) and that the observed LCST values for all of the copolymer compositions were at or above the physiological temperature (Figure 2); therefore, all of the polymers were soluble in the dissolution media. In addition, the solubility of the copolymer formulations was found to increase with an increase in VP content (Figure 2b). The polymer solubility for all the copolymers except the homopolymer of E

DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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(9) Friesen, D.; Shanker, R.; Crew, M.; Smithey, D.; Curatolo, W.; Nightingale, J. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions: An overview. Mol. Pharmaceutics 2008, 5, 1003−1019. (10) Desai, J.; Alexander, K.; Riga, A. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int. J. Pharm. 2006, 308 (1−2), 115−123. (11) Urbanetz, N. Stabilization of solid dispersions of nimodipine and polyethylene glycol 2000. Eur. J. Pharm. Sci. 2006, 28, 67−76. (12) Huang, J.; Wigent, R.; Bentzley, C.; Schwartz, J. Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery - Effect of drug loading on release kinetics. Int. J. Pharm. 2006, 319, 44−54. (13) Shamma, R.; Basha, M. Solupluse (R): A novel polymeric solubilizer for optimization of Carvedilol solid dispersions: Formulation design and effect of method of preparation. Powder Technol. 2013, 237, 406−414. (14) Bühler, V. Polyvinylpyrrolidone Excipients for Pharmaceuticals:Povidone, Crospovidone and Copovidone; Springer-Verlag Berlin Heidelberg: Berlin, Heidelberg, 2005. (15) Di Martino, P.; Joiris, E.; Gobetto, R.; Masic, A.; Palmieri, G.; Martelli, S. Ketoprofen-poly(vinylpyrrolidone) physical interaction. J. Cryst. Growth 2004, 265, 302−308. (16) Tantishaiyakul, V.; Kaewnopparat, N.; Ingkatawornwong, S. Properties of solid dispersions of piroxicam in polyvinylpyrrolidone. Int. J. Pharm. 1999, 181, 143−151. (17) Zhang, X.; Sun, N.; Wu, B.; Lu, Y.; Guan, T.; Wu, W. Physical characterization of lansoprazole/PVP solid dispersion prepared by fluidbed coating technique. Powder Technol. 2008, 182, 480−485. (18) Paradkar, A.; Ambike, A.; Jadhav, B.; Mahadik, K. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int. J. Pharm. 2004, 271, 281−286. (19) Thybo, P.; Pedersen, B.; Hovgaard, L.; Holm, R.; Mullertz, A. Characterization and physical stability of spray dried solid dispersions of probucol and PVP-K30. Pharm. Dev. Technol. 2008, 13, 375−386. (20) Nair, R.; Gonen, S.; Hoag, S. Influence of polyethylene glycol and povidone on the polymorphic transformation and solubility of carbamazepine. Int. J. Pharm. 2002, 240, 11−22. (21) Miller, D.; DiNunzio, J.; Yang, W.; McGinity, J.; Williams, R. Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition. Drug Dev. Ind. Pharm. 2008, 34, 890−902. (22) Vasanthavada, M.; Tong, W.; Joshi, Y.; Kislalioglu, M. Phase behavior of amorphous molecular dispersions - II: Role of hydrogen bonding in solid solubility and phase separation kinetics. Pharm. Res. 2005, 22, 440−448. (23) Sekikawa, H.; Fujiwara, J.; Naganuma, T.; Nakano, M.; Arita, T. Dissolution Behaviors and Gastrointestinal Absorption of Phenytoin in Phenytoin-Polyvinylpyrrolidone Coprecipitate. Chem. Pharm. Bull. 1978, 26, 3033−3039. (24) Yakou, S.; Yamazaki, S.; Sonobe, T.; Nagai, T.; Sugihara, M. Dissolution and Bioavailability of Phenytoin in Phenytoin Polyvinylpyrrolidone Sodium Deoxycholate Coprecipitate. Chem. Pharm. Bull. 1986, 34, 3408−3414. (25) Jachowicz, R. Dissolution Rates of Partially Water-Soluble Drugs from Solid Dispersion-Systems 0.2. Phenytoin. Int. J. Pharm. 1987, 35, 7−12. (26) Franco, M.; Trapani, G.; Latrofa, A.; Tullio, C.; Provenzano, M.; Serra, M.; Muggironi, M.; Biggio, G.; Liso, G. Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions. Int. J. Pharm. 2001, 225, 63−73. (27) Nam, I.; Bae, J.; Jee, K.; Lee, J.; Park, K.; Yuk, S. Poly(Nisopropylacrylamide-co-N-vinylpyrrolidone) as a novel implant materials: Preparation and thermo-gelling behavior. Macromol. Res. 2002, 10, 115−121. (28) Dincer, S.; Rzaev, Z.; Piskin, E. Synthesis and characterization of stimuli-responsive poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidone). J. Polym. Res. 2006, 13, 121−131.

is the key to improve the solubility and prevent the drug crystallization at the same time. This improvement in dissolution and supersaturation maintenance may aid in improving bioavailability and dose reduction of various drug species and can be used as a general design parameter in excipient design.

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ASSOCIATED CONTENT

S Supporting Information *

Synthesis of poly(NIPAAm-co-VP) by free radical polymerization, polymer characterization by 1H NMR, SEC, DSC analysis, lower critical solution temperature (LCST) measurements, determination of polymer solubility, method of spray drying, PXRD patterns for SDDs with 10 and 25 wt % phenytoin loadings, procedure for in vitro dissolution test, and dissolution data of SDDs with 25 wt % phenytoin for all poly(NIPAAm-coVP) compositions. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.molpharmaceut.5b00202.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Dow Chemical Company for funding of this project. We thank Professors Marc A. Hillmyer, Timothy P. Lodge, and Frank Bates at the University of Minnesota as well as Dr. Steven J. Guillaudeu and Dr. Robert L. Schmitt at The Dow Chemical Company for many helpful discussions. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org) via the MRSEC program, and we thank Professor Valérie C. Pierre at the University of Minnesota for allowing us to use the UV−vis instrument for LCST measurements.

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DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.molpharmaceut.5b00202 Mol. Pharmaceutics XXXX, XXX, XXX−XXX