Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects.

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects DEV PRASAD,1 HARSH CHAUHAN,2 EMAN ATEF1 1 2

School of Pharmacy, MCPHS University-Boston, Boston, Massachusetts 02115 School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska 68178

Received 27 April 2014; revised 23 July 2014; accepted 31 July 2014 Published online 5 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24137 ABSTRACT: The purpose of this study was to understand the combined effect of two polymers showing drug–polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%–40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug–polymer interaction C 2014 Wiley Periodicals, Inc. and the offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions. American Pharmacists Association J Pharm Sci 103:3511–3523, 2014 Keywords: poorly water-soluble drugs; solid dispersion; solubility; supersaturation; amorphous; Interaction; Crystallization Inhibition; Indomethacin; Polymer

INTRODUCTION Enhancing the oral bioavailability of poorly water-soluble compounds is an important challenge during formulation development.1,2 Various methods, such as micronization,3 salt formation,4 use of surfactants, lipid formulations,5 formation of prodrugs, and development of amorphous solid dispersion6,7 have increasingly been utilized to enhance the solubility and dissolution rate of drugs. The amorphous formulations have recently gained attention and offers solubility advantages to a large number of poorly soluble drugs. Being a high-energy form, the solubility and dissolution rate of the amorphous form are higher than the stable crystalline form.8,9 However, the higher free energy of the amorphous form gives rise to physical instability and crystallization tendency. Thus, the solubility and dissolution advantage is offset by the possibility of crystallization during dosage form processing or storage.1,10–12 In an attempt to improve the physical stability of these amorphous forms and delay crystallization, different polymers have been used to prepare amorphous binary solid dispersions. Polymers, usually used at high concentrations, stabilize the amorphous form of the drug by increasing the glass transition temperature (Tg ) of the system, thus reducing the molecular mobility of the amorphous drug in binary systems. Another important mechanism of stabilization is the crystallization inhibition of Correspondence to: Eman Atef (Telephone: +617-732-2982; Fax: +617-7322228; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 3511–3523 (2014)

C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

amorphous drugs due to drug–polymer intermolecular interaction in amorphous binary solid dispersion.13,14 The selection of appropriate polymers and their quantities are crucial for the success of solid dispersion formulations. Currently, the empirical screening of various polymers at different concentrations is common practice for binary solid dispersions formulations.15,16 Further, high polymer concentrations are often utilized to guarantee the stability of the amorphous drug in these binary dispersions. This can lead to an increased mass load in successive formulation processes, which may result in multiple challenges, including failure of tablet disintegration, sticking to punches, final size of the dosage form, and so on. Moreover, organic solvents used in the solid dispersion preparation are proportional to the polymer–drug ratio. The increased use of such solvents is neither environmentally safe nor economically sound. High concentrations of polymers in formulations can also add significant toxicity to the formulations.17–20 Thus, there is an obvious need to develop amorphous solid dispersions with higher stability using minimum polymer concentration. Recently, amorphous ternary systems had been successfully used for dissolution enhancement and stabilizing the amorphous form of drugs. However, in most of these studies, high concentrations of polymers were used to achieve the desired results.21,22 In many cases, polymers were combined with surfactants to achieve higher dissolution rates. A challenge for these amorphous ternary dispersions has been the characterization of these complex systems. Still, amorphous ternary solid dispersions can give formulation scientists a window for

Prasad, Chauhan, and Atef, JOURNAL OF PHARMACEUTICAL SCIENCES 103:3511–3523, 2014

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significantly decreasing the concentration of polymers and reducing the toxicity associated with polymers. As discussed earlier, drug–polymer interactions can play an important role in amorphous stabilization in binary solid dispersions. There are many examples in the literature proving the role of specific interactions in stabilizing solid dispersions, for example, Taylor and Zografi13 showed the presence of intermolecular hydrogen bonding interactions in solid dispersions of indomethacin (IND) and PVP. Polymers interacting with drugs have shown a stabilization effect even with no significant change in the molecular mobility of these systems. In the study, no change in the Tg of the system was observed, confirming limited anti-plasticizing effects (specially at low polymer concentrations).13 Further, the role of hydrogen bonding has been confirmed by many researchers in stabilizing the amorphous phase through disruption of drug–drug interactions and the formation of drug–polymer interactions.12,23–26 Therefore, combining two polymers having interaction with drugs for solid dispersions development can be utilized as an approach to achieve the above goals. Based on the above concepts, we decided to investigate the effect of combining two polymers showing drug–polymer interaction for solubility enhancement and stabilization of the solid dispersion. The study emphasizes the effectiveness of two polymers at low concentrations in amorphous ternary solid dispersions. We studied the combined stabilization effect of polymers showing drug–polymer interaction on amorphous stabilization of IND (figure 1), with the goal of investigating this effect and probing the mechanism behind the solid-state stabilization. Eudragit E100 and PVP K90 (figure 1) were chosen as polymers based on their interaction IND. Chauhan et al.27 from our research group had screened different polymers in solution and have reported Eudragit E100 and PVP K90 to be very efficient in precipitation inhibition because of molecular interactions. Both the polymers have shown interaction with IND individually and have been successfully used in solubility and stability enhancement of poorly soluble drugs as reported by many studies.13,28,29 Finally, both the polymers are listed in United

States Food and Drug Administration inactive ingredient list and it would be judicious to understand their behavior in solid dispersion development. This will add to the existing knowledge of polymers in solid dispersions and will help in future product development.

MATERIALS AND METHODS Materials Indomethacin was purchased from Sigma–Aldrich, St. Louis, Missouri. Eudragit E100 was a gift from Degussa (Parsippany, New Jersey). PVP K90 was purchased from Sigma. HPLCgrade organic solvents (acetonitrile, methanol) were purchased from J.T. Baker, Phillipsburg, New Jersey. Hydrochloric acid, 10 N, ACS grade (lot #SN0543), potassium phosphate monobasic, crystals, lot #VQ 0785, and sodium hydroxide, lot #QX0299 were purchased from Spectrum Chemical Mfg. Corporation, New Brunswick, New Jersey. Methods Solubility Determination A test of the solubility of IND in 0.1 N hydrochloric acid was carried out. An excess amount of IND (50 mg) was added to the 20 mL vial containing 10 mL of media. The vials were shaken for 24 h at 25◦ C. After centrifugation and filtration through 0.22 :m filters, the samples were analyzed using HPLC. HPLC Assay An HPLC method was used to quantify IND (Hewlett Packard 1100 series HPLC system, HP ChemStation software, A Hypersil ODS C18, 150 × 5.4 mm2 column). The mobile phase consisted of acetonitrile and 0.1 M glacial acetic acid (60:40, v/v), at 0.8 mL/min, using UV detection at 8 = 228 nm.30 Preparation of Solid Dispersions The solid dispersions were prepared by the solvent evaporation method. The required amounts of drug and polymer or polymers were dissolved in methanol, which was then evaporated using a rotary evaporator at 60◦ C. The solid dispersions were sieved through 350 :m mesh, dried under vacuum for 12 h, and then stored in desiccators over phosphorous pentoxide. The solid dispersions were characterized by modulated differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), IR, and Raman spectroscopy. Preparation of Physical Mixtures Drug–Polymer Physical Mixtures The binary and ternary physical mixtures were prepared by geometric mixing of the drug and polymer or polymers using a spatula at the required drug–polymer ratio. The obtained physical mixtures were sieved, dried, stored, and characterized using the same conditions and techniques as the solid dispersions. Polymer Physical Mixtures and Coevaporates

Figure 1. Structure of (a) indomethacin (IND), (b) Eudragit E100, and (c) PVP K90.

To probe any possible polymer–polymer interaction, the polymer physical mixture and solid dispersion were prepared and characterized following the same methods as drug–polymer


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solid dispersions. The weight ratios of PVP K90–Eudragit E100 (70:30, 50:50, and 30:70) were studied.

from both the polymers were added. If the experimental values show higher affect then that will suggest synergistic advantage.

Characterization

Dissolution Studies

Thermal Analysis

Drug release from solid dispersion formulations was studied under non-sink conditions using USP apparatus II (paddle) at 37◦ C and a paddle speed of 100 rpm. The release medium consisted of 500 mL of 0.1 N HCl. Powdered solid dispersions and physical mixtures were added to the dissolution media after sieving through 300 :m sieve. During the release studies, samples of 2 mL were collected after 10, 20, 30, 45, 60, 90, 120, and 240 min using a syringe and were replaced with the same volume of release medium. The final time point was taken at 24 h. The samples were subsequently filtered using 0.22 :m pore size syringe filters. All samples were analyzed with HPLC. Experiments were performed in triplicate. Theoretical dissolution profile for ternary system was proposed based on the percentage dissolution contribution from each polymer in binary dispersions at the ratios they are present in ternary system. For example, if a ternary system contains 15% of a polymer, its dissolution contribution will be half of what was experimentally determined in binary dispersions containing 30% of that polymer. It was assumed that 50% of the polymer will create 50% of the effect. Similarly, the effect from second polymer was calculated and added to get the theoretical profile of ternary systems.

Tg determination using modulated DSC. The thermal analysis was carried out using TA Q1000 modulated DSC (TA Instruments, New Castle, Delaware) equipped with a liquid nitrogen cooling assembly. The dry nitrogen at a flow rate of 50 mL/min was used as purge gas. Samples (5–10 mg) were prepared in a sealed pan. The amplitude used was ±0.32◦ C, the period was 60 s, and the underlying heating rate was 2.00◦ C/min. The samples were analyzed in the range from 25.00◦ C to 200.00◦ C and each measurement was performed in duplicate. Melting point depression determination. For melting point depression determination, the prepared physical mixtures were equilibrated at 25◦ C in the DSC instrument followed by heating with a scan rate of 1◦ C/min. Melting point depression has been carried out by various authors using polymers having high Tg than drug melting temperature.31–33 It has been found that if polymer has good miscibility with drug, they can show the melting point depression even though their Tg is high. Ideally, during DSC experiments, third heating cycle should be utilized to measure the melting point depression. We attempted heat–cool–heat cycle in DSC but IND having low crystallization potential forms amorphous systems. In the third heat cycle of DSC, no melting endotherm was observed therefore first heat cycle with 1o C/min was used for melting point depression. Powder X-ray Diffraction Powder X-ray diffraction was performed using Bruker AXSXRD utilizing CuK" radiation to determine the crystalline or amorphous state of a drug. The PXRD patterns were collected in the angular range of 1◦ < 22 < 40◦ in step scan mode. IR Spectroscopy IR spectra were acquired with Thermo Scientific Nicolet iS10 instrument with OMNIC 8.1 software. Sixty-four scans were collected for each sample. The IR spectrophotometer has a resolution of 4 cm−1 . Stability Studies Accelerated stability studies were conducted to determine the effect of high temperature and humidity on the physical stability of binary and ternary solid dispersions and to differentiate the stability of different dispersions. The samples were stored in desiccators over saturated solutions of various relative humidity (RH) at 40◦ C. Saturated salts solutions of magnesium chloride (33% RH) and sodium chloride (75% RH) were prepared to control for RH. The samples were regularly checked for crystalline form and were characterized using PXRD, IR, Raman, and mDSC. For comparison with experimental values, theoretical stability values for ternary systems were proposed based on the contribution from each polymer in binary dispersions. The stability effects in binary dispersions were assumed to be similar in ternary system if present in the same concentrations. For example, if a polymer in solid dispersions forms amorphous dispersions at 20%, similar stabilization was expected in ternary dispersions at this concentration. Because ternary dispersions contain two polymers, the stability effects DOI 10.1002/jps.24137

RESULTS AND DISCUSSION Preparation and Characterization of IND Binary and Ternary Amorphous Solid Dispersions with PVP K90 and Eudragit E100 Indomethacin, an indole acetic acid derivative, was used as a model drug in our study. It exhibits polymorphism and exists in two polymorphic forms: " and (. Both the polymorphic forms show sharp diffraction peaks, whereas amorphous IND show no diffraction peaks. The melting point of " and ( polymorphs are 155◦ C and 161◦ C, respectively.34 IND is a good choice of model drug because it has low aqueous solubility, low Tg (∼41◦ C), and crystallization tendency even below its Tg . Eudragit E100 and PVP K90 were used a polymers in amorphous binary and ternary solid dispersions. Both the polymers are amorphous in nature, show no diffraction peaks, and have a Tg of 48◦ C and 179◦ C, respectively. The PXRD patterns of binary solid dispersions confirmed the amorphous nature of IND at ratios up to 95% (w/w) drug loading with PVP K90 and 90% (w/w) with Eudragit E100 (Fig. 2) Solid dispersions with 5% (w/w) Eudragit E100 showed sharp diffraction peaks, indicating crystalline IND. For IND and PVP K90 binary systems, the solid dispersion with the lowest PVP concentration, that is, 2.5% (w/w) PVP K90, was also prepared; however, it was found to be crystalline. The results confirm that both polymers can be used individually to prepare amorphous solid dispersions of IND. Amorphous stabilization of IND with as low as 5% PVP K90 suggests that it is more effective compared with Eudragit E100. For ternary solid dispersions, all were found to be amorphous, as confirmed by PXRD (Fig. 2). The presence of 2.5% (w/w) of each polymer was enough, in the case of ternary dispersions, to get an amorphous system, although 5% (w/w) of Eudragit E100 and 2.5% (w/w) of PVP K90 were not enough to stabilize the amorphous drug in the case of binary solid


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Figure 2. X-ray diffraction pattern of—(1) 80:20 (w/w) (IND–PVP K90), (2) 90:10 (w/w) (IND–PVP K90), (3) 95:05 (w/w) (IND–PVP K90), (4) 80:20 (w/w) (IND–E100), (5) 90:10 (w/w) (IND–E100), (6) 80:10:10 (w/w) (IND–PVP K90:E100), (7) 90:05:05 (w/w) (IND–PVP K90:E100), (8) 95:2.5:2.5 (w/w) (IND–PVP K90:E100) solid dispersions after preparation confirm that the binary and ternary systems were amorphous in nature. Table 1.

Day5 Day 10 Day 90 Day 180 a

Stability Result Summary of 80% (w/w) Drug-Loaded Binary and Ternary Systems at 40◦ C/33% RH Binary IND–Eudragit E100 (80:20)

Binary IND–PVPK90 (80:20)

Ternary Experimental IND–PVPK90–E100 (80:10:10)

Ternary Theoretical 1J\D–PVPK90–E100 (80:10:10)

Amorphous Amorphous Partial Crystalline Crystalline

Amorphous Amorphous Partial Crystalline Crystalline

Amorphous Amorphous Amorphousa Amorphousa

Amorphous Amorphous Partial crystalline Crystalline

Synergistic effect upon comparing the theoretical to the experimental effect of the ternary dispersions.

dispersions. This confirms the improved efficiency of combined polymers in formation of stable ternary solid dispersions compared with binary dispersions. Solid-State Stability of IND Binary and Ternary Amorphous Solid Dispersions with PVP K90 and Eudragit E100 The amorphous forms of pure drugs tend to recrystallize rapidly under accelerated storage conditions. However, in solid dispersions, recrystallization is delayed because of the presence of polymers.35 The physical stability of the amorphous solid dispersions was assessed under accelerated storage conditions (40◦ C/33% RH and 40◦ C/75% RH). Raman spectroscopy was previously used and validated by our group for qualitative and quantitative characterization to determine the crystallinity of IND and was used for stability testing.36 Table 1 summarizes the stability results of binary and ternary solid dispersions under 40◦ C/33% RH conditions at various time points along with theoretically proposed prediction. At 40◦ C/33% RH, the IND/PVP K90 stabilized binary system was amorphous for up to 3 months and crystallized out at 6 months. The solid dispersions of IND/Eudragit E100 showed similar stability. The crystallized drug form showed distinct " IND peaks. Theoretical profile of ternary system predicts that the dispersion will be

partially crystalline on day 90 and will crystallize on day 180 at 40◦ C/33% RH. The solid dispersions at 40◦ C/75% RH displayed lower stability, as expected, compared with less humid conditions (Table 2). The Raman spectra of IND/PVP K90 (Fig. 3a) and IND/Eudragit E100 (Fig. 3b) binary systems showed crystalline peaks at day 10 and day 30, respectively, and by day 45, showed sharp peaks, confirming recrystallization of amorphous IND. At 40◦ C/75% RH, it was predicted that the solid dispersion will crystallize on day 30. Comparative Evaluation of Stability in Binary and Ternary Amorphous Solid Dispersions Under both 40◦ C/33% RH and 40◦ C/75% RH conditions, ternary dispersions were found to be amorphous up to 6 months, suggesting better stability of amorphous IND in ternary solid dispersions (Fig. 3c). The significant improvement in the stability of the amorphous form provides evidence that the amorphous form can be rendered more stable in the ternary systems compared with the binary systems. Ternary systems were found to be more efficient in stabilizing amorphous dispersions compared with the predicted theoretical stability profiles that account for additive effects.


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Table 2.

Day 5 Day 10 Day 30 Day 45 Day 60 Day 180 a

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Stability Result Summary of 80% (w/w) Drug-Loaded Binary and Ternary Systems at 40◦ C/75% RH IND–Eudragit E10C (80:20)

IND–PVPK90 (80:20)

Experimental IND–PVPK90–E100 (80:10:10)

Theoretical IND–PVPK90–E100 (80:10:10)

Amorphous Amorphous Partial Crystalline Crystalline Crystalline Crystalline

Amorphous Partial Crystalline Crystalline Crystalline Crystalline Crystalline

Amorphous Amorphous Amorphousa Amorphousa Amorphousa Amorphousa

Amorphous Unpredictable Partial crystalline/Crystalline Crystalline Crystalline Crystalline

Synergistic effect upon comparing the theoretical to the experimental effect of the ternary dispersions.

Figure 3. Raman spectra of 80% (w/w) drug-loaded solid dispersions with (a) PVP K90, (b) Eudragit E100, and (c) PVP K90–Eudragit E100 at various time intervals at 40◦ C/75% RH. Peak specific to " indomethacin at 1649.9 cm−1 appears at day 10 for PVP K90 and at day 30 for Eudragit E100 indicating recrystallization of solid dispersion into "-indomethacin. No changes in spectra were observed, indicating stability of solid dispersion until 6 months.

Dissolution Enhancement of IND Binary and Ternary Amorphous Solid Dispersions with PVP K90 and Eudragit E100 Dissolution of Physical Mixtures The dissolution of physical mixtures showed that the solubility and dissolution rate of the IND cannot be improved noticeably by physical mixing with PVP K90 or Eudragit E100, individDOI 10.1002/jps.24137

ually or in combination (Fig. 4a). The achieved concentration stayed around the solubility (3 :g/mL) of IND in the dissolution medium. The 70/30 (w/w) IND/PVP K90 physical mixture showed 1.9 :g/mL drug release after 30 min, which reached 3.2 :g/mL in 4 h. The physical mixtures of 70/30 (w/w) IND/Eudragit E100 showed 3.3 :g/mL drug release in 30 min, which increased


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Figure 4. Release profile of (a) crystalline indomethacin, IND–PVP K90 (70:30), IND–E100 (70:30), and IND–PVP K90–E100 (70:15:15) physical mixtures (PM) and (b) amorphous indomethacin, IND–PVP K90 (70:30), IND–E100 (70:30), and IND–PVP K90–E100 (70:15:15) solid dispersions (SD). In physical mixtures, no enhancement in release was observed with both binary and ternary systems. After 24 h, the amount of indomethacin release was similar to its equilibrium solubility. Significant enhancement in release was observed with both binary and ternary systems. The release in ternary solid dispersions was significantly higher after 30 min, even compared with binary solid dispersions. Data expressed as mean ± SD (n = 3).

slightly to 4.9 :g/mL in 4 h. Ternary physical mixtures 70/15/15 (w/w) (IND/PVP K90/Eudragit E100) showed 2.8 :g/mL IND release in 30 min, which stayed same after 4 h. Further, the dissolution of amorphous powder showed no improvement because of the instant recrystallization. Amorphous substances have a higher solubility than the corresponding thermodynamically stable crystalline forms. The greater entropy of the amorphous form contributes to the higher free energy and thus higher solubility. The weak internal bonding forces in the amorphous form also contribute to higher solubility. Solutions derived from amorphous forms are supersaturated, and crystallization begins as soon as a crystal of the stable form develops.37 This process is triggered off when the amorphous drug contacts the dissolution medium. In our case, the initial supersaturation due to amorphous form was not achieved because of the nonwetting behavior of amorphous IND. Comparative Evaluation of Dissolution Enhancement in Binary and Ternary Amorphous Solid Dispersions The dissolution of IND from the binary solid dispersions was compared with the ternary solid dispersions (Fig. 4b). The 70/30 (w/w) IND/PVP K90 binary dispersion showed 4.8 times increase in 10 min (8 :g/mL) compared with amorphous IND, which rises to 21 :g/mL in 4 h. This achieved supersaturation was maintained for 24 h. The 70/30 (w/w) IND/Eudragit E100 solid dispersions showed 6.2 times (10 :g/mL) increases in drug release in 10 min compared with amorphous IND. The concentration further increased to 13 :g/mL in 20 min. However, after 20 min, the supersaturation started to decrease gradually to 10 :g/mL in 1 h and 8 :g/mL in 4 h. The 8 :g/mL concentration was maintained for 24 h. These resulting higher solution concentrations than the equilibrium solubility of IND indicate that supersaturated solutions were generated and maintained for 24 h. In both cases, the amount of drug dissolved is significantly more than the dissolution of the pure drug. The enhanced dissolution is due to the presence of the amorphous form of IND, along with other factors, such as reduced particle size of the drug in the solid dispersions and wetting and solubilization characteristics of the carrier.38 As described before, the drop in the concentration after 20 min from solid dis-

persions with Eudragit E100 can be attributed to the conversion of the amorphous form to crystalline. The difference in the dissolution profile of dispersions containing PVP K90 compared with Eudragit E100 was due to different characteristics of the polymers, such as molecular weight, wetting, and penetration of water through dispersion to release the drug. Theoretical dissolution profile of ternary system predicts that 9.2 :g/mL will dissolve in initial 10 min reaching 11.2 :g/mL in 60 min. The dissolution will reach to the maximum concentration (14.6 :g/mL) in 2 h and maintain that concentration for 24 h. The binary solid dispersions were compared with 70% (w/w) drug-loaded ternary dispersions containing 15% (w/w) each of PVP K90 and Eudragit E100 (Fig. 4b). Ternary solid dispersions showed 7.4 times (10 :g/mL) increase in IND release, which gradually increased to 18 :g/mL after 1 h compared amorphous drug. This concentration was maintained until 4 h, after which the concentration fell slightly to 15 :g/mL. Ternary solid dispersion showed an IND release profile with characteristics similar to individual binary dispersions. An initial spike in concentration was observed similar to IND/Eudragit E100 binary dispersion. This spike in concentration increased gradually and was maintained as in IND/PVP K90 binary solid dispersions. Thus, combination of two polymers seems to have a synergistic effect on drug dissolution. It was also observed that after 2 h, the supersaturation was not maintained and decreases below the PVP K90 binary solid dispersion, even though it was higher than Eudragit E100 binary dispersions. The ternary dispersions used in the dissolution have 15% each of the polymers, whereas the binary dispersions contain 30% of individual polymer. The dissolution is higher even though the amount of polymer is half than binary suggesting synergistic effect. Also, all the dispersions were prepared in a same manner and passed through same size sieve to get similar particle size. This helps in neglecting any effect of PSD on dissolution. Eudragit E100 has shown to increase the initial drug release, whereas PVP has shown to maintain the concentration. Both can be observed in the profile and at the half the amount used in the binary systems. This strongly suggests the synergistic effect during dissolution. Further, ternary systems were found to be more efficient in providing dissolution advantage compared


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Figure 5. DSC thermograms of physical mixtures of indomethacin with (a) PVP K90, (b) Eudragit E100, and (c) PVP K90–Eudragit E100 at various drug loads. Melting point depression was observed with an increase in polymer content, indicating drug–polymer mixing.

with the predicted theoretical dissolution profiles which only account for additive effects. Mechanistic Understanding of Amorphous Stabilization and Dissolution Enhancement in Amorphous Ternary Solid Dispersions Solubility Parameters Solubility parameters (*) are widely used as a means of quick and effective miscibility screenings. As a first tool, estimates of the solubility parameter were used to predict miscibility. The solubility parameter of IND is 23.19 MPa1/2 ; for the polymers, solubility parameters are 20.15 and 25.79 MPa1/2 for Eudragit E100 and PVP K90, respectively.26,39 It has been postulated that compounds with a * of less than 7.0 MPa1/2 are likely to be miscible because the enthalpy of mixing within the components is balanced by the energy released by the interaction between the components. On the other hand, compounds with a * of more than 10.0 MPa1/2 are likely to be immiscible. In this study, both polymers were likely to be miscible with the drug in the solid dispersions, as they exhibited * of less than 3 MPa1/2 . Depression in Melting Point At the melting point, the chemical potential of crystalline material is equal to the chemical potential of molten material. When the molten drug is miscible with the polymer, the chemical potential of the drug in the solution will be lower than the pure molten drug. This leads to a melting point depression of the DOI 10.1002/jps.24137

drug dissolved in polymer.40 Melting point depression measurements have been widely utilized to investigate drug–polymer mixing thermodynamics. Strong exothermic mixing should produce a large melting point depression, whereas weakly exothermic, athermal, or endothermic mixing should result in less significant melting point depression. Furthermore, if the drug and the polymers are immiscible, no change in the chemical potential of the molten drug will occur and, thus, no melting point depression will occur. Figure 5a represents the DSC thermograms for physical mixtures at different weight ratios with PVP K90. The onset of the melting point of IND decreases with the increase of the weight fraction of PVP K90. This clear evidence of the depression of the melting point of IND in the mixture indicates a significant degree of mixing at the melting temperature. Similar results were observed with Eudragit E100 (Fig. 5b). On comparison, the depression in melting point from a ternary system containing half of each polymer is similar to the binary physical mixtures (Fig. 5c). The depression in ternary physical mixtures containing 10% of each polymer is similar to the binary solid dispersions containing 20% of individual polymers, suggesting synergism (Fig. 6a and Table 3). Tg /Molecular Mobility Miscibility of the drug in a polymer matrix is an important parameter that governs the stability of amorphous solid dispersions. Incomplete miscibility of the drug in a polymer matrix


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Figure 6. (a) Depression in melting point of physical mixtures of indomethacin at various % w/w drug loading. Experimental and calculated glass transition temperatures of various (b) IND/PVP K90 binary solid dispersions, (c) IND/Eudragit E100 binary solid dispersions, and (d) IND/PVP K90/Eudragit E100 ternary solid dispersion. Table 3.

Depression in Melting Point of Physical Mixtures of Indomethacin at Various Polymer Concentrations

IND–PVPK90 60:40 70:30 80:20 90:10 95:05

Onset Melting Temperature (◦ C)

IND–E100


IND–PVP K90–E100


79.71 94.01 126.11 138.27 148.47

60:40 70:30 80:20 90:10 95:05

88.38 92.95 97.36 102.99 144.51

60:20:20 70:15:15 80:10:10 90:5:5 95:2.5:2.5

94.98 93.25 95.58 105.88 141.62

can result in the formation of concentrated drug domains. These domains add instability to the amorphous dispersions, as they are prone to recrystallization during various drug development stages.41 Thus, it is necessary to achieve a homogenous singlephase miscible system of drug and polymer. The formation of a homogeneous singe-phase system of solid dispersions could be determined using the Tg of the mixture. Single Tg of solid dispersions usually indicates the existence of a homogeneous single phase of the drug and polymers. Multiple Tg s signify the existence of multiple phase systems in the solid dispersions.35 These can be due to the presence of various drug concentrated domains. Mixing of the two components (drug and polymers) can either be ideal or non-ideal. The deviation from ideal mixing in amorphous solid dispersions can be examined by comparing the experimental Tg with the predicted Tg obtained from Gordon– Taylor equation. Similarity in experimental and predicted Tg values indicates ideal mixing, whereas positive and negative deviation indicates non-ideal mixing. Tg(mix) =

(w1 Tg1 + K 1 w2 Tg2 + K 2 w3 Tg3 ) (w1 + K 1 w2 + K 2 w3 )

(1)

Equation 1 is the Gordon–Taylor equation in which w1 and Tg1 are the weight fraction and the glass transition tempera-

ture, respectively; Eudragit E100, w2 , and Tg2 are the weight fraction and the glass transition temperature of IND, respectively; w3 and Tg3 are the weight fraction and the glass transition temperature of PVP K90, respectively; K1 and K2 are constants that were calculated with the Simha–Boyer rule, in which: D1 Tg 1 K∼ = D2 Tg 2 D1 and Tg1 are, respectively, the density and the glass transition temperature of the amorphous component with the lowest Tg ; and D2 and Tg2 are, respectively, the density and glass transition temperature of the amorphous component with the highest Tg .42 In the present study, the Tg of amorphous IND, prepared by quench cooling, was found to be 41◦ C, which is similar to the reported value. The mDSC of PVP K90 and Eudragit E100 showed the Tg of 179◦ C and 48◦ C, respectively. These values also confirm the values in the literature. The experimental and calculated Tg values for IND and PVP K90 solid dispersions are plotted in Figure 6b. The concentration-dependent increase in the experimental Tg values of the dispersions were obtained for IND/PVP K90 solid dispersions. Single Tg of these dispersions indicated the formation of a homogeneous single-phase system.


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The significant negative deviation in the Tg values between experimental and calculated values was observed. The negative deviation suggests non-ideal mixing between the drug and polymers in the prepared solid dispersions. These deviations can be attributed to the possibility of complex formation between IND and PVP K90. It can also be due to a non-uniform distribution of the free volume between the components with very different Tg values (IND Tg vs. PVP K90 Tg ). The experimental and calculated Tg values for IND and Eudragit E100 solid dispersions are plotted in Figure 6c. IND solid dispersions with Eudragit E100 showed that there was an increase in Tg with the increase in polymer concentration from 10% to 20%. However, no significant change in Tg was observed in solid dispersions containing 20%, 30%, or 40% polymer concentration. In all dispersions, single Tg was observed, suggesting the formation of a homogeneous single-phase system. These experimental Tg values are found to be higher than calculated Tg values and indicates non-ideal behavior. The positive deviation from ideal mixing strongly suggests the existence of strong molecular interactions between IND and Eudragit E100. The dispersions showed high Tg , indicative of low molecular mobility compared with ideal behavior, which arises because of drug–polymer interactions. These interactions decrease the molecular mobility of the system. The effect of molecular interactions on the Tg of non-ideal binary polymer blends can be explained by the competition between the interactions between like molecules and the interactions between unlike molecules. When the drug–polymer interaction is stronger than drug–drug, the non-ideal mixture will have a Tg higher than the value calculated from the Gordon–Taylor equation. Figure 6d compares the experimental and calculated Tg values of ternary solid dispersions. The calculated Tg values were obtained by considering the effect of both polymers, as explained in the above equation. In the case of ternary solid dispersions, an increase in experimental Tg from 5% to 40% in combined polymer concentrations was observed. Single Tg was observed in all the solid dispersions, confirming the formation of homogeneous single-phase ternary dispersions. In the case of ternary dispersions, no deviation from calculated Tg signifies ideal mixing behavior. In binary solid dispersions (IND/PVP K90 and IND/Eudragit E100), the existence of a drug–polymer interaction has been shown, as explained above and by spectroscopy techniques (explained in the next section). The absence of any deviation in ternary systems shows that both PVP K90 and Eudragit E100 are contributing to the formation of a single phase. It also signifies the presence of both IND/PVP K90, as well as IND/Eudragit E100, interactions in a ternary system in a combined manner, leading to no deviation from ideal mixing. Drug–Polymer Interactions The significant IR vibration peaks of " and ( IND polymorphic forms in the carbonyl region are reported in various literature.13,30 It has previously been reported that the ( IND polymorph exists as a cyclic dimer form, whereas the " IND polymorph exists as chain consisting of three IND molecules interacting through acid moiety with a free terminal acid carbonyl (C=O) group of IND. The L1712 ¯ cm−1 peak in ( IND signifies the presence of a cyclic dimer, whereas L1650 ¯ and L1679 ¯ cm−1 peaks in " IND polymorphs are because of hydrogen-bonded acid C=O. The IR absorption peak at DOI 10.1002/jps.24137

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L1692 ¯ cm−1 for the ( IND and at L1688 ¯ cm−1 for the " IND are assigned to the benzoly C=O group. In " IND, peak at L1735 ¯ cm−1 occurs because of nonhydrogen-bonded acid C=O. The amorphous form of IND has ¯ cm−1 . peaks at L1705 ¯ and L1684 ¯ cm−1 and a shoulder at L1735 The L1705 ¯ cm−1 peak is assigned to the asymmetric acid C=O of a cyclic dimer. The peak at L1684 ¯ cm−1 is assigned to ben−1 zoyl C=O, and the L1735 ¯ cm shoulder is present because of the non-hydrogen-bonded acid C=O. Polyvinyl pyrollidone K90 (PVP K90) has a single peak in this region at L1663 ¯ cm−1 , which represents the C=O in the amide group. Eudragit E100 has the characteristic C=O ester vibration at L1721 ¯ cm−1 . In addition, the absorptions at L2773 ¯ and L2822 ¯ cm−1 in Eudragit E100 have been assigned to the dimethylamino [(CH3 )2 N] groups. The IR spectra of the PVP K90 and Eudragit E100 coevaporates were studied to probe polymer–polymer intermolecular interactions (spectra not shown). The spectra showed no vibrational changes and were similar to the individual polymers, suggesting no polymer–polymer interaction. These results were expected, as both the polymers have proton acceptor groups. Polyvinyl pyrollidone K90 (PVP K90) has C=O and N–H, whereas Eudragit E100 has C=O and [(CH3 )2 N] groups. IND Binary Dispersion with PVP K90. Interactions between IND and PVP K90 in amorphous solid dispersions have been studied by other research groups and similar results were observed (Fig. 7). To study the molecular interactions, the spectrum of amorphous IND was used as a reference. Polyvinyl pyrollidone has a proton acceptor group (C=O), whereas IND has one proton donor group (OH); therefore, the hydrogen bonding was expected between these two moieties. The drug– polymer interactions could be detected by vibrational changes. The spectrum of dispersions with 10% (w/w) concentration of PVP K90 was similar to the amorphous IND spectra. However, at higher PVP K90 concentrations, changes in spectra become more prominent. The L1705 ¯ cm−1 assigned to asymmetric acid C=O of cyclic dimer showed a decrease in intensity with simultaneous increase in the L1735 ¯ cm−1 shoulder because of the non-hydrogen-bonded acid C=O (in cyclic dimer). These changes suggest that IND no longer exists as a cyclic dimer form. At higher polymer concentrations, a peak at L1726 ¯ cm−1 −1 develops. This L1726 ¯ cm peak is assigned to the C=O of the acid group of IND, which is hydrogen bonded through the hydroxyl group to a PVP molecule. Also, a shoulder at L1636 ¯ cm−1 is present in the solid dispersions, which increases in intensity with an increase in PVP K90 content. This peak is assigned to hydrogen-bonded C=O of PVP K90. These results suggest the formation of a hydrogen bond between IND and PVP K90 in solid dispersions. IND Binary Dispersion with Eudragit E100. As discussed earlier, no peak shifts were observed in IND/Eudragit E100 physical mixtures, indicating no interaction or polymorphic transformation in physical mixtures. The IND/Eudragit E100 solid dispersion spectra showed changes in two regions: 1600– 1800 cm−1 C=O and 2770–2840 cm−1 NH, suggesting interactions between drug and polymer (Figs. 8). In the spectra of lowest concentration solid dispersions (10%, w/w Eudragit E100), no significant changes were observed compared to amorphous IND in the C=O region; however, both amino groups of Eudragit E100 disappeared. Similar to IND/PVP K90 solid


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Figure 7. IR spectra of (a) PVP K90, (b) amorphous IND, (c) IND–PVP K90 (95:05), (d) IND–PVP K90 (90:10), (e) IND–PVP K90 (80:20), (f) IND–PVP K90 (70:30), and (g) IND–PVP K90 (60:40) solid dispersion in the 1400 to 1800 cm−1 region. Changes in the carbonyl regions were observed, suggesting drug–polymer interaction.

Figure 8. IR spectra of (a) Eudragit E100, (b) amorphous IND, (c) IND–Eudragit E100 (90:10), (d) IND–Eudragit E100 (80:20), (e) IND–Eudragit E100 (70:30), and (f) IND–Eudragit E100 (60:40) solid dispersion in the (I) 1400–1800 cm−1 region and (II) 2600–3200 cm−1 region. Changes in the spectra were observed suggesting drug–polymer interaction.


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Figure 9. IR spectra of (a) PVP K90, (b) Eudragit E100, (c) amorphous IND, (d) IND–PVP K90–Eudragit E100 (95:2.5:2.5), (e) IND–PVP K90–Eudragit E100 (90:05:05), (f) IND–PVP K90–Eudragit E100 (80:10:10), (g) IND–PVP K90–Eudragit E100 (70:15:15), and (h) IND–PVP K90–Eudragit E100 (60:20:20) solid dispersions in the (I) 1400–1800 cm−1 region and (II) 2600–3200 cm−1 region. Changes in the spectra were observed suggesting drug–polymer interaction.

dispersions, the peak at L1710 ¯ cm−1 assigned to the C=O stretch of the cyclic dimer of amorphous IND disappears above 90% Eudragit E100 concentration, suggesting the disruption of the dimer structure and implying the formation of an IND/Eudragit E100 interaction stronger than the IND dimer. Similarly, at a higher polymer concentration, a peak at L1726 ¯ ¯ cm−1 peak is assigned to the C=O of cm−1 develops. This L1726 the acid group of IND, which is hydrogen bonded through the OH group to a Eudragit E100 molecule. No shift was detected for the L1732 ¯ cm−1 peak of the C=O of Eudragit E100, indicating that the carbonyl group of Eudragit E100 is not involved in the interaction. The molecular structure of Eudragit E100 has a dimethylamino group that is capable of hydrogen bond formation; thus, the spectral changes at the 3000 cm−1 region were analyzed. As discussed earlier, the absorption bands of the dimethylamino group are present at L2772 ¯ and L2880 ¯ cm−1 . In the solid dispersions, the disappearance of both these peaks was observed at all drug–polymer concentrations. The disappearance is related to the involvement of the dimethylamino group in drug–polymer interactions.

IND Ternary Dispersion with PVP K90 and Eudragit E100. In the ternary solid dispersions, changes in the 1600–1800 cm−1 carbonyl region and the 2770–2840 cm−1 amino region were observed (Fig. 9). The spectral changes that appeared in the binary systems were found to be intact in the ternary systems. The dispersions with lower polymer content (10%, w/w) have similar spectra as amorphous IND, but clear spectral changes were observed at higher polymer concentrations. In binary dispersions, the C=O group of IND hydrogen bonded with polymer appears at L1721 ¯ cm−1 in IND/PVP K90 −1 and L1724 ¯ cm in IND/Eudragit E100. This C=O was observed at L1723 ¯ cm−1 in 60% drug-loaded ternary dispersions. The L1635 ¯ cm−1 peak assigned to the hydrogen-bonded PVP K90 DOI 10.1002/jps.24137

C=O group appeared at same wavenumber as in IND/PVP K90 binary dispersions. Similarly, L2770 ¯ and L2822 ¯ cm−1 assigned to the dimethylamino groups in Eudragit E100 disappeared in all ternary solid dispersions, as was the case in IND/Eudragit E100 binary dispersions. These observations suggest that the ternary systems have same interaction as present in binary systems. Synergistic Advantage of Using Combination of Polymers The IND ternary amorphous dispersions showed higher stability and dissolution compared with binary dispersions even though overall low polymer concentrations was used in these systems. PVP K90 and Eudragit E100 act complementary to each other to give enhanced stability as well as solubilization. For solid-state stability, PVP K90 is more effective in initial formation of amorphous dispersion, whereas both PVP K90 and Eudragit E100 were found to be effective in stabilization of those solid dispersions. For dissolution, Eudragit E100 is more effective in achieving high initial concentrations, whereas PVP K90 helps in the maintenance of high level of supersaturation. This synergistic efficiency of polymers when used in combination in ternary solid dispersions could be correlated to (a) greater IND miscibility in ternary dispersions compared with binary as confirmed by melting point depression and (b) IND– polymer interaction in the ternary systems as confirmed by IR results. Further, Raman spectroscopy confirmed the presence of drug–polymer interactions in ternary dispersions (results not presented in this manuscript). Intermolecular interaction between IND and polymers (with both PVP K90 and Eudragit E100) has been confirmed using IR. In case of IND/PVP K90 dispersions, hydrogen bond forms between a proton acceptor group (carbonyl) of PVP K90 and hydroxyl group of acid in IND. Whereas in IND/Eudragit E100, dimethylamino group of Eudragit E100 is involved with


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hydroxyl group in IND. In ternary dispersions, similar interaction has been observed at all the concentrations indicating the presence of intermolecular interaction between IND with PVP K90 and Eudragit E100. Thermal analysis showed comparable melting point depression in case of ternary physical mixtures than binary physical mixtures although they contain lower concentration of polymers. This indicates better miscibility in ternary solid dispersions compared with binary solid dispersions. Further, the Tg of binary solid dispersions showed negative deviation (with PVP K90) and positive deviation (with Eudragit E100). The negative deviation can be attributed to the possibility of complex formation between IND and PVP K90, whereas positive deviation between IND and Eudragit E100 indicates the formation of strong intermolecular interactions. In ternary solid dispersion, no deviation in the theoretical and experimental values was observed. The result suggests the formation of a stable amorphous complex between IND, PVP K90, and Eudragit E100 with intermolecular interaction playing important role in stabilization of this amorphous system. In solution, the presence of molecular interactions is responsible for achieving and maintaining high drug concentrations for long period of time. Solution precipitation results for IND in binary systems carried out by Chauhan et al. revealed that PVP K90 and Eudragit E100 inhibit both crystal nucleation and crystal growth rates of IND. It was also observed that polymers effect on both crystal nucleation and crystal growth and their efficiency can vary significantly. In our case, Eudragit E100 is more effective in inhibiting IND crystal nucleation, whereas PVP K90 is effective in both crystal nucleation and crystal growth. The effect of crystal nucleation by PVP K90 is not as much as Eudragit E100. In case of ternary system, both the polymers are acting synergistically leading to effective inhibition of crystal nucleation and growth rates resulting in high dissolution rates. Similarly, crystallization of amorphous IND in solid state needs the drug molecule to have favorable orientation for the crystal nucleation. It has been confirmed that surface crystallization is about 10 times higher than bulk crystallization. In ternary systems, presence of two interacting polymers might be increasing both the barrier for crystallization in surface and bulk by inhibiting nucleation and also by increasing overall entropy of the system. Ternary systems are complicated systems consisting of drug and two polymers. Drug-polymer interactions involved in the solubilization and stabilization in ternary solid dispersions are weak interactions. At low polymer concentrations, these molecular interactions play predominant role in differentiating between the efficiency of various polymers because Tg remains same for all the dispersions. Quantitative characterization of these weak interactions can further provide insight into the mechanistic understanding of synergistic effects reported in this paper. The author hopes that future researchers including our group will focus in understanding and utilizing more drug– polymer blends for synergistic effects using advance techniques such as solid-state NMR, dielectric spectroscopy, and others.

CONCLUSIONS The combination of PVP K90 and Eudragit E100 at low concentration was found to significantly improve the stability and dissolution of the amorphous form of the poorly soluble drug

IND in ternary dispersions. These ternary solid dispersions were found to be more effective than binary solid dispersions because of the synergistic effects exhibited by the combination of polymers. Drug–polymer interactions between IND and both polymers were found to be intact in ternary systems. These drugs–polymer interactions are key to achieving the synergistic effects of solubility and stability. Enhanced miscibility in ternary dispersion was observed compared with binary dispersions. These types of ternary solid dispersions have a potential for significantly enhancing the stability and dissolution of poorly soluble compounding using low concentrations of polymers.

ACKNOWLEDGMENT The author wishes to acknowledge MCPHS University, Boston for funding and the use of instruments in completing this project.

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